http://www.gponline.

com/Clinical/article/1059596/Clinical-Review-Type-1-diabetesmellitus/ Section 1: Epidemiology and aetiology Type-1 diabetes is a disease of pancreatic islet beta-cell destruction, caused by an autoimmune process in more than 95 per cent of cases. The clinical manifestation of type-1 diabetes mellitus is preceded by an asymptomatic prodromal period (months to years) during which time immune destruction progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections (mumps, rubella) are the most likely environmental triggers contributing to the aetiopathogenesis. The diabetes autoimmunity study in the young (DAISY), followed newborns from birth and found no evidence that bovine milk ingestion, enteroviral infection or vaccination contribute to an increased risk of diabetes. The 'hygiene hypothesis' states that a sterile environment for young infants predisposes to deficiencies in immunoregulation in later life leading to T-helper 2 (Th2) diseases (asthma) and Th1 diseases (type-1 diabetes).1 The HLA on chromosome 6 was the first locus shown to be associated with the disease and contributes to about half of the familial basis of type-1 diabetes.2 Two combinations of HLA genes, which are of particular importance, the DR4-DQ8 and DR3DQ2, are present in 90 per cent of children with type-1 diabetes. A third haplotype, DR15-DQ6, is found in less than one per cent of children with type-1 diabetes, compared with more than 20 per cent of the general population and is considered to be protective.2 The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the affected family member with type-1 diabetes. If one haplotype is shared, the risk is 6 per cent and if two are shared the risk is 12 to 25 per cent. The highest risk is for identical twins with a concordance rate of 25 to 50 per cent. Epidemiology According to Diabetes UK, there are 2.6 million people diagnosed with diabetes in the UK. Among adults, it is estimated that up to 10 per cent of people with diabetes have type-1 diabetes. The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence of 3 to 4 per cent, with a larger increase in some central and eastern European countries. The incidence of type-1 diabetes in the UK has doubled every 20 years since 1945.3 Half of patients are diagnosed under the age of 15 and 90 per cent are diagnosed by the age of 30 years. The peak age for diagnosis in the UK is 10-14 years but is becoming younger, with a steep rise in patients diagnosed before the age of five years.

Section 2: Making the diagnosis The symptoms and signs relate to hyperglycaemia and the effects on fluid and electrolyte imbalance. Typical symptoms of polyuria, polydipsia and weight loss tend to develop insidiously over a period of weeks. In very young children, nocturnal enuresis may signal the onset. When insulin deficiency is severe and acute, the patient may present with diabetic ketoacidosis (DKA), an acute metabolic complication of type-1 diabetes, where ketone bodies are produced instead of the usual metabolic substrate for energy production. Symptoms may include abdominal pain, nausea, vomiting and a change in mental status varying from slight drowsiness to profound lethargy and in severe cases, coma. Investigations Hyperglycaemia is present in all cases. In autoimmune diabetes the three principal autoantigens for diagnosis are glutamic acid decarboxylase (GAD 65), 43a protein tyrosine phosphatase-like molecule (IA-2A) and insulin (IAA). About 90 per cent of caucasian children will have at least one of these autoantibodies at diagnosis.4 Tests for these antibodies are often only requested by a specialist when there is uncertainty between a diagnosis of type-1 and type-2 diabetes. These patients and their first degree relatives are at increased risk of other autoimmune diseases. Detection of two or more autoantibodies in relatives of patients with type-1 diabetes has a positive predictive value of more than 90 per cent. Guidelines on diagnosis The following points summarise recommendations from the NICE guidelines on type-1 diabetes (CG15).5 If classical symptoms are present, confirm diagnosis by a single laboratory glucose measurement. If classical symptoms are not present then two separate glucose readings are needed. HbA1c measurement may support diagnosis. Where a patient appears to have type-2 diabetes, consider type-1 diabetes if ketonuria is detected, or weight loss is marked, or the patient does not have features of the metabolic syndrome or other contributing illness. Consider the possibility that apparent type-1 diabetes is not type-1 diabetes in younger people with obesity or with a family history of diabetes, especially if of non-white ethnicity. Do not routinely use measurement of specific autoantibodies or C-peptide to confirm the diagnosis of type-1 diabetes - consider their use to discriminate type-1 from type-2 diabetes. Section 3: Managing the condition Management should be individualised and regular review of the patient's individual care plan should be performed and modified according to changes in circumstances and medical findings. The following recommendations for a structured care plan are based on the NICE guidelines (CG15).5

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Provide patients with diabetes education, including advice on nutrition, physical activity and smoking. Teach self monitoring and set targets, aiming where possible for preprandial glucose levels of 4-7mmol/L and postprandial levels of <9mmol/L, and an HbA1c of <7.5 per cent. Arterial risk factors Where significant arterial risk exists, aim for an HbA1c of <6.5 per cent. Do not use arterial risk tables, equations or engines for arterial risk factor surveillance and management. Assess urine albumin excretion. If the result is abnormal (>2.5mg/mmol for men, >3.5mg/mmol for women) confirm the result at a subsequent visit. In all patients with confirmed kidney damage (including those with microalbuminuria alone), start ACE inhibitors and titrate to full dose. Check the patient's lipid profile, aiming for total cholesterol of <4mmol/L and LDL <2mmol/L. Use statins as first-line therapy. If triglyceride levels are still raised despite optimal glucose control, consider fibrates. Intervention is required if BP is above 135/85mmHg, or above 130/80mmHg with abnormal albumin excretion rate or another feature of the metabolic syndrome. Complications Assess annually for neuropathy, retinopathy and nephropathy. Give advice regarding foot care and assess for complications.

Give advice regarding foot care and assess for complications (Photograph: SPL) Structured education programmes Two major studies, the diabetes prevention trial (DPT)6 and the European nicotinamide diabetes intervention trial (ENDIT)7 have shown that strategies to prevent type-1 diabetes have not been successful. Thus, for individuals with type-1 diabetes, life-long insulin replacement and monitoring of blood glucose levels are required.

Structured education programmes like 'dose adjustment for normal eating' (DAFNE)8 and the 'Dusseldorf diabetes treatment and teaching programme'9 have demonstrated substantial benefits in improving glycaemic control and quality of life while saving costs, without increasing the risk of severe hypoglycaemia. These two structured education programmes emphasise the importance of carbohydrate counting and insulin dose adjustment according to the carbohydrate meal content and glucose levels. Section 4: Prognosis When an optimal glucose level is achieved and maintained in patients with type-1 diabetes, the risk of new eye disease is reduced by 76 per cent, worsening of existing eye disease by 54 per cent, early kidney disease by 54 per cent, more serious kidney problems by 39 per cent and development of neuropathy by 60 per cent.10

Retina damage from diabetes (Photograph: SPL) Cardiovascular risk The diabetes control and complications trial (DCCT) showed there was no glucose threshold for the development of microvascular complications. When the DCCT ended in 1993, researchers continued to study more than 90 per cent of participants over the next 10 years. The follow-up study, called epidemiology of diabetes interventions and complications10 reported that the risk of any heart disease was reduced by 42 per cent in patients who had been in the intensive treatment group. Patients in the intensive treatment group also cut their risk of non-fatal heart attack, stroke, or death from cardiovascular causes by 57 per cent. According to the National service framework for diabetes standards document published in 2001, life expectancy is reduced on average by more than 20 years in patients with type-1 diabetes and up to 10 years in type-2 diabetes. Mortality rates are up to five times higher for patients with diabetes.

Section 5: Case study A 37-year-old female was admitted to hospital with sore throat and general malaise. She was diagnosed with type-1 diabetes 18 years ago. She had a significant history of poor attendance to specialist clinics and had not seen her family doctor for three years. There was no record of any previous diabetes-related hospital admissions. She had attended the eye clinic in the past for extensive laser treatment to both her eyes. Kidney function She was on a basal bolus regimen and on admission she was not in DKA. Her HbA1c was 11 per cent and her creatinine was 849micromol/L with an eGFR value of 5ml/min. She had raised urine protein excretion of 8.49g per day. Vasculitic screen and ultrasound of kidneys were unremarkable. With fluid resuscitation over a period of one week her kidney function improved slightly (creatinine 514micromol/L and eGFR 8ml/min) and her urine output improved. She was transferred to a regional kidney unit for renal replacement therapy. Need for routine review This case highlights the debilitating and relentless nature of poorly controlled diabetes. A strong commitment to routine review by both the patient and the healthcare team should lead to prevention or delay of complications in many patients. This case highlights NICE's recommendation to establish diabetes registers to support recall systems for surveillance of complications and vascular risk. Section 6: Evidence base Clinical trials Intermediate-acting versus long-acting insulin for type-1 diabetes. A Cochrane review in 2008 analysed 23 RCTs where two insulin regimens were used for a period ranging from three months to one year.11 The weighted mean difference for the level of glycosylated haemoglobin was -0.08 (95 per cent confidence interval (CI) -0.12 to -0.04) in favour of the long acting insulin arm, but the observed difference was of doubtful clinical significance. Longer acting insulins were superior mostly in their nocturnal effect, which resulted in a lower level of fasting glucose levels and fewer episodes of nocturnal hypoglycaemia.

Another systematic review and meta-analysis of 20 studies reported that achieved HbA1c was significantly superior in the CSII group.51 per cent.001) with significant reduction in the incidence of severe hypoglycemia. 2004. with a difference in HbA1c of 0. CPD IMPACT: EARN MORE CREDITS These further action points may allow you to earn more credits by increasing the time spent and the impact achieved. NICE. young people and adults.org Visit our GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum.3 per cent (95 per cent CI 0.   Online Diabetes UK www. Insulin replacement therapy (Photograph: SPL) Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials.diabetes.4 to -0. p=0.1. London. CG15.diabetes.12 The study also reported a threefold reduction in severe hypoglycaemia with CSII compared with multiple daily injections. American Diabetes Association www. A meta-analysis of 12 trials found that glycaemic control was better with CSII compared with multiple daily injections in patients who had severe hypoglycaemia. the mean difference was -0.org.13 Thus. CSII is likely to be a clinically useful alternative for those patients in whom there is concern about severe hypoglycaemia. Guidelines NICE. . Type-1 diabetes: diagnosis and management of type-1 diabetes in children.uk This website provides useful links for both patients and healthcare professionals in the UK.

Int J Clin Pract 2010. Training in flexible. 7. 11. Gillespie K. et al. 3. CMAJ 2006. Hold a practice meeting to decide how to manage poorly attending patients with diabetes. 9. et al. 8. 175(2). Gale E A. Effects of insulin in relatives of patients with type 1 diabetes mellitus. Jacobson E.com References 1. Leiter L A. Diabetes prevention trial-type 1 diabetes study group.com/cpd Take clinical tests and claim certificates for CPD at myCME.685-9. Kerry S.   . Intermediate acting versus long acting insulin for type 1 diabetes mellitus. 12. CD006297. Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Cochrane Database Syst Rev 2008. Barnett T. ENDIT. Save this article and add notes with your free online CPD organiser at gponline. N Engl J Med 2005. Diabetologia 2003. 6.643-53. 358: 221-9. Practical steps to improving the management of type 1 diabetes. 4. 46(3): 339-46. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: metaanalysis of randomised controlled trials. DAFNE. 45: 588-94. Atkinson M A. 64(3): 305-15. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. CG15. 10. 3. The insulin treatment of Diabetes: A practical guide. BMJ 2002. 346(22): 1. Lancet 2001. Hold a diabetes 'roadshow' for your local community. 2010. Screen for diabetes and hypertension. Mattock M. London. intensive insulin management to enable dietary freedom in people with type 1 diabetes. Eisenbarth GS. Horton E. BMJ 2002. N Engl J Med 2002. A missing link in the hygiene hypothesis? Diabetologia 2002. and talk about the risk factors for diabetes as well as complications and treatment. Nini A. 325: 746. 324: 705. Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial. NICE. Type 1 Diabetes: Pathogenesis and Prevention. 353: 2. 5. EMAP Healthcare 1998. Remind your team how to manage diabetic emergencies and ensure your doctor's bag has all the necessary equipment. Pickup J C. Type 1 diabetes in children. 2. Aschner P. Vardi M. NICE. young people and adults.

CD005103. Misso M L. Egberts K J. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus.13. Cochrane Database Syst Rev 2010. Issue 1. Page M. . et al.

org/wiki/Diabetes_mellitus_type_1 Diabetes mellitus type 1 (type 1 diabetes.000 in [4] Scandinavia to a low of 1 per 100. it is believed to be of immunological origin. polyphagia (increased hunger).wikipedia.1 Genetics 2.1 Immunosuppressive drugs 5.1 Autoantibodies 5 Prevention o o  5. Type 1 treatment must be continued indefinitely in all cases.2 Environmental 3 Pathophysiology 4 Diagnosis o  4. treatment remains quite burdensome for many people.2 Diet 6 Management o o 6. However. formerly insulin dependent or juvenile diabetes) is a form [2] of diabetes mellitus that results fromautoimmune destruction of insulin-producing beta cells of the pancreas.000 in Northern Europe and the U. which measures endogenous insulin production. appropriate care.2 Pancreas transplantation . type 1 diabetes is fatal unless treated with insulin. awareness. Complications may be associated with both low blood sugar and high blood sugar. Incidence varies from 8 to 17 per 100. Transplantation is experimental yet [5] growing. Injection is the most common method of administering insulin although other methods are insulin pumps and inhaled insulin. The classical symptoms are polyuria (frequent [3] urination).000 in Japan and China.1 Insulin therapy 6. Low blood sugar may lead to seizures or episodes of unconsciousness.http://en. High blood sugar may lead to increased fatigue and can also result in long-term damage to organs. with a high of about 35 per 100. Eventually. [6] Although the cause of type 1 diabetes is still not fully Type 1 can be distinguished from type 2 diabetes via a C-peptide assay.S. and requires emergency treatment. understood. T1DM. Other alternatives are Pancreatic transplants that have been used and also pancreatic islet cell transplantation. Most people who develop type 1 are otherwise healthy. discipline in testing and dosing of insulin is taken. polydipsia (increased thirst). Treatment should not significantly impair normal activities but can be done adequately if sufficient patient training. and weight loss. both largely due to the nonphysiological manner in which insulin is replaced. Contents [hide]   1 Signs and symptoms 2 Cause o o   2. The subsequent lack of insulin leads to increased blood and urine glucose.

[edit]Cause Diabetes type 1 is induced by one or more of the following: genetic susceptibility. blood sugar levels can be in a very high range for long periods of time which could cause diabetic ketoacidosis. fatigue.3 T helper cell shift 10 Brittle diabetes 11 See also 12 References 13 External links [edit]Signs and symptoms Overview of the most significant symptoms of diabetes The classical symptoms of type 1 diabetes include: polyuria (frequent urination). and weight loss. and copremsis (vomiting).1 Foundations 9. [edit]Genetics .2 GAD65 vaccine 9. polydipsia (increased [3] thirst). rapid. polyphagia(increased hunger). These symptoms could be xeroderma (dry skin).1 Economics 9 Research o o o     9. deep breathing. Xerostomia (dry mouth). [7] drowsiness. gastralgia(abdominal pain).o  6.1 Driving 8 Epidemiology o  8. Before a person knows they have diabetes.3 Islet cell transplantation 7 Complications o  7. a diabetogenic trigger and/or [8] exposure to a driving antigen.

the other twin only had it 30%–50% of the time. and about 1% if the mother [10] was over 25 years old when the child was born. resulting in [14] [12] . No connection has been established between autoantibodies. Zanosar is the trade name for streptozotocin. where the other did not. this suggests environmental factors. In type 1. a small proportion of type 2 cases manifest a genetic form of the disease [citation needed] called maturity onset diabetes of the young. [edit]Chemicals and drugs Some chemicals and drugs preferentially destroy pancreatic cells. Some variants also appear to be protective. Pyrinuron (Vacor. discussed by DeLisa Fairweather and Noel R. Despite having exactly the same genome. if any. Certain variants of this gene increase the risk for decreased histocompatibility characteristic of type 1. for not everyone infected by the suspected virus develops type 1 [13] diabetes. meaning many different genes contribute to its onset. so is often confused with type 2. about 10% if a sibling has it. decreasing endogenous insulin production. although the evidence is inconclusive. This distinguishes type 1's origin from type 2. DRB1 0405. recessive. resulting in type 1 diabetes after accidental or intentional ingestion. which are common in North Americans of European ancestry and in [9] [9] Europeans. it can be dominant. antibodies to cow's milk proteins. IDDM1.Type 1 diabetes is a polygenic disease. is obscure. a rodenticide introduced in the United States in 1976.S. N-3-pyridylmethyl-N'-pnitrophenyl urea). and a tendency to acquire the incidence of the disease of the [8] destination country for people who migrate. among others. at staining region 6p21. The strongest gene. [edit]Diet Some researchers believe the autoimmune response is influenced by antibodies against cow's milk proteins. when one twin had type 1 diabetes. DQA 0301. Vacor was withdrawn from the U. or somewhere in between. The causal connection. Vitamin D in doses of 2000 IU per day given during the first year of a child's life has been connected in one study in northern Finland (where intrinsic production of Vitamin D is low due to low natural light levels) with an 80% reduction in the risk of getting type 1 diabetes later in life. Such variants include DRB1 0401. [edit]Environmental Environmental factors can influence expression of type 1. In addition. The type of diabetes a patient has is determined only by the cause— fundamentally by whether the patient is insulin resistant (type 2) or insulin deficient without insulin resistance (type 1). A subtype of type 1 (identifiable by the presence of antibodies against beta cells) typically develops slowly. an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer. The risk of a child developing type 1 diabetes is about 10% if the father has it. Short breastfeeding period and short attendance at day care is associated with the risk of type 1 diabetes [15] in Czech children. This vulnerability is not shared by everyone. Other indications of environmental influence include the presence of a 10-fold difference in occurrence among Caucasians living in different areas of Europe. [edit]Virus One theory. Rose. about 4% if the mother has type 1 diabetes and was aged 25 or younger when the child was born. in addition to genetic factors. can influence disease [11] prevalence. Depending on locus or combination of loci. it also kills beta cells. DQB1 0302 and DQB1 0201. For identical twins. The Coxsackie virus family or rubella is implicated. It has been traced to particular HLA genotypes. pancreatic beta cells in the islets of Langerhans are destroyed. market in 1979. DRB1 0402. selectively destroys pancreatic beta cells. proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas. is located in the MHC Class II region on chromosome 6. and type 1 diabetes. one twin had the disease. but is still used in some countries. though the connection between them and the triggering of an autoimmune reaction is still poorly understood. This has suggested presence of a genetic vulnerability and there is indeed an observed inherited tendency to develop type 1.

4 Impaired glucose tolerance ≥7. in turn.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in aglucose tolerance test. [edit]Pathophysiology The pathophysiology in diabetes type 1 is basically a destruction of beta cells in the pancreas. Symptoms of hyperglycemia and casual plasma glucose at or above 11. pancreatitis or tumors (either malignant or benign). (This criterion was recommended by theAmerican [19] Diabetes Association in 2010.0–6. regardless of which risk factors or causative entities have been present.5 Diabetes mellitus is characterized by recurrent or persistent hyperglycemia.1 (≥200) ≥7. Still.loss of insulin production. autoantibody-producing B cells and activation [9] of the innate immune system.8 (≥140) <7.) About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is caused by high concentrations of ketone bodies.1 (<110) <6. [edit]Diagnosis See also: Glycosylated hemoglobin and Glucose tolerance test Diabetes diagnostic criteria [16][17] edit Condition 2 hour glucose Fasting glucose HbA1c mmol/l(mg/dl) mmol/l(mg/dl) % Normal <7.0 (≥126) ≥6.4 Diabetes mellitus ≥11. including trauma. Glycated hemoglobin (hemoglobin A1C) at or above 6.0 (<126) 6. cause this beta cell destruction. can also lead to loss of insulin production. formed by the breakdown of fatty acids .8 (<140) <6. a process that appears to be common to most risk factors is anautoimmune response towards beta cells. Plasma glucose at or above 11.0 mmol/L (126 mg/dL).0(<126) 6. involving an expansion of autoreactive CD4+ and CD8+ T helper cells.5.8 (<140) ≥ 6.1 mmol/L (200 mg/dL).0–6. although it has yet to be adopted by the WHO. Individual risk factors can have separate pathophysiological processes to. and is diagnosed by demonstrating any [18] one of the following:     Fasting plasma glucose level at or above 7. Other pancreatic problems.1(≥110) & <7.0 Impaired fasting glycaemia <7.

certain fungal infections. A probable mechanism of this effect was believed to be preservation of regulatory T cells that suppress activation of the immune [9] system and thereby maintain immune system homeostasis and tolerance to self-antigens. and secondary symptoms such as vision changes or unexplainable fatigue. which takes two hours to [20] complete and offers no prognostic advantage over the fasting test. By definition. A positive result. but long-term effects of this have not been reported. These include ordinary health screening. Diabetes is often detected when a person suffers a problem that may be caused by diabetes. Some researchers believe it might be prevented at the latent [9] autoimmune stage. In 2011. The time interval from emergence of autoantibodies to frank diabetes type 1 can be a few months in infants [8] and young children.1 mmol/L). According to the current definition. however.0 mmol/L) is considered diagnostic for diabetes mellitus. two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Patients with plasma glucose at or above 140 mg/dL (7. has apparently halted destruction of beta cells (on the basis of [9] reduced insulin usage). inhibits B cells and has been shown to provoke C-peptide responses three months [9] after diagnosis of type 1 diabetes. Not everyone with autoantibodies progresses to diabetes type 1. detection of hyperglycemia during other medical investigations. while the rest are measured with [8] specific radiobinding assays. an immunosuppressive agent.and the deamination of amino acids) by the time the diabetes is recognized.8 mmol/L). rituximab. Islet cell autoantibodies are detected by conventional immunofluorescence.9 mmol/L) are considered to have impaired fasting glucose. [edit]Prevention Type 1 diabetes is not currently preventable. Phase III studies with otelixizumab and teplizumab both failed to show clinical [23][24] efficacy. The duration of the effect [9] is still unknown. neuropathy. should be confirmed by a repeat of any of the abovelisted methods on a different day. with three to four antibody types giving a risk of progressing to diabetes type 1 of 60%– [8] 100%. Patients with fasting glucose levels from 100 to 125 mg/dL (5. [edit]Autoantibodies The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any hyperglycemia arises. certain eye problems. in the absence of unequivocal hyperglycemia. but the emergence of autoantibodies may itself be termed "latent autoimmune diabetes". poor wound healing or a foot ulcer. Of these two pre-diabetic states. the main ones being islet cell autoantibodies. before it starts destroying beta cells. had suggested evidence of preserving insulin production [9] (as evidenced by sustained C-peptide production) in newly diagnosed type 1 diabetes patients. autoantibodies targeting the 65-kDa isoform of glutamic acid decarboxylase (GAD) and autoantibodies targeting [8] the phosphatase-related IA-2 molecule. but the risk increases with the number of antibody types. or delivering a baby with macrosomia or hypoglycemia. potentially due to an insufficient dosing schedule. but in some people it may take years – in some cases more than 10 years. but its nephrotoxicity and other side effects make it highly inappropriate for long-term use. The diagnosis of other types of diabetes is usually made in other ways. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing. two fasting glucose measurements above 126 mg/dL (7. such as a heart attack.6 to 6. An anti-CD20 antibody. including teplizumab and otelixizumab. the latter in particular is a major risk factor for progression to full-blown diabetes mellitus and [21] cardiovascular disease. stroke. [edit]Immunosuppressive [22] drugs Cyclosporine A. the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs. Anti-CD3 antibodies. insulin autoantibodies. [edit]Diet . but not over 200 mg/dL (11.

[edit]Management Further information: Diabetes management [edit]Insulin [25][26] therapy Type 1 is treated with insulin replacement therapy—either via subcutaneous injection or insulin pump. along with attention to dietary management. Treatment of diabetes focuses on lowering blood sugar or glucose (BG) to the near normal range. and treated with vitamin B3 (niacin). approximately 80– [32] 140 mg/dl (4. so is generally only used with or some time after a kidney transplant. it [31] makes ketoacidosis the most common cause of death in pediatric diabetes. from several suppliers. BG less than 70 mg/dl (3.Some research has suggested breastfeeding decreases the risk in later life. A more recent trend. Ketoacidosis causes cerebral edema (accumulation of liquid in the brain). cattle or pig insulins were used.e. and the cardiovascular system (e. but technical limitations have limited the impact these devices have had on clinical practice so far. [edit]Pancreas transplantation Main article: Pancreas transplantation In more extreme cases.g. [edit]Islet cell transplantation Main article: Islet cell transplantation . had less than half the diabetes onset incidence in a seven-year time span than did the general population. functioning pancreas to a patient with diabetes without any additional immunosuppressive therapy. food and physical activity. but treatment can lead to low BG (hypoglycemia). formerly. and Sanofi-Aventis. Today. often from diabetic ketoacidosis. typically including carbohydrate tracking. heart attacks. The ultimate goal of normalizing BG is to avoid long-term complications that affect the nervous system (e. various other nutritional risk factors [27] are being studied.9 mmol/l).g. Novo Nordisk. Nevertheless this allows the introduction of a new. although the nonphysiological method of delivery also plays a role. a pancreas transplant can restore proper glucose regulation. Untreated type 1 diabetes commonly leads to coma. and even sometimes insulin from [30] fish. Children with antibodies to beta cell proteins (i. and careful monitoring of blood glucose levels using glucose meters. Major global suppliers include Eli Lilly and Company. and an even lower incidence relative to those with antibodies as above. Continuous glucose monitors have been developed and marketed which can alert patients to the presence of dangerously high or low blood sugar levels. the surgery and accompanying immunosuppression required is considered by many physicians to be more dangerous than continued insulin replacement therapy. i. peripheral neuropathy leading to pain and/or loss of feeling in the extremities). vision loss).e.8 mmol/L).4–7. which is fatal if untreated. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine. at early stages of an immune reaction to them) but no overt diabetes. Hypoglycemia is a very common occurrence in people with diabetes. However. though the causal relationship is obscure. However. but no firm evidence has been found. People with type 1 diabetes always need to use insulin. This complication is very life-threatening. but [29] who received no vitamin B3. usually the result of a mismatch in the balance among insulin. the most common insulins are biosynthetic products produced using genetic recombination techniques. pancreas transplants alone can be wise in patients with [33] extremely labile type 1 diabetes mellitus. is insulin analogs which are slightly modified insulins with different onset or duration of action times. Giving children 2000 IU of Vitamin D during their first year [28] of life is associated with reduced risk of type 1 diabetes.

drivers with type 1 diabetes and a history of driving mishaps are recommended to never drive when their BG is less than 70 mg/dl. However. For example. drivers who had two or more mishaps reported fewer warning symptoms. Additionally. Studies funded by the National Institutes of Health (NIH) have demonstrated that face-to-face training programs designed to help individuals with type 1 diabetes better anticipate. coordination. For example. Instead. as well. The liver is expected to be the most reasonable choice because it is more accessible than the pancreas. hypoglycemia can affect a person’s thinking processes. patients now also need to undergo treatment involving immunosuppressants. and prevent extreme BG can reduce the [45][46][47] occurrence of future hypoglycemia-related driving mishaps. A study involving people with type 1 diabetes found that individuals reporting two or more hypoglycemia-related driving mishaps differ physiologically and [42] behaviorally from their counterparts who report no such mishaps. which reduce immune system activity. placing pig islets within a protective capsule derived of seaweed which enables insulin to flow out and nutrients to flow in. [edit]Complications Further information: Complications of diabetes mellitus Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease. diabetic retinopathy (loss of peripheral vision or visual acuity). among others. demonstrating the increased risk ofdriving collisions in the type 1 diabetes population. can impair driving ability. and use this information to avoid future hypoglycemia while driving. This [39][41] disruption in brain functioning. An internet-version of this training has also been [39][40] [37] [38] . and state of consciousness. Islet cell transplantation is less invasive than a pancreas transplant. The immune system will attack the cells as it would a bacterial infection or a skin graft. apply appropriate pressure to the brakes. etc. Given the above research findings. Thus. [35] [36] and diabetic retinopathy. will treat the new cells just as it would any other introduction of foreign tissue. these drivers are advised to treat hypoglycemia and delay [42] driving until their BG is above 90 mg/dl. unless a method is developed to produce them from the patient's own stem cells or an identical twin is available who can donate stem cells. First. cardiovascular disease as well as neuropathy may have an autoimmune basis. Scientists in New Zealand with Living Cell Technologies are currently in human trials with Diabecell. there is a subgroup of type 1 drivers who are more vulnerable to such events. control the speed of the vehicle. Second. In one variant of this procedure. while protecting the islets from immune system attack via white blood cells. These findings indicate that although anyone with type 1 diabetes may be at some risk of experiencing disruptive hypoglycemia while driving. Such drivers should also learn as much as possible about what causes their hypoglycemia.Experimental replacement of beta cells (by transplant or from stem cells) is being investigated in several research programs. The patient's body. their driving was more impaired. [edit]Driving Studies conducted in the United States and Europe showed that drivers with type 1 diabetes had twice as many collisions as their nondiabetic spouses. which is currently the most commonly used approach in humans. during hypoglycemia. Diabetes can compromise driving safety in several ways. neuroglycopenia. long-term complications of diabetes can interfere with the safe operation of a vehicle. however. detect. islet cells are injected into the patient's liver. and islet cells seem to produce insulin well in that environment. or peripheral neuropathy (loss of feeling in the feet) can impair a driver’s ability to read street signs. and their body released less epinephrine (a hormone that helps raise BG). individuals with a history of hypoglycemia[43] related driving mishaps appear to use sugar at a faster rate and are relatively slower at processing [44] information. Recent studies have shown islet cell transplants have progressed to the point where 58% of the patients in one study [34] were insulin-independent one year after transplantion. diabetic neuropathy. where they take up residence and begin to produce insulin.

Two prevention studies. Pacific Northwest Diabetes Research Institute conducts clinical and basic research on type 1 and type 2 diabetes. Canada. it may be administered to prevent commencement of diabetes type 1. and insulinoma-associated autoantibodies) to distinguish between type 1 and type 2 diabetes demonstrate that most new-onset type 1 diabetes is seen in adults. and in Northern Europe and the U. including type 2 diabetes. [edit]GAD65 [50] [22] [48] vaccine Injections with a vaccine containing GAD65. where the vaccine is given to persons who have not yet [60][61][62] developed diabetes are underway. Israel. Type 1 diabetes was previously known as juvenile diabetes to distinguish it from type 2 diabetes.000 per year. islet cell antibodies. however. In Finland. researching. The disease was estimated to cause $10. which generally has a later onset. Diabetes Australia is involved in promoting research and education in Australia on both type 1 and type 2 diabetes. Studies using antibody testing (glutamic acid decarboxylase antibodies. This Th1-Th2 shift occurs via a change in the type of cytokine signaling . Rates vary widely by country. USA. [edit]T helper cell shift If a biochemical mechanism can be found to prevent the immune system from attacking beta cells.shown to have significant beneficial results. [edit]Research [edit]Foundations The Juvenile Diabetes Research Foundation funds type 1 diabetes research and has offices in the UK. in Japan and China a low of 1 to 3 per 100. Mexico and India. The Diabetes Research Institute Foundation was founded by a group of parents of children with diabetes and funds research for a cure for type 1 diabetes. [edit]Economics In the US in 2008. [edit]Epidemiology Type 1 diabetes causes an estimated 5–10% of all diabetes cases or 11–22 million worldwide. Denmark.000 per year. The International Diabetes Federation is a worldwide alliance of over 160 countries to address diabetes research and treatment. gestational diabetes and others) that looks at treatments and prevention.. and sustaining type 1 diabetes patients in Canada. The Canadian Diabetes Association is involved in educating.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4. Australia.S. Several groups are trying to achieve this by causing the activation state of the immune system to change from type 1 T helper cell (Th1) state ("attack" by killer T Cells) to Th2 state (development of new antibodies). an intermediate of 8 to 17 per 100. about one million people were diagnosed with type 1 diabetes. thought to protect the beta cells.4 billion in indirect [54] costs ($366 per month per diabetic). as well as some cure-specific research. an autoantigen involved in type 1 diabetes. has in clinical trials delayed [9] the destruction of beta cells when treated within six months of diagnosis. The American Diabetes Association funds some type 1 research along with other a variety of diabetes-related research (not necessarily cure-specific). Phase III trials are under way in the [56] [57][58][59] USA and in Europe. Additional NIH funded research to develop internet interventions [49] specifically to help improve driving safety in drivers with type 1 diabetes is currently underway. Patients treated with the substance [55] showed higher levels of regulatory cytokines. The incidence of type 1 diabetes has been increasing by about 3% per year. Adult-onset type 1 autoimmune diabetes is two to three times more common than classic childhood-onset [53] autoimmune diabetes. the incidence is a high of 35 per 100. In 2006 it affected 440 thousand children under 14 years of age and was the primary cause of diabetes in those less than 10 [51] [51] years of age. the majority of new-onset type 1 diabetes is seen in adults.000 per [4][52] year.

it can have many causes. the T-cells begin to release cytokines that [63] inhibit inflammation. though in most patients these effects are [70] small. though suffering high rates of complications. There have been a number of reports that insulin autoantibodies can act as a "sink" for insulin and affect the time to peak. some of which include:     errors in diabetes management. antibodies may also fail to buffer the release of the injected insulin into the bloodstream after subcutaneous injection. were no longer [67] brittle. This phenomenon is commonly known as "acquired immune tolerance". psychological problems.5 years. . Instead of proinflammatory cytokines. [69] constantly disrupt a patient's life". biological factors that interfere with how insulin is processed within the body. [65] Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics. 10 of 20 brittle diabetic patients aged 18-23 years who could be traced had died within 22 years.molecules being released by T-cells. often occurring for no apparent reason. An insulin pump may be recommended for brittle diabetes to reduce the number of hypoglycemic episodes and better control the morning rise of blood sugar [66] due to the dawn phenomenon. changing the type of insulin administered can resolve [69] this problem. frequently involving ketosis. half-life. and sometimes serious hypoglycemias. The results of such swings can be irregular and unpredictablehyperglycemias. although some experts [64] say the "brittle diabetes" concept "has no biologic basis and should not be used". which can include too much insulin being given. and the remainder. However. In some cases. interactions with other medical conditions. unstable diabetes or labile diabetes. distribution space. Because brittle diabetes is defined as "episodes of hypoglycemia or hyperglycemia that. High antibody titers can cause episodes of hyperglycemia by neutralizing the insulin. is sometimes known as brittle diabetes. whatever their cause. These results were similar to those of an earlier study by the same authors which found a 19% mortality in [68] 26 patients after 10. [edit]Brittle diabetes Insulin-dependent diabetes characterized by dramatic and recurrent swings in glucose levels. resulting in episodes of hypoglycemia. cause clinical insulin resistancerequiring doses of over 200 IU/day. One of these biological factors is the production of insulin autoantibodies. In a small study. and metabolic clearance.

In a genetically susceptible individual.http://emedicine.) Despite the differences between type 1 and type 2 DM. type 1 DM is responsible for $14. Tao et al estimated that in the United States. It is most common in juveniles but can also develop in adults. which was equally present in both type 1 and type 2 DM.[1] Pathophysiology Type 1 DM is the culmination of lymphocytic infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas.[3] This finding. those with type 1 DM usually are not obese and usually present initially with diabetic ketoacidosis (DKA). and Addison disease. decrease hyperglucagonemia.) (See alsoGlucose Intolerance. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. nurse. Hashimoto thyroiditis. prevent ketosis. ketosis and eventually ketoacidosis develop.medscape.4 billion in medical costs and lost income each year. glucagon stimulation test results. autoimmunity is considered the major factor in the pathophysiology of type 1 DM. fat. the costs of the 2 conditions are often combined. and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. Pilia et al found a higher prevalence of islet cell antibodies (IA2) and antiGAD antibodies in patients with autoimmune thyroiditis. such as Graves disease. an enzyme found within pancreatic beta cells. and normalize lipid and protein metabolism. with regular specialist consultation. The prevalence of type 1 DM is increased in patients with other autoimmune diseases. Angiopathy . these patients are dependent on exogenous insulin. Many factors are involved. In contrast. hyperglycemia develops and diabetes may be diagnosed. Approximately 85% of type 1 DM patients have circulating islet cell antibodies. and dietitian. The distinguishing characteristic of a patient with type 1 DM is that if his or her insulin is withdrawn. including the accumulation of sorbitol in peripheral sensory nerves from sustained hyperglycemia. may also explain the associated exocrine dysfunction that occurs in DM. as well as to limit the development of its devastating complications and manage such complications when they do occur. After 80-90% of the beta cells are destroyed. insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode DR and DQ are the major genetic determinants of type 1 DM.) Type 1 DM can occur at any age. Currently. and fecal elastase-1 measurements to confirm reduced pancreatic volume in individuals with DM. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. is needed to control glycemia. Motor neuropathy and cranial mononeuropathy result from vascular disease in blood vessels supplying nerves. HLA-DQs are also considered specific markers of type 1 DM susceptibility. (See Pathophysiology. It is a chronic disease of carbohydrate.[2] A study by Philippe et al used computed tomography (CT) scans.) Unlike people with type 2 DM.[4] Sensory and autonomic neuropathy Sensory and autonomic neuropathy in people with diabetes are caused by axonal degeneration and segmental demyelination. some haplotypes (eg. Patients need exogenous insulin to reverse this catabolic condition. and protein metabolism caused by the lack of insulin. which results from the marked and progressive inability of the pancreas to secrete insulin because of autoimmune destruction of the beta cells.com/article/117739-medication#showall Background Type 1 diabetes mellitus (DM) is a multisystem disease with both biochemical and anatomic/structural consequences. especially in those in their late 30s and early 40s. (See Presentation. A multidisciplinary approach by the physician. In a study that focused on type 1 alone. (See Treatmentand Medication. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD). As beta-cell mass declines.) Treatment of type 1 DM requires lifelong insulin therapy. Therefore. viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. HLA-DR2) confer strong protection against type 1 DM. (See Epidemiology.

Children whose mother has type 1 DM have a 2-3% risk of developing the disease.[14. with people from northern Europe more often affected than those from Mediterranean regions. Hyaline arteriosclerosis. with multiple genes involved. and peripheral nerves. is the location of several susceptibility loci for type 1 DM—in particular.[7] Nephropathy In the kidneys. the risk rises to almost 30%. The genetic contribution to type 1 DM is also reflected in the significant variance in the frequency of the disease among different ethnic populations. This reflects a generalized microvessel involvement in both type 1 and type 2 DM. Vitamin D deficiency is an important independent predictor of development of coronary artery calcification in individuals with type 1 DM.[6] Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications. the major histocompatibility complex (MHC). The genomic region most strongly associated with other autoimmune diseases.DQB1*0302 (OR 1. Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. is widespread and is responsible for ischemic changes in the kidney.[5] Microvascular disease causes multiple pathologic complications in people with diabetes.DQA1*0301 . It is a significant component of multiple renal lesions in diabetes.[10] monozygotic twins will share the diagnosis more than 50% of the time by the age of 40 years.DQB1*0401 .DQB1*0201 (odds ratio [OR] 3.03) . the risk varies according to whether the mother or the father has diabetes. which begins early in the course of diabetic nephropathy. there is a high sibling relative risk.64) DRB1*0405 .25) Other haplotypes appear to offer protection against type 1 DM. and chronic renal failure. class II HLA DR and DQ haplotypes. Single-nucleotide polymorphisms affecting the factors involved in its pathogenesis appear to influence the risk for diabetic nephropathy in different people with type 1 DM.DQA1*0501 .[8] Etiology Type 1A DM results from autoimmune destruction of the beta cells of the pancreas and involves both genetic predisposition and an environmental component. retina. which is characterized by proteinuria. Exacerbated expression of cytokines such as tumor growth factor beta 1 is part of the pathophysiology of glomerulosclerosis.DQA1*0301 .DQB*0302 (OR 8.DQA1*0301 .39) DRB1*0402 .59) DRB1*0801 . In addition. These include the following [17] : DRB1*1501 . a characteristic pattern of wall thickening of small arterioles and capillaries. [11] For the child of a parent with type 1 DM. 16] A hierarchy of DR-DQ haplotypes associated with increased risk for type 1 DM has been established.DQB1*0402 (OR 1. but few causal relations have been established. the characteristic wall thickening of small arterioles and capillaries leads to diabetic nephropathy. brain.DQB1*0302 (OR 11.DQB1*0602 (OR 0.63) DRB1*0404 .[9] Whereas dizygotic twins have a 5-6% concordance rate for type 1 DM.37) DRB1*0401 .DQB1*0302 (OR 3.Using nailfold video capillaroscopy.DQA1*0102 . 15. the risk for children of parents with type 1 DM is slightly higher if onset of the disease occurred before age 11 years and slightly lower if the onset occurred after the parent’s 11th birthday. When both parents are diabetic. glomerular hyalinization (Kimmelstiel-Wilson). Barchetta et al detected a high prevalence of capillary changes in patients with diabetes. particularly those with retinal damage. whereas those whose father has the disease have a 5-6% risk. Type 1 DM is most prevalent in European populations. The most susceptible haplotypes are as follows[17] :        DRB1*0301 .DQA1*0301 . Genetic factors influence the development of diabetic nephropathy.[12] The disease is least prevalent in East Asians. Genetic factors Although the genetic aspect of type 1 DM is complex.[13] Genome-wide association studies have identified several loci that are associated with type 1 DM.

6 per 100. other ethnic groups are less well studied.02) From 90% to 95% of young children with type 1 DM carry HLA-DR3 DQB1*0201. genome-wide association studies have implicated numerous other genes. [25] One meta-analysis found a weak but significant linear increase in the risk of childhood type 1 DM with increasing maternal age. the DRB1*07:01 .[23] mumps. Carriage of both haplotypes (ie. Epidemiology United States statistics A 2011 report from the US Centers for Disease Control and Prevention (CDC) estimated that approximately 1 million Americans have type 1 DM.DQA1*03:01 -DQB1*02:01g haplotype is associated with increased risk (OR 3.  DRB1*1401 . rubella. the Middle East. for example. enterovirus. Potential triggers for immunologically mediated destruction of the beta cells include viruses (eg. a negative regulator of T-cell kinase signaling).[20] Other genes that have been reported to be involved in the mechanism of type 1 DM include CTLA4 (important in Tcell activation). which may promote deletion of insulin-specific T cells.[24] and cytotoxins.[26] However. [29] Type 1 DM is the most common metabolic disease of childhood.DQB1*0503 (OR 0.02) DRB1*0701 . little evidence supports any substantial increase in childhood type 1 DM risk after pregnancy complicated by preeclampsia. In adults. In African Americans.600 young people. rates of type 1 DM are increasing by 2-5% per year.DQA1*0201 . Lempainen et al found that signs of an enterovirus infection by 12 months of age were associated with the appearance of type 1 DM–related autoimmunity among children who were exposed to cow's milk before 3 months of age. the annual rate of new cases was 19.[30] The prevalence of type 1 DM is highest in Scandinavia (ie.000 population. [28] This study was based in Denver. HLA-DR4 DQB1*0302. In Europe. which encodes for the pre-proinsulin peptide. whereas the DRB1*07:01-DQA1*02:01 . may be involved in the increased risk not only of type 1 DM but also of other autoimmune disease and Down syndrome. exposure to cow’s milk in infancy. Combinations of factors may be involved. or both.DQB1*0303 (OR 0. UBASH3A (also known as STS2).[19] Different VNTR alleles may promote either resistance or susceptibility to type 1 DM through their effect on INS transcription in the thymus. DR3/4 heterozygotes) confers the highest susceptibility. Among children younger than 10 years. About 1 in every 400-600 children and adolescents has type 1 DM. rates of type 1 DM are increasing. protective VNTRs are associated with higher INS expression. These high-risk haplotypes are found primarily in people of European descent. Colorado.[18] The insulin gene (INS).7 per 100. including the following [22] :       SH2B3 ERBB3 CLEC16A IL18RAP PTPN2 CCR5 Environmental factors Extragenetic factors also may contribute.3.[29] The CDC estimated that each year from 2002 to 2005.[21] In addition. type 1 DM was newly diagnosed in 15. and coxsackievirus B4).000 population. type 1 DM constitutes approximately 5% of all diagnosed cases of diabetes. it is located on locus chromosome 21q22. toxic chemicals.34).[27] A study by Simpson et al found that neither vitamin D intake nor 25-hydroxyvitamin D levels throughout childhood were associated with islet autoimmunity or progression to type 1 DM. approximately 20% of the . and Australia. and has been following children at increased risk of diabetes since 1993. the rate was 18. PTPN22 (produces LYP. These results suggest an interaction between the 2 factors and provide a possible explanation for the contradictory findings obtained in studies that examined these factors in isolation. and IL2RA (encodes for CD25 which is involved with regulating T-cell function).DQA1*0101 . among those 10 years or older. [29] International statistics Internationally. is adjacent to a variable number of tandem repeats (VNTR) polymorphism at chromosome 11p15.5.96).DQB1*02:01g haplotype appears to be protective (OR 0.

while patients with preserved coronary flow reserve have event rates similar to non-diabetic patients.[35] A greater risk is that mild diabetic nephropathy in type 1 diabetic persons appears to be associated with an increased likelihood of cardiovascular disease. More than 60% of patients with type 1 DM do not develop serious complications over the long term. In diabetic patients without coronary artery disease. peripheral vascular disease with gangrene of lower limbs. coordinated care management for improved outcomes and suggests structural changes to existing systems of long-term care delivery.2% at 20 years after diagnosis and 7. The risk of ESRD and proliferative retinopathy is twice as high in men as in women when the onset of diabetes occurred before age 15 years. [32] Patients with type 1 DM who survive the period 10-20 years after disease onset without fulminant complications have a high probability of maintaining reasonably good health.5:1.[29] The risk of development of antibodies (anti-islet) in relatives of patients with type 1 DM decreases with increasing age. [36] Moreover. cerebral vascular disease. its incidence is relatively low: 2. end-stage renal disease (ESRD). [37] . Type 1 DM is most common among non-Hispanic whites. coronary vasodilator dysfunction is a strong independent predictor of cardiac mortality. It is comparatively uncommon among Asians. Type 1 DM usually starts in children aged 4 years or older. and. In populations of European origin. in whom the disease tends to present less aggressively (ie.and long-term complications. followed by African Americans and Hispanic Americans. This finding supports annual screening for antibodies in relatives younger than 10 years and 1 additional screening during adolescence. in some cases. type 1 DM is typically diagnosed in childhood. and autonomic and peripheral neuropathy. and intelligence level. retinopathy and nephropathy) Neuropathic complications Macrovascular disease These complications result in increased risk for ischemic heart disease. those with impaired coronary flow reserve have event rates similar to those with prior coronary artery disease. 50% of patients with new-onset type 1 DM are older than 20 years of age. Some of these differences may relate to definitional issues and the completeness of reporting.[31] Sex. with early hyperglycemia without ketoacidosis and gradual onset of ketosis). adolescence. as well as the leading cause of nontraumatic lower-extremity amputation and ESRD. Such complications include the following:      Hypoglycemia from management errors Increased risk of infections Microvascular complications (eg. Diabetes is the major cause of blindness in adults aged 20-74 years. reduced visual acuity and blindness. chronic renal disease.[33] The morbidity and mortality associated with diabetes are related to the short. The 2012 American Diabetes Association (ADA) standard of care emphasizes the importance of long-term. Other factors affecting long-term outcomes are the patient’s education. or early adulthood. In both diabetic and non-diabetic patients. There is also a relatively high incidence in people in their late 30s and early 40s. This slower-onset adult form of type 1 DM is referred to as latent autoimmune diabetes of the adult (LADA). early death. in early adolescence and puberty). awareness.and race-related demographics Type 1 DM is more common in males than in females. the long-term risk of an impaired glomerular filtration rate (GFR) is lower in persons treated with intense insulin therapy early in the course of disease than in those given conventional therapy. Age-related demographics Previously referred to as juvenile-onset diabetes.total number of people with DM) and lowest in China and Japan (ie. but many of the rest experience blindness. with the peak incidence of onset at age 11-13 years (ie.[34] Although ESRD is one of the most severe complications of type 1 DM. Although the onset of type 1 DM often occurs early in life. the male-to-female ratio is greater than 1.8% at 30 years after diagnosis. fewer than 1% of all people with diabetes). Prognosis Type 1 DM is associated with a high morbidity and premature mortality. appearing fairly abruptly. motivation.

the parents—about the disease process. polydipsia. In particular. studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years of starting effective preventive care. altering its normal focal length. . blood pressure. hypovolemia. Patients with diabetes face a lifelong challenge to achieve and maintain blood glucose levels as close to the normal range as possible. It is not unusual for patients with type 1 DM to present with diabetic ketoacidosis (DKA). lipids. Blurred vision results from the effect of the hyperosmolar state on the lens and vitreous humor. For patient education information. and polyphagia. all of which result from the hyperglycemia itself. At the transition between pediatric and adult health care.Although mortality from early-onset type 1 DM (onset age. by teaching patients that they have a chronic condition that requires lifestyle modification and that they are likely to have chronic complications if they do not take control of their disease)  Reassure patients about the prognosis in properly managed type 1 DM ADA guidelines urge that attention be paid to older adolescent patients who may be leaving their home and their current health care providers. Severe nocturnal enuresis secondary to polyuria can be an indication of onset of diabetes in young children. and long-term complications. and referrals to specialists (eg. and weight significantly affects prognosis. The onset of symptomatic disease may be sudden. Glucose and its metabolites cause osmotic swelling of the lens. foot and neurologic examinations). or even years. along with lassitude. Fatigue and weakness may be caused by muscle wasting from the catabolic state of insulin deficiency. One study suggest that women tend to fare worse in both cohorts and that alcohol and drug use account for more than one third of deaths. the clinician should educate the patient—and. beta-cell destruction may have started months. With appropriate glycemic control. aggressive treatment of hypertension and hyperlipidemia decreases the risk of macrovascular complications. A dietitian should provide specific diet control education to the patient and family. and blurred vision. [33] The guidelines identify the National Diabetes Education Program (NDEP)as a source of materials that can help smooth the transition to adult health care. nausea. an ophthalmologist or podiatrist). examinations (eg. However. which may occur de novo or secondary to the stress of illness or surgery. Patients with new-onset type 1 DM require extensive education if they are to manage their disease safely and effectively and to minimize long-term complications. Patient Education Education is a vital aspect of diabetes management. see the Diabetes Center. However. clinicians should do the following:   Make patients aware of the signs and symptoms of hypoglycemia and knowledgeable about ways to manage it Help patients understand and acknowledge the course of diabetes (eg. An explosive onset of symptoms in a young lean patient with ketoacidosis always has been considered diagnostic of type 1 DM. before the onset of clinical symptoms. goals. putting their medical care and their glycemic control at risk. Muscle cramps are caused by electrolyte imbalance. as well as Diabetes History The most common symptoms of type 1 diabetes mellitus (DM) are polyuria. 0-14 y) has declined. Physicians must ensure that the care for each patient with diabetes includes all necessary laboratory tests. [38] Control of blood glucose. the risk of both microvascular and neuropathic complications is decreased markedly. Education about an appropriate treatment plan and encouragement to follow the plan are especially important in patients with diabetes. Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks. hemoglobin A1c (HbA1c). Thirst is a response to the hyperosmolar state and dehydration. in the case of children. the same may not be true for lateonset type 1 DM (onset age. Polyuria is caused by osmotic diuresis secondary to hyperglycemia. A nurse should educate the patient about self–insulin injection and performing fingerstick tests for blood glucose level monitoring. The benefits of glycemic control and control of comorbidities must be weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. older teens can become detached from the health care system. At every encounter. In addition. 15-29 y). management. Such education is best coordinated by the patient’s long-term care providers. and hypokalemia.

Over time. nocturia. which should be considered in the emergency department (ED)? Does the patient self-monitor his or her blood glucose levels? (Note the frequency and range of values at each time of day. especially if the patient drives) Does the patient have diabetic nephropathy that might alter the use of medications or intravenous (IV) radiographic contrast material? Does the patient have macrovascular disease. or weight loss? Has the patient had episodes of unexplained hypoglycemia? If so. The chronic complications of diabetes are related to the length of time the patient has had the disease. and clinical judgment. therapy. an increasing number of patients monitor with continuous sensors) When was the patient’s hemoglobin A1c (HbA1c) value (an indicator of long-term glucose control) last measured? What was it? In assessing glycemic exposure of a patient with established type 1 DM. Determination of the type of diabetes is based on history. Ask the following questions as needed:   Has the patient experienced recent polyuria. if any. proteins. History in patients with established diabetes It is important to inquire about the type and duration of the patient’s diabetes and about the care the patient is receiving for diabetes. review of self-monitored blood glucose levels is necessary. and how does the patient treat these episodes? . in a glove-and-stocking pattern. Patients using a pump or a multiple-injection regimen have a basal insulin (taken through the pump or with the injection of a long-acting insulin analogue) and a premeal rapid-acting insulin. because of depletion of water and a catabolic state with reduced glycogen. dose. it is bilateral. Gastrointestinal (GI) symptoms of type 1 DM are as follows:     Nausea. how often. Also ask about oral antidiabetic agents. Questions regarding hypoglycemia and hyperglycemia Hypoglycemia and hyperglycemia should be considered. and change in bowel movements may accompany acute DKA Acute fatty liver may lead to distention of the hepatic capsule. with near-normal blood glucose levels? (Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications) Does the patient have severe hypoglycemic reactions? (If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness. polydipsia. such as coronary artery disease (CAD).and date-stamped levels from the patient’s meter to assure full understanding of the frequency of testing and the actual levels. Ask about the type of insulin being used. units of insulin per grams of carbohydrate. despite normal or increased appetite. Weight loss may not occur if treatment is initiated promptly after the onset of the disease. Peripheral neuropathy presents as numbness and tingling in both hands and feet. when. generally 0. symmetric. delivery system (pump vs injections). Ideally. how far the blood glucose level is expected to decrease per unit of rapid-acting insulin.5 U/h. causing right upper quadrant pain Persistent abdominal pain may indicate another serious abdominal cause of DKA (eg. generally 1 unit of rapid-acting insulin per 10-15 g carbohydrate)  Correction dose (ie. abdominal discomfort or pain. ask about the following:  Basal rates (eg. developing after many years of chronic prolonged hyperglycemia. this possibility must be addressed. but symptomatic neuropathy is typically a late development. and frequency. In these patients. units per hour by pump. a full review of all medications and over-the-counter supplements being taken is crucial in the assessment of patients with type 1 DM. this done by uploading time. and triglycerides. potentially varying on the basis of time of day). though individuals with insulin resistance may need 1 U per 25-mg/dL decrease)  Some patients may be taking premeal pramlintide (an amylin analogue) A focused diabetes history should also include the following questions:       Is the patient’s diabetes generally well controlled. the dose of which may be determined as a function of the carbohydrate count plus the correction (to adjust for how high the premeal glucose level is).4-1. pancreatitis Chronic GI symptoms in the later stage of DM are caused by visceral autonomic neuropathy Neuropathy affects up to 50% of patients with type 1 DM. and ascending. patients with new-onset type 1 DM will lose weight. often 1 U of insulin per 50-mg/dL decrease. Of course. the total daily dose as basal insulin is a helpful value to know  Carbohydrate ratio (ie.

Patients with DKA. Physical Examination In new cases of diabetes. limited vascular and neurologic examinations. Other organ systems should be assessed as indicated by the patient’s clinical situation. and. If the respiratory rate and pattern suggest Kussmaul respiration. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy. if so. Questions should include the following:      Does the patient have hypertension? What medications are taken? Does the patient have symptoms of claudication or a history of vascular bypass? Has the patient had a stroke or transient ischemic attack? What are the patient’s most recent lipid levels? Is the patient taking lipid-lowering medication? Questions regarding neuropathy Potential neuropathy should be taken into account. which cannot be evaluated accurately unless the patients’ pupils are dilated. should be considered as well. funduscopic examination. DKA must be considered immediately. Other questions The possibility of foot disease should be addressed. patients should be examined every 3 months for macrovascular and microvascular complications. If hemorrhages or exudates are seen. Measurement of the pulse is important. at what sites. in that relative tachycardia is a typical finding in autonomic neuropathy.) The possibility of infection also should be considered. and appropriate tests must be ordered. will have Kussmaul respiration. They should undergo funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy. such as retinopathy and nephropathy. Funduscopic examination The funduscopic examination should include a careful view of the retina. does the patient lack the adrenergic warning signs of hypoglycemia)? (Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia) Questions regarding microvascular complications Microvascular complications. A comprehensive examination is not necessary at every visit. Foot examination . often preceding the development of orthostatic hypotension. in some cases. Assessment of vital signs Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. signs of dehydration. In established cases. (See Diabetic Foot and Diabetic Foot Infections. Does the patient have hypoglycemia unawareness (ie. however. the patient should be referred to an ophthalmologist as soon as possible. physical examination findings are usually normal. Inquire as to whether the patient has a history of foot ulcers or amputations or whether any foot ulcers are present. hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy. and foot examination. altered mental status. Ask the following questions as appropriate:    When was the patient’s last dilated eye examination? What were the results? Does the patient have known kidney disease? What were the dates and results of the last measurements of urine protein and serum creatinine levels? Questions regarding macrovascular complications Macrovascular complications should be explored. Be sure to inquire about whether frequent infections are a problem and. Ask whether the patient has a history of neuropathy or symptoms of peripheral neuropathy or whether autonomic neuropathy is present (including erectile dysfunction if the patient is a man). Both the optic disc and the macula should be visualized. Diabetes-focused examination A diabetes-focused physical examination includes assessment of vital signs.

Named for their snowflake or flocculent appearance. (SeeDiabetic Retinopathy. though they are fairly rare even in this population. but it also may be seen when high glucose levels are lowered rapidly. and some patients are almost completely unable to read small print or do close work during this period. the metabolic derangements of diabetes may facilitate infection. erysipelas. (See Infections in Patients with Diabetes Mellitus. 42. it does not affect acuity  Proliferative retinopathy involves extensive proliferation of new retinal small blood vessels. it causes a marked reduction of acuity Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control.[39] Ophthalmologic complications Diabetes can affect the lens. Infection may precipitate metabolic derangements. Rarely. A few infections. The most common sites are the skin and urinary tract.[41. recovery to baseline visual acuity can take up to a month.The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. those with frequent episodes of DKA) can acutely develop a ―snowflake‖ (or ―metabolic‖) cataract. If peripheral neuropathy is found. In either case. rhinocerebral mucormycosis.) Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. Infections such as pneumococcal pneumonia affect patients with diabetes and other patients with the same frequency and severity. This effect. Infections such as staphylococcal sepsis occur more frequently and are more often fatal in patients with diabetes than in others. Patients with diabetes tend to develop senile cataracts at a younger age than persons without diabetes. usually occurs as hyperglycemia increases.) Diabetic retinopathy is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:  Background retinopathy involves retinal small vessel abnormality leading to hard exudates. such as malignant otitis externa. This is particularly important in patients who have foot infections: poor lower-extremity blood flow can delay healing and increase the risk of amputation. Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient’s ability to protect the feet and ankles. cellulitis. and microaneurysms.) Complications Infections Infections cause considerable morbidity and mortality in patients with diabetes. superficial fungal infections. Both lower urinary tract infections and acute pyelonephritis are seen with greater frequency. epidemiologic studies have yielded conflicting results. 43] The following are the 5 stages in the progression of diabetic retinopathy: 1. and retina. patients with type 1 DM that is very poorly controlled (eg. 2. Diabetes increases susceptibility to various types of infections. Diabetic retinopathy is the principal ophthalmologic complication of DM. Dermatologic infections that occur with increased frequency in patients with diabetes include staphylococcal follicular skin infections. Dilation of the retinal venules and formation of retinal capillary microaneurysms Increased vascular permeability . vitreous. which is caused by osmotic fluxes of water into and out of the lens. and oral or genital candidal infections. occur almost exclusively in patients with diabetes.[40] Glaucoma in diabetes relates to the neovascularization of the iris (ie. the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation. rubeosis iridis diabetica). these cataracts can progress rapidly and create total opacification of the lens within a few days. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury. and emphysematous pyelonephritis. hemorrhages. and conversely. a sudden loss of vision can occur because of vitreous hemorrhage from proliferating new vessels or retinal detachment  Maculopathy involves edema and hard exudate or retinal ischemia. (See Diabetic Foot andDiabetic Foot Infections. causing visual symptoms that may prompt the patient to seek emergency care. Whether diabetes increases the risk of glaucoma remains controversial.

focal lesions of the brachial or lumbosacral plexus. or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. and brainstem stroke. Macular edema can cause visual loss. the pupil is usually spared. magnetic resonance imaging (MRI). 5. It is important to consider nondiabetic causes of cranial nerve palsies.3. Vascular occlusion and retinal ischemia Proliferation of new blood vessels on the surface of the retina Hemorrhage and contraction of the fibrovascular proliferation and the vitreous The first 2 stages of diabetic retinopathy are jointly referred to as background or nonproliferative retinopathy. The vessels undergo cycles of proliferation and regression. followed by the sixth nerve (abducens) and the fourth nerve (trochlear). mononeuropathy multiplex. therefore.[46] Therefore.) Diabetic neuropathy In the peripheral nerves. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. During proliferation. If a superficial capillary ruptures. Proliferative retinopathy is characterized by neovascularization.) Preproliferative (stage 3) and proliferative diabetic retinopathy (stages 4 and 5) are the next phases in the progression of the disease. Macrovascular complications . which usually include multiple microaneurysms. (See Diabetic Nephropathy.) The 4 types of diabetic neuropathy are as follows:     Peripheral distal symmetrical polyneuropathy. Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies. some have irreversible renal failure. the third cranial nerve (oculomotor) is most commonly affected. Although most recover from contrast medium–induced renal failure within 10 days. whereas in third-nerve palsy due to intracranial aneurysm or tumor. including intracranial tumors. Cotton-wool spots can be seen in preproliferative retinopathy. cranial nerve III. Diabetic nephropathy About 20–30% of patients with type 1 DM develop evidence of nephropathy. preferably. These represent retinal microinfarcts from capillary occlusion and appear as off-white to gray patches with poorly defined margins. this type of neuropathy eventually results in the loss of peripheral sensation. reflecting leakage of plasma. (See Diabetic Lumbosacral Plexopathy and Diabetic Neuropathy. aneurysms. Contraction also tears the new vessels. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. These rings usually mark an area of edematous retina. which hemorrhage into the vitreous. and radiculopathies. Neurologic consultation is recommended. Patients can present with diplopia and eye pain. a flame-shaped hemorrhage appears. or VI) Of these 4 types. The microaneurysms or retinal capillaries become more permeable. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. diabetes causes peripheral neuropathy. Rupture of intraretinal capillaries results in hemorrhage. the retinal venules dilate. [44] and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common. In diabetic third-nerve palsy. The patient may not notice a change in visual acuity unless the center of the macula is involved. Initially. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies. all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. IV. the pupil is affected in 80-90% of cases. fibrous adhesions develop between the vessels and the vitreous. Hard exudates are often found in partial or complete rings (circinate pattern). 4. then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. evaluation should include nonenhanced and contrast-enhanced compute4d tomography (CT) or. Chronically elevated blood pressure contributes to the decline in renal function. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Of the cranial neuropathies. and hard exudates appear. (See Macular Edema in Diabetes .[45] Besides causing pain in its early stages. predominantly sensory Autonomic neuropathy Proximal painful motor neuropathy Cranial mononeuropathy (ie.

which is a significant component of multiple renal lesions in diabetes. acanthosis nigricans (genetic disorders with insulin resistance) Drugs . not all people with type 1 DM are at risk for nephropathy. these result from the involvement of much smaller and more peripheral arteries. brain. or it may occur during pregnancy as a consequence of the increased glucose load placed on tubules by the elevated glucose filtration rate Peripheral neuropathy from alcohol abuse or vitamin B-12 deficiency Type 1 versus type 2 diabetes Determining whether a patient has type 1 or type 2 DM is an important diagnostic and therapeutic concern because patients with type 1 DM depend on continuous exogenous insulin for survival. this may occur because of an autosomal genetic disorder or dysfunction of the proximal renal tubule (eg. Addison disease.People with diabetes experience accelerated atherosclerosis. However. Hashimoto thyroiditis. who has always been dependent on insulin. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease. obesity. Graves disease. Fanconi syndrome or chronic renal failure). increasing the risk of ischemic heart disease. The HbA1c value per se. Risk factors for macrovascular disease Macrovascular disease is the leading cause of death in patients with diabetes. A lean patient who has had diabetes since childhood. Diagnostic Considerations The following conditions and factors should be taken into account in considering a diagnosis of type 1 diabetes mellitus (DM):             Type 2 DM Monogenic DM. Coronary atherosclerosis often occurs at a younger age and is more severe and extensive than in those without diabetes.Glucose appears in urine despite normal glucose concentration in blood. and hypogonadism associated with DM Nondiabetic glycosuria Renal glycosuria . phenytoin. affecting the small arteries of the heart. adipose tissue) Endocrine disorders .Mental retardation. muscles. robustly predicts MI odds.Thiazide diuretics.[49] previously known as maturity-onset diabetes of youth (MODY). a rare autosomal dominant condition found primarily in whites Secondary hyperglycemia Disorders of target tissues (liver. because there are some polymorphisms in the various factors involved in its pathogenesis. and somatostatin. Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia. which can modulate the course of this disease from one person to the other. [48]Diastolic dysfunction is common in patients with diabetes and should be considered in patients who have symptoms of congestive heart failure and a normal ejection fraction. and glucocorticoids Chronic pancreatitis Cystic fibrosis Prader-Willi syndrome . and kidney. catecholamines. glucagon. and the risk of peripheral vascular disease is 4 times that of people without diabetes. [47] The risk of stroke in people with diabetes is double that of nondiabetic people. Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 DM. . compared with approximately 35% of deaths in people without diabetes. Each 1% increment in HbA1c independently predicts 19% higher odds for MI. Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. rather than self-reported diabetes status or other established risk factors. glucocorticoids.Endocrine tumor causing increased production of growth hormone. and many patients have other risk factors for MI as well. lower extremity. muscular hypotonia. Diabetes by itself increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women. short stature. causing 65-75% of deaths in this group. or who has a history of diabetic ketoacidosis (DKA) almost certainly has type 1 DM. Patients with diabetes may have an increased incidence of silent ischemia.

to present with DKA and subsequently be found to have type 2 DM. without type 2 features (eg. the guidelines recommend HbA1c testing every 3 months. treat the patient with insulin and close monitoring of glucose levels. Hemoglobin A1c HbA1c is the stable product of nonenzymatic irreversible glycation of the beta chain of hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma glucose levels. it is important to avoid misdiagnosis of monogenic DM as type 1 or type 2 DM. The reference range for nondiabetic people is 6% in most laboratories.99 mmol/L) or higher. When in doubt. 50] Differential Diagnoses       Diabetes Mellitus. American Diabetes Association (ADA) guidelines recommend measuring HbA1c at least every 6 months in patients with diabetes who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals. HbA 1c levels provide an estimate of plasma glucose levels during the preceding 1-3 months.Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and who are younger but clinically appear to have type 2 DM and (2) older patients with late-onset diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 DM. it will not be possible to fully distinguish type 1 DM from type 2. especially in young. the diagnosis of DM can be confirmed with a random (nonfasting) plasma glucose concentration of 200 mg/dL or a fasting plasma glucose concentration of 126 mg/dL (6. polyuria. In such cases. the ADA suggests consulting the 2009 clinical practice consensus guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) at the ISPAD website. Individually measured glucose levels may differ considerably from estimated glucose averages calculated from measured hemoglobin A1c (HbA1c) levels. Intravenous (IV) glucose testing may be considered for possible early detection of subclinical diabetes. For further information about the diagnosis and management of monogenic diabetes. the difference between the 2 has a potential impact on decision making. Glycated hemoglobin levels also predict the progression of diabetic microvascular complications.[51.) It should be noted that for many patients. The American Diabetes Association (ADA) advises considering a diagnosis of monogenic diabetes when the following criteria are present [33] :     Diabetes is diagnosed within 6 months of birth A strong family history of diabetes is present. but islet cell autoantibodies.[33] . All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis.[52]Therefore. obesity. polyphagia). (This latter group is now said to have latent autoimmune diabetes of the adult [LADA]. obesity or higher-risk ethnicity) Mild fasting hyperglycemia is observed.[33. polydipsia. it is increasingly feasible to obtain a true genetic diagnosis through commercially available genetic testing. Type 2 Diabetic Ketoacidosis Diabetic Nephropathy Diabetic Ulcers Insulin Resistance Lead Nephropathy Laboratory Studies Plasma glucose Patients with type 1 diabetes mellitus (DM) typically present with symptoms of uncontrolled hyperglycemia (eg. caution is urged when the decision is made to estimate rather than actually measure glucose concentration. nonobese children Diabetes is present. and insulin resistance are absent If a form of monogenic diabetes is suspected. Monogenic diabetes Although monogenic diabetes syndromes are not very common. particularly Hispanic or African-American patients. 49] A fingerstick glucose test is appropriate in the emergency department (ED) for virtually all patients with diabetes. All other laboratory studies should be selected or omitted on the basis of the individual clinical situation. It is not unusual for adolescents or young adults. representing fewer than 5% of pediatric diabetes cases.

[54] This effect was seen in school-aged children but not preschoolers and may hold importance for studies using HbA 1c as a primary endpoint and HbA1c -based diagnosis of diabetes. in patients at high risk (eg. residual beta-cell function). Urine ketones are not reliable for diagnosing or monitoring diabetic ketoacidosis (DKA).5% or higher as a criterion for diabetes diagnosis. HbA1c cannot be used as an indicator of glycemic control in patients with neonatal diabetes mellitus (NDM) because of the high levels of fetal hemoglobin (HbF) remaining in the blood. Drawbacks included a lack of international standardization and insensitivity for the detection of milder forms of glucose intolerance. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines note that to help distinguish between the 2 types in children. polyphagia. with confirmation from repeat testing (unless clinical symptoms are present and the glucose level exceeds 200 mg/dL). the European Association for the Study of Diabetes. The committee noted the improvement in standardization and cited the following advantages of HbA 1c testing over glucose measurement:     Ability to capture long-term glucose exposure Less biologic variability No requirement for fasting or timed samples Current use in guiding management decisions Consequently. A study by Suzuki et al found that glycated albumin. however. along with 1 additional screening during adolescence. may show a change in control before HbA1c and often is helpful when applying intensive treatment and in short-term clinical trials. although they may be useful in screening to see whether a hyperglycemic individual may have some degree of ketonemia. therefore.6 ng/mL) suggests type 1 DM. and lower levels of solar irradiance. polydipsia. [49] C-peptide is formed during conversion of proinsulin to insulin.[51] One study found seasonal variability in HbA1c levels of school-age children with higher levels (0. as well as obtain a detailed family history. HbA1ctesting cannot be used in patients with abnormal red blood cell (RBC) turnover (as in hemolytic or iron-deficiency anemia). HbA 1c may not be significantly elevated despite frank diabetes. Screening for type 1 DM in asymptomatic low-risk individuals is not recommended. more strongly correlated with 1-month average postprandial blood glucose and was therefore a better marker of diabetes in neonates. Fructosamine is formed by a chemical reaction of glucose with plasma protein and reflects glucose control in the previous 1-3 weeks.[55] ADA guidelines recommend measuring HbA1c at least every 6 months year in patients who are meeting treatment goals and who have stable glycemic control. An insulin or C-peptide level below 5 µU/mL (0. along with measurement of plasma bicarbonate or arterial pH as clinically required. the committee recommended using the test only when the condition is suspected but the classic symptoms of type 1 DM—polyuria. The plasma acetone level—specifically. a random glucose level of 200 mg/dL. [31] Tests to Differentiate Type 1 from Type 2 Diabetes Although the oral glucose tolerance test with insulin levels is usually considered unnecessary for diagnosing type 1 DM. those who have first-degree relatives with type 1 DM). the guidelines recommend HbA1c testing every 3 months. In children with rapidly evolving type 1 DM. since 2010 the ADA has included an HbA1c level of 6. the dramatic increase of type 2 DM in the young suggests that assessment of insulin secretion may become more important. fewer hours of sunlight. the beta-hydroxybutyrate level—is a more reliable indicator of DKA. This finding is important to neonatologist and those caring for newborns. This assay. glutamic acid decarboxylase [GAD] autoantibodies). An exception is the individual with type 2 DM . an international expert committee appointed by the ADA.In the past. and unexplained weight loss—are absent.[53] In the case of type 1 DM. and the International Diabetes Association recommended the HbA1c assay for diagnosing type 1 and type 2 DM. a fasting C-peptide level greater than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 (ie. A white blood cell (WBC) count and blood and urine cultures may be performed to rule out infection.44%) coinciding with colder outdoor temperatures. physicians should measure insulin and C-peptide levels and immune markers (eg. For patients whose therapy has changed or who are not meeting glycemic goals.[51] However. however. it may be appropriate to perform annual screening for antiislet antibodies before the age 10 years. In a 2009 report. which is not affected by HbF levels. HbA1c measurements were not considered useful for the diagnosis of DM.[33] Other laboratory studies Fructosamine levels also test for glucose levels.

and weight loss. with doses adjusted on the basis of self-monitoring of blood glucose levels. the patient with new-onset type 1 DM who presents with mild manifestations and who is judged to be compliant can begin insulin therapy as an outpatient. bedtime/overnight.) Testing for islet autoantibodies can substitute for expensive genetic testing in those patients suspected of having maturity-onset diabetes of the young (MODY). Measurements of IA2 autoantibodies within 6 months of diagnosis can help differentiate between type 1 and type 2 DM. Although patients with type 1 DM have normal incretin response to meals. and neuropathy. A positive test for positive islet autoantibodies makes MODY highly unlikely. the disease recurs. Thus. It is performed most commonly with simultaneous kidney transplantation for end-stage renal disease (ESRD). and patients require insulin therapy. Long-term effects of exogenously administered GLP-1 analogues warrant further studies. as assessed over 7 years. Long-term management requires a multidisciplinary approach that includes physicians. administration of exogenous glucagonlike peptide 1 (GLP-1) reduces peak postprandial glucose by 45%. Tight glycemic control The association between chronic hyperglycemia and increased risk of microvascular complications in patients with type 1 DM was demonstrated in the Diabetes Control and Complications Trial (DCCT). a patient who is ultimately found to have type 1 DM presents with subtle symptoms because of residual insulin secretion. proteinuria. However. including polyuria. This remission is caused by a partial return of endogenous insulin secretion. polydipsia.[33] Goals should be further individualized on the basis of awareness of hypoglycemia. 60] Benefits Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality. Ultimately. fatigue.who presents with a very high glucose level (eg. improved glycemic control should prevent heart failure as well. microalbuminuria. [61] . These benefits occurred even though subjects in the intensively treated group and those in the standard treatment group maintained similar HbA1c levels (about 8%). Often. The DCCT ended in 1993. In some patients. Islet-cell (IA2). the signs.[56] Approach Considerations Patients with type 1 diabetes mellitus (DM) require lifelong insulin therapy. a confirmatory random plasma glucose level of greater than 200 mg/dL is adequate to establish the diagnosis of DM.[57] Pancreatic transplantation for patients with type 1 DM isg a possibility in some referral centers. >300 mg/dL) and a temporarily low insulin or C-peptide level but who will recover insulin production once normal glucose is restored. however. and the need to self-monitor blood glucose levels. intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy.985 patients with type 1 DM. nurses. In these patients. starting 1 year after the DCCT ended. this approach requires close follow-up and the ability to provide immediate and thorough education about the use of insulin. and 13-19 years. However. nocturia. [58] In that trial. and response to treatment. with different targets for preprandial. These titers decrease after 6 months. On occasion. anti-GAD65. (See also Type 2 Diabetes Mellitus. and hemoglobin A 1c (HbA1c) levels in patients aged 0-6. frequency of hypoglycemia. dietitians. The American Diabetes Association (ADA) recommends using patient age as one consideration in the establishment of glycemic goals. an observational study that continues to follow the patients previously enrolled in the DCCT. has demonstrated continued benefit from intensive treatment. the Epidemiology of Diabetes Interventions and Complications Study (EDIC). Most patients who present with undiagnosed type 1 DM have the classic symptoms of uncontrolled hyperglycemia. It is postulated that a ―metabolic memory‖ exists and that better early glycemic control sets the stage for outcomes many years in the future. Most require 2 or more injections of insulin daily. 6-12. The prevalence of these antibodies is the same in patients with MODY as in the healthy population. and it may last for several weeks or months (sometimes for as long as 1-2 years). Anti-GAD65 antibodies can be present at diagnosis of type 1 DM and are persistently positive over time. and anti-insulin autoantibodies can be present in early type 1 but not type 2 DM. and treatment of hypoglycemia.[59. symptoms. the onset of type 1 DM is marked by an episode of diabetic ketoacidosis (DKA) but is followed by a symptom-free ―honeymoon period‖ in which the symptoms remit and the patient requires little or no insulin. and selected specialists. Increasing HbA1c levels correlated with increasing risk of developing heart failure in a study of 20.

Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia. continuous glucose monitoring is associated with reduced time spent in hypoglycemia. with a premeal blood glucose level of 80–130 mg/dL. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines support the creation of individualized targets that consider these factors as part of a comprehensive treatment plan. Advise patients to test for urine ketones whenever they develop any of the following:      Symptoms of a cold. or abdominal pain Polyuria An unexpectedly high plasma glucose level on self-monitoring Persistent. Second. Instruct patients with type 1 DM in the method of testing for urine ketones with commercially available reagent strips. in some cases 1-2 hours after meals. an increased risk of severe hypoglycemia accompanies lower blood glucose levels. patients often obtain 2-4 measurements each day. Use of CGMs may help prevent significant glucose variability in patients receiving either multiple daily injection therapy or continuous insulin infusion therapy. The guidelines suggest the intermittent use of CGM systems for short-term retrospective analysis in the following cases[67] : . which either is a pagerlike device or is integral to an insulin pump. vomiting. In practice.Risks For many patients. so that the levels recorded by the CGM may differ from a fingerstick (capillary) glucose reading. Guidelines from the Endocrine Society[67] recommend the use of real-time CGMs in adult patients with type 1 DM who have demonstrated that they are able to use these devices on a nearly daily basis. advanced complications. This information is useful in advising patients with type 1 DM interested in preserving cognitive function.[62] Although tight glycemic control is beneficial. recurrent and chronic hypoglycemia has been linked to cognitive dysfunction. substance abuse. However. and marked fluctuation in the degree of hyperglycemia Continuous glucose monitoring Continuous glucose monitors (CGMs) contain subcutaneous sensors that measure interstitial glucose levels every 15 minutes. Insulin-dependent patients ideally should test their plasma glucose daily before meals. in any event. [64] An 18-year follow-up of the DCCT by Jacobson et al found that HbA1c levels and retinal and renal complications were independently linked to cognitive declines. however. and at bedtime. targets should be individualized. rapid. such as an HbA 1c of less than 8% and preprandial glucose levels of 100-150 mg/dL. CGMs transmit to a receiver. All patients with type 1 DM should learn how to self-monitor and record their blood glucose levels with home analyzers and adjust their insulin doses accordingly. there is a lag between glucose levels in the interstitial space and levels in capillary blood. preprandially and at bedtime). The 2011 AACE guidelines for developing a comprehensive care plan emphasize that hypoglycemia should be avoided. including fasting levels and levels checked at various other times (eg.[66] Whether glucose variability is detrimental in the absence of hypoglycemia remains an unresolved question.[49] In patients with type 1 DM. memory. the HbA1c target should be less than 7%. variability leads to the expense of frequent testing. flu.[65]Additionally. cardiovascular disease.[63] This has important implications in the management of children with type 1 DM. which allows rational adjustments in insulin doses. A smoking history was modestly associated with decrements in learning. Self-Monitoring of Glucose Levels Optimal diabetic control requires frequent self-monitoring of blood glucose levels. spatial information processing. or untreated mental illness may require higher targets. providing alarms when glucose levels are too high or too low or are rapidly rising or falling. or other intercurrent illness Nausea. First. whether the glucose levels are rising or falling) tend to be more helpful. and psychomotor efficiency. CGMs have several drawbacks. For that reason. the trends (ie. No relation with macrovascular risk factors or severe hypoglycemic events was found. patients may overtreat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough—a phenomenon known as stacking) as well as overtreat low glucose levels (because the glucose levels rise slowly with ingestion of carbohydrate). Individuals with recurrent episodes of severe hypoglycemia.

   Patients with suspected nocturnal hypoglycemia. A new ultralong-acting basal insulin. instituting new insulin or switching from multiple daily injections to pump therapy) Insulin Therapy Types of insulin Rapid-. this is not true of regular insulin. Intermediate-acting insulins include NPH insulin. Rapid-acting insulin analogues may be slightly better at lowering HbA1c and are preferred by most US diabetologists. In addition.[69] Both regular human insulin and rapid-acting insulin analogues are effective at lowering postprandial hyperglycemia in various basal bolus insulin regimens used in type 1 DM. areas under the curve were similar for the 2 strengths. however. dawn phenomenon. its onset of action occurs in 0. neutral protamine Hagedorn (NPH) insulin will not inhibit the action of insulin lispro when the 2 agents are mixed together right before injection. Insulin detemir has a duration of action that may be substantially shorter than that of insulin glargine but longer than those of intermediate-acting insulins.29 in the B chain. a short interval to peak action (45-75 minutes). Accidental prescribing of U-500 rather than U-100 is a potential safety issue. Short-acting insulin includes regular insulin. When it is administered subcutaneously. These insulins are absorbed more quickly and have a rapid onset of action (5-10 minutes). or postprandial hyperglycemia Patients with hypoglycemic unawareness Patients experimenting with important changes to their diabetes regimen (eg. Various pork.[68] A study by de la Pena et al found that although the overall insulin exposure and effects of 500 U/mL insulin are similar to those of 100 U/mL insulin. [71] Mixtures of insulin preparations with different onsets and durations of action frequently are administered in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. insulin degludec. Therefore. and beef-pork insulins were previously used. Novolin 70/30 and Humulin 70/30) are available. but the differences are clinically insignificant. recombinant human insulin is now used almost exclusively. they can be administered shortly before eating. in the United States. and the duration of action is normally 14–24 hours. has been developed. but 500 U/mL (U-500) insulin is increasingly used. Aspart insulin substitutes aspartic acid for proline in position 28 of the B chain. and aspart insulin. a crystalline suspension of human insulin with protamine and zinc.5-5 hours. The exceptions are insulin glargine and insulin detemir. NPH provides a slower onset of action and longer duration of action than regular insulin does. [70] Semilente insulin is like regular insulin and is a rapid-acting insulin with a slightly slower onset of action. It awaits approval by the US Food and Drug Administration (FDA). short-.5 hours. glulisine. though patients requiring lower doses typically are given twice-daily injections. the peak effect is noted at 4-12 hours. Glulisine insulin substitutes glutamic acid for lysine in position B29. Rapid-acting insulins include lispro. intermediate-. and a short duration of action (2-4 hours). This insulin zinc suspension is equivalent to a mixture of 30% prompt insulin zinc (Semilente) and 70% extended insulin zinc (Ultralente). Insulin glargine has no peak and produces a relatively stable level lasting more than 24 hours. Regular insulin is a preparation of zinc insulin crystals in solution. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline at B28. which has a duration of action of up to 42 hours. albeit mostly in type 2 DM. but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use. beef. Insulin glargine and cancer . peak concentration was significantly lower with U-500. Lente insulin is a suspension of insulin in buffered water that is modified by the addition of zinc chloride. and long-acting insulin preparations are available. which should not be mixed with any other form of insulin. In some cases. its peak activity comes at 2. Preparations that contain a mixture of 70% NPH and 30% regular human insulin (eg. It contains zinc insulin microcrystals in an acetate buffer. It is not used in the United States. it can produce a stable basal serum insulin concentration with a single daily injection. and its duration of action is 4-12 hours. It is not readily available in the United States. The onset of action usually occurs at 1-2 hours. Commercially prepared mixtures of insulin are also available. and the effect after the peak was prolonged. Long-acting insulins used in the United States include insulin glargine and insulin detemir. The standard strength of regular insulin is 100 U/mL (U-100).

This finding was attributed to allocation bias and differences in baseline characteristics. NPH insulin is being used less frequently. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). and one fourth at bedtime. new insulin vials should be opened and used. The validity of the link remains in question. and patient characteristics differed across treatment groups. 4. For patients on intensive insulin regimens (multiple daily injections or insulin pumps). This method allows patients more flexibility in caloric intake and activity.[72] The FDA communication was based on 4 observational studies that evaluated large patient databases and found some association between insulin glargine (and other insulin products) and various types of cancer. [74] Common insulin regimens The goal of treatment in type 1 DM is to provide insulin in as physiologic a manner as possible. however. Initiation of insulin therapy The initial daily insulin dose is calculated on the basis of the patient’s weight. More frequent adjustments of regular insulin can be made if a risk of hypoglycemia is present. whereas insulin glargine and insulin detemir are being used more frequently. lispro. This dose is usually divided so that one half is administered before breakfast. one fourth before dinner. 2009. it may have lost its clinical effectiveness. aspart. On July 1. although patients who used only insulin glargine had a higher rate of cancer than those who used another type of insulin. The preprandial insulin is either rapid-acting (lispro. no increase in breast cancer rates was associated with insulin glargine use. If a patient is experiencing unexplained high blood sugar levels. Insulin kept in a pump reservoir for longer than 3 days may lose its clinical effectiveness (though insulin aspart has now been approved for use for as long as 6 days in a pump). Currently. the FDA issued an early communication regarding a possible increased risk of cancer in patients using insulin glargine (Lantus). [73] A study by Johnson et al found the same incidences for all cancers in patients receiving insulin glargine as in those not receiving insulin glargine. it should be used for no more than 28 days and then discarded. and NPH before bedtime (the idea is to reduce fasting hypoglycemia by giving the NPH later in the evening)  Multiple daily injections (MDI) – A long-acting insulin (eg. the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg. insulin distributed from the pharmacy has been exposed to heat or other environmental factors and therefore may be less active. The insulin dose is often adjusted in increments of 10% at a time. and the effects are assessed over about 3 days before any further changes are made. . even if there is still some insulin in the bottle. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use. The risk tended to increase after 5 years. and timing according to the plasma glucose levels. and significantly so for the women who had taken other forms of insulin before starting insulin glargine. adjust the amounts. Adjust the dose to maintain preprandial plasma glucose at 80-150 mg/dL (ie. or glulisine) or short-acting (regular). however. In a study by Suissa et al. or glulisine) or regular insulin before breakfast and supper Split or mixed variant – NPH with rapid-acting or regular insulin before breakfast. Additionally. Sometimes.Controversy has arisen over a disputed link between insulin glargine and cancer. The duration of these observational studies was shorter than that considered necessary to evaluate for drug-related cancers. aspart. with additional boluses given before each meal and correction doses administered if blood glucose levels exceed target levels Insulin is sensitive to heat and exposure to oxygen.44-8. Overall. Common insulin regimens include the following:   Split or mixed – NPH with rapid-acting (eg. Once a bottle of insulin is open. glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients) and a rapid-acting insulin before meals or snacks (with the dose adjusted according to the carbohydrate intake and the blood glucose level)  Continuous subcutaneous insulin infusion (CSII) – Rapid-acting insulin infused continuously 24 hours a day through an insulin pump at 1 or more basal rates. rapid-acting or regular insulin before supper. findings were inconsistent within and across the studies. After selecting the initial dose. types.33 mmol/L). an additional 2 U of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). but it requires more blood glucose monitoring and closer attention to the control of their diabetes.

Children with hyperglycemia and ketonuria but without acidosis or dehydration may be started on 0. The patient self-monitors preprandial glucose levels to adjust the bolus dose(s).623% of cartridge volume was demonstrated as a result of bubble formation and expansion of preexisting bubbles. pruritus. Some cases may require epinephrine and intravenous (IV) steroids. but once metabolic control is achieved. Such reactions usually resolve spontaneously without any intervention.[77] Local allergic reactions Generalized insulin allergy is rare.[76] Increased bedtime doses of hypoglycemic agents with nighttime peaks in action may correct early morning hyperglycemia but may be associated with undesirable nocturnal hypoglycemia. particularly after meals that are high in protein or fat. These complications are less common with the human insulins now in use than with the animal insulins once widely employed. Symptoms occur immediately after the injection and include urticaria. Initially.7 U/kg of intermediate-acting insulin and subcutaneous injections of 0.5 U/kg of intermediate-acting insulin alone. This may increase the risks of hypoglycemia. Because patients may experience hyperglycemic episodes despite strict adherence to carbohydrate counting. Local fat atrophy or hypertrophy at injection sites was common with animal insulins but is rare with human insulin and insulin analogues. During the flight of a commercial airliner (200 mm Hg pressure decrease). allergy may be treated with antihistamines. pruritus.5-0. rarely. a basal insulin such as glargine or detemir is preferred to NPH. The CSII method provides better control than the MDI method does. Bergenstal et al determined that sensor-augmented pump therapy led to better glycemic control and that more patients reached targets with this technology than with injection therapy. hypoglycemia is common with pump therapy. Local allergic reactions can occur at the site of insulin injections and can cause pain. the risk is the same as with MDI. Changes in altitude may affect delivery from insulin pumps.or long-acting insulin in the morning for all-day coverage. As a rule. a small or missed meal. patients should be well educated about their disease and about self-monitoring of plasma glucose levels. The researchers showed that use of this algorithm improved glycemic control. Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake. circulatory shock.[78] Management of Hypoglycemia Hypoglycemia may result from a change in insulin dose. and induration.3-0. bronchospasm.1 U/kg of regular insulin at 4. or strenuous exercise. Targeted CSII programming can facilitate the prevention of early-morning hyperglycemia in selected patients. or is vomiting. Australian researchers developed an algorithm for estimating the mealtime insulin dose on the basis of measurements of physiologic insulin demand evoked by foods in healthy adults. Multiple daily injections Multiple subcutaneous insulin injections are administered to control hyperglycemia after meals and to maintain normal plasma glucose levels throughout the day. burning.[75] Initiation of insulin therapy in children Children with moderate hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous injection of 0. Therefore. Changing to a different insulin preparation may be necessary. These patients may need additional intermediate. Where available. excess insulin delivery of 0. Patients should adjust their daily dosage(s) on the basis of their self-monitoring of glucose levels before each meal and at bedtime. local erythema. has gastroparesis. .to 6-hour intervals. programmed basal rate(s) of insulin and a manually administered bolus dose before each meal. Continuous subcutaneous insulin infusion A small battery-operated infusion pump that administers a continuous subcutaneous infusion of rapid-acting insulin can provide selected. and.Carbohydrate counting may be used to determine the meal-time insulin dose. Patients should also assess their plasma glucose levels at 2:00-4:00 AM at least once per week during the first few weeks of treatment and thereafter as indicated. About 25% of the total daily dose is administered as intermediate-acting insulin at bedtime. angioedema. with additional doses of rapid-acting insulin before each meal (4-dose regimen). Patients do not require any specific treatment of local fat hypertrophy. but injection sites should be rotated.

In general. In a follow-up to the DCCT. coronary artery disease (CAD). If the blood glucose level exceeds the renal threshold for glucose (which is typically 240 mg/dL in a healthy person but is lower in older patients. hyperglycemia impairs leukocyte function through a variety of mechanisms. leading to osmotic diuresis and dehydration. In patients with known. Adequacy of follow-up is extremely important. an osmotic diuresis ensues. In cases of the dawn phenomenon. However.[63] In another study. [81] In some patients. [80] Management of Hyperglycemia Acute hyperglycemia. Family members can be taught to administer a subcutaneous injection of glucagon. The existence of a true Somogyi phenomenon is a matter of debate. dizziness. regardless of the duration of diabetes. such as infection. and specific metabolic corrections are the keys to treatment of DKA. and hyperglycemia impairs wound healing. the patient should check blood glucose levels at 2:00-4:00 AM. Thus. sweating. Patients with diabetes have an increased rate of wound infection. poorly controlled type 1 DM. This rise. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis. with loss of glucose. In an emergency situation. lowering the patient’s glucose level in the ED does not correct the underlying cause and has no long-term effect on the patient’s glucose levels.Common symptoms of hypoglycemia are light-headedness. in the process of designing treatment plans aimed at reducing the glycemic burden and minimizing vascular complications. insulin therapy. is harmful for a number of reasons. Use of insulin . DKA is characterized by hyperglycemia. electrolytes. shakiness. Patients should be made aware of these symptoms and educated to respond rapidly with sugar intake. hypoglycemic episodes might negate some benefits. Patients with type 1 DM can have coexisting illnesses that aggravate hyperglycemia. and headache.[79] Controversy surrounds the question of whether severe hypoglycemia in youths with type 1 DM has lasting cognitive consequences. and no association between early severe hypoglycemia and subsequent reduced adult cognition or EEG changes was found. both the dawn phenomenon and the Somogyi phenomenon are characterized by morning hyperglycemia. and pregnant women). (See Diabetic Ketoacidosis. nocturnal hypoglycemia may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (the Somogyi phenomenon). no absolute level of blood glucose elevation mandates admission to the hospital or administration of insulin in the emergency department (ED). They should be advised to carry candy or sugar cubes. The dawn and Somogyi phenomena can be ameliorated by administering intermediate insulin at bedtime. a plan for lowering and monitoring the patient’s glucose levels is needed.) Dawn and Somogyi phenomena The dawn phenomenon is the normal tendency of the blood glucose to rise in the early morning before breakfast. confusion. is probably enhanced by increased hepatic gluconeogenesis secondary to the diurnal rise in serum cortisol. ketosis. and water. recurrent and chronic hypoglycemia was linked to cognitive dysfunction. can be corrected with intensified insulin therapy. even when not associated with DKA (or hyperosmolar hyperglycemic state [HHS]. initial treatment consists of a bolus injection of 25 mL of 50% glucose solution followed by a continuous glucose infusion. electroencephalography (EEG) and cognition studies were performed at baseline and 16 years later in patients with type 1 DM. or fever. however. Repeated hypoglycemia may be an aggravating factor in preclinical atherosclerosis. Thus. and acidosis. which may result from the nocturnal spikes in growth hormone that cause insulin resistance. Volume repletion. certain medications can aggravate the condition. which occurs most commonly in type 2 DM). Diabetic ketoacidosis DKA involves acute metabolic changes in the body that develop as a result of lack of insulin or poor response to insulin arising from stress or illness. Most endocrinologists now believe this phenomenon reflects waning of insulin action with consequent hyperglycemia. Therefore. In addition. Augmented hepatic gluconeogenesis and glycogen cycling are known to occur in patients with type 1 DM. Additionally. those with renal insufficiency. both abnormalities. however. but the latter is considered to be rebound (counterregulation) hyperglycemia.

frequency. patients who participate in Ramadan may be at higher risk of acute diabetic complications.[82] Diet management includes education about how to adjust the timing. Diet One of the first steps in managing type 1 DM is diet control. NPH or Lente) insulin at 50-70% of the daily dose divided into 2 or. Also. In some cases. . 1-1. that includes the following:    A daily caloric intake prescription Recommendations for amounts of dietary carbohydrate. Administer supplemental regular insulin on a sliding scale. should not be the only intervention for correcting hyperglycemia. especially if it is provided before hemorrhage occurs. fat. Laser therapy is effective in this condition. and protein Instructions on how to divide calories between meals and snacks Caloric distribution is an important aspect of dietary planning in these patients. All patients on insulin should have a comprehensive diet plan. midmorning and midafternoon snacks are important to avoid hypoglycemia. insulin may be used inappropriately when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia. Patients should minimize consumption of sugars and ensure that they have adequate fiber intake. Although these patients do not eat during the annual observance. These include the following:          Malignant otitis externa Rhinocerebral mucormycosis Bacteriuria Pyuria Cystitis Upper urinary tract infection Intrarenal bacterial infection Skin and soft tissue infections Osteomyelitis Ophthalmologic complications Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation. Patients should be encouraged to exercise regularly. For example. with a sliding scale for insulin administration. If patients participate in rigorous exercise for more than 30 minutes. Fat intake should be limited to no more than 30% of the total calories. 35% for lunch. The minimum protein requirement for good nutrition is 0. and a low-cholesterol diet is recommended. 3-4 daily doses. size. but a reduced protein intake is indicated in cases of nephropathy. dietary treatment is based upon nutritional assessment and treatment goals. Activity Exercise is an important aspect of diabetes management. Blood glucose should be monitored before meals and at bedtime. they should be encouraged to actively monitor their glucose. 30% for dinner. they may develop hypoglycemia unless they either decrease the preceding insulin injection by 10-20% or have an extra snack. because it is reactive rather than proactive. occasionally. created with the help of a professional dietitian. According to ADA policy. Dietary recommendations should take into account the patient’s eating habits and lifestyle. Educate the patients about the effects of exercise on the blood glucose level.The insulin coverage. Patients must also make sure to maintain their hydration status during exercise. and seek dietary counseling and patient education to counteract these complications. A recommended distribution consists of 20% of daily calories for breakfast. and composition of meals so as to avoid hypoglycemia or postprandial hyperglycemia. alter the dosage and timing of their medication. Continue intermediate-acting (ie. and 15% for a late-evening snack.5 g/kg/day).9 g/kg/day (usual range. Management of Complications Infections Diabetes predisposes patients to a number of infectious diseases (see Infections in Patients with Diabetes Mellitus).

Potentially nephrotoxic drugs should be avoided whenever possible. [33] All adults with diabetes should have serum creatinine measured at least annually. and symptoms tend to wax and wane. Metabolic control.) Diabetic nephropathy Extreme care should be exercised whenever any nephrotoxic agent is used in a patient with diabetes. or symptomatic orthostatic hypotension. and their renal function should be carefully monitored.[83] A better solution is to seek equivalent clinical information by using an alternative modality that does not require the use of contrast material (eg. Patients with diabetes who must undergo such studies should be well hydrated before. reduction of protein intake may improve renal function. and blood pressure control are all protective. (See Diabetic Nephropathy. absence of retinopathy.) In particular.) Diabetic foot disease Patients with diabetes who present with wounds. Tight glycemic control. the patient should immediately be referred to an ophthalmologist for possible laser therapy. 87] Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting. Indeed. An ACE inhibitor or an angiotensin II receptor blocker (ARB) should be used because these classes of agents decrease proteinuria and slow the decline in renal function independent of the effect on blood pressure. so that the blood settles to the inferior portion of the retina and thus obscures less of the central visual area. If kidney disease is advanced or difficult to manage or its etiology is unclear. the use of angiotensin-converting enzyme (ACE) inhibitors and good metabolic control can usually induce remission. and a favorable lipid profile are associated with improved outcome. [88] In addition to appropriate use of antibiotics. Before these therapies are started. lower blood pressure.[86] ACE inhibitors and ARBs tend to increase the serum potassium levels and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels. Patients with disabling orthostatic hypotension may be treated with salt tablets. (SeeDiabetic Retinopathy and Macular Edema in Diabetes. In severe cases. and after the study. better glucose control. ultrasonography. wheelchairs. (See Diabetic Neuropathy and Diabetic Lumbosacral Plexopathy. Microalbuminuria and macroalbuminuria are not permanent features in most diabetic children and adolescents. Multifactorial intervention is important for slowing the progression of diabetic retinopathy. Because subsequent hemorrhages can be larger and more serious. Patients with active proliferative diabetic retinopathy are at increased risk for retinal hemorrhage if they receive thrombolytic therapy. or fludrocortisone. Current ADA guidelines recommend annual screening for nephropathy. or bed rest is mandatory for preventing .[84] Regression of microalbuminuria is common. [85] When chronic kidney disease is present. the first hemorrhage is small and is noted by the patient as a fleeting dark area (or ―floater‖) in the field of vision. such studies should absolutely be avoided in patients with a creatinine level higher than 3 mg/dL. In adults (and children aged 10 years or older) who have had type 1 DM for 5 or more years. during. Progression and regression of kidney disease are common even after development of persistent microalbuminuria. consider referral to a physician with experience in kidney disease patient care. Renally excreted or potentially nephrotoxic drugs should be given at reduced doses appropriate to the patient’s serum creatinine level. therefore. noncontrast computed tomography [CT]. Patients with gastroparesis may benefit from metoclopramide or erythromycin. or ulcers of the foot should be treated intensively. annual assessment of urine albumin excretion is appropriate. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping).[45. this condition is a relative contraindication to the use of thrombolytic agents. lower blood pressure. Treatment of gastroparesis is symptomatic. and other serious causes of vomiting must be excluded. severe diarrhea. the use of crutches. Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating for both doctor and patient. smoking cessation. bladder dysfunction and urinary retention.[85] In patients with persistent microalbuminuria. caution should be exercised when contrast-enhanced radiologic studies are being considered in patients with diabetes who have a creatinine level higher than 2 mg/dL. Control of blood pressure is a critical element of care. and better lipid control favor this outcome. infections. the degree of dehydration and metabolic imbalance must be assessed. support stockings. female gender.Often. Diabetic neuropathy Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. or magnetic resonance imaging [MRI]). gastric pacing has been used.

silent ischemia is common in many patients with CAD. their prevention is extremely important.[91] Prediction of cardiovascular risk in diabetic patients on the basis of the lipid profile is not affected by the timing of blood specimen. is a progressive deterioration of foot joints caused by underlying neuropathy. it may be unnecessary to insist on using fasting blood samples to determine the lipid profile. these agents can mask the adrenergic symptoms of insulin-induced hypoglycemia and can impair the normal counterregulatory response. cortisol. Hyperglycemia can occur even in patients without diabetes as a consequence of stress-induced insulin resistance coupled with the use of dextrose-containing IV fluids. (See Diabetic Footand Diabetic Foot Infections. The ADA advises that a systolic blood pressure below 130 mm Hg is an appropriate goal for most patients with diabetes and hypertension. Nevertheless. Persistent lipid abnormalities remain in patients with diabetes. osteomyelitis is present. a placebo-controlled study by Lund et al found that metformin (1000 mg orally twice daily) significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with type 1 DM.[33] Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. ACE inhibitors are the drugs of choice for hypertension because of their renal protective action.[92] In a study involving diabetic adolescents and children. Macrovascular disease Hypercholesterolemia and hypertension increase the risk of specific late complications and require special attention and appropriate treatment. the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. Increases in glucagon. and hospitalization for IV antibiotic therapy is often necessary. despite evidence supporting the benefits of lipidmodifying drugs. especially early in the course of the disease. and the apparent increase in its incidence may come about because patients with diabetes are more likely than others to have CAD to begin with. catecholamines.[93] Patients with diabetes may have increased incidence of silent ischemia. malaise. Up-titration of the statin dose and addition of other lipid-modifying agents are needed. and growth . nocturnal hypertension was significantly associated with higher daytime blood pressure and carotid intima-media thickness. these findings warrant confirmation and longitudinal follow-up. Although physicians can safely use beta blockers (eg. propranolol) in most patients. Other neuromuscular foot deformities also may be present. Because ulcers and foot infections are difficult to cure. Referral to a podiatrist is indicated for diabetic patients with any of the following:     Distal sensory neuropathy with inability to feel a pinprick or light touch Decreased peripheral pulses Moderate-to-severe onychomycosis Impending skin breakdown Charcot joint.) If bone or tendon is visible. lipid abnormalities must be treated aggressively to reduce the risk of serious atherosclerosis. Early diagnosis and treatment are important for preventing further joint degeneration. Tarsometatarsal and midtarsal joints are affected most commonly. The emergency physician can facilitate this practice by briefly inspecting the feet of patients with diabetes and by educating them about the need for proper foot care. a type of arthropathy observed in people with diabetes. Therefore. it is prudent to perform electrocardiography (ECG) in patients who have diabetes and a serious illness or who present with generalized weakness. Diastolic blood pressure should be less than 80 mm Hg.[94] Although metformin is used principally in type 2 DM because of its lipid-lowering effect. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease.[90] This is important from an epidemiologic point of view and has a bearing on the treatment strategies that must be used to mitigate the risk.[89] At one clinic. which could be precursors of atherosclerotic cardiovascular disease later in life. [48]However.[95] Glycemic Control During Serious Medical Illness and Surgery Serious medical illness and surgery produce a state of increased insulin resistance and relative insulin deficiency. or other nonspecific symptoms that are not usually expected to result from myocardial ischemia.further trauma to the healing foot. Therefore. but it also recommends modifying systolic blood pressure targets in accordance with individual patient characteristics.

8-10 mmol/L) for the majority of critically ill patients. and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. The same principles of providing a constant source of insulin and carbohydrate apply to patients with type 1 DM who must also take nothing by mouth for medical reasons. consult medical specialists when appropriate. lispro. Counterregulatory hormones also directly increase hepatic gluconeogenesis. Rapid-acting insulins may be given every 3 hours. Near-normal blood glucose levels should be maintained in medical and surgical patients with diabetes. frequentblood glucose monitoring is not always possible. glargine or detemir insulin) with additional correction doses of regular insulin or a rapid-acting insulin. may be appropriate for selected patients. perioperative care. because a dose is effective for up to 6 hours. for the following reasons:     To prevent the development of ketosis To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis To prevent the impairment of leukocyte function that occurs when blood glucose levels are elevated To prevent the impairment of wound healing that occurs when glucose levels are elevated Patients with type 1 DM must take in insulin and carbohydrate at all times to prevent ketosis. Nonetheless. or brain injury settings. aspart. The ADA recommends that in critically ill patients. rather than a sliding-scale regular insulin regimen. and promptly initiate a thorough medical evaluation. such as 110-140 mg/dL (6.1-7.8 mmol/L). in certain circumstances. provided that these targets can be safely achieved. and the use of a preprinted order facilitates administration and reduces dosing errors.0 mmol/L). It is strongly recommended that continuous IV infusions of dextrose and insulin be used in patients who are undergoing general anesthesia or who are critically ill. Patients should receive a basal insulin (eg. In recommending 200 mg/dL as the upper target. or glulisine) To prevent hypoglycemia. provided that significant hypoglycemia can be avoided. and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The guidelines on glycemic control in hospitalized patients formulated by the American College of Physicians (ACP) recommend a target blood glucose level of 140-200 mg/dL if insulin therapy is used to manage patients with diabetes in nonsurgical (medical) intensive care units (ICUs). and the rates of insulin and dextrose infusion must be adjusted accordingly to prevent hypoglycemia or persistent hyperglycemia.[97] These guidelines were based on a review of 21 trials in intensive care.hormone levels antagonize the effects of insulin. such as after cardiovascular surgery and during treatment in a surgical ICU.8 mmol/L) with random blood glucose levels below 180 mg/dL (10. infection rates. [33] It may be appropriate to use more stringent targets in stable patients with previous tight glycemic control and less stringent targets in patients with severe comorbidities. [100] . [98] The ACP found no convincing evidence that intensive insulin therapy reduced short-term or long-term mortality. which recommended a target range of 140-180 mg/dL in critically ill patients. Much less is known about optimal blood glucose levels in hospitalized patients with preexisting diabetes whose hyperglycemia reflects both their diabetes and a stress response to illness. For patients who are less seriously ill or are undergoing minor surgery. regular insulin should not be given more often than every 3-4 hours. length of hospital stay. Blood glucose levels must be measured with a glucose meter every hour. A basal bolus insulin regimen. Cardiovascular disease or renal dysfunction increases surgical morbidity and mortality. In many localities. should be used in these patients. Recent guidelines have trended away from stressing intensive glucose control in ill patients with diabetes. These patients may do as well with subcutaneously injected insulin. myocardial infarction. insulin therapy should be initiated if the glucose level exceeds 180 mg/dL (10 mmol/L). Once the patient is eating. with a target range of 140-180 mg/dL (7. it is clear that management of hospitalized patients with preexisting diabetes requires modification of treatment regimens to compensate for both the decreased caloric intake and the increased physiologic stress. it is very important to maintain near-normal blood glucose levels in patients with acute hyperglycemia of illness. These patients should receive sufficient insulin to maintain glucose levels around 100 mg/dL. the ADA suggests that reasonable targets are premeal blood glucose levels lower than 140 mg/dL (7. the ACP guidelines depart from the 2009 AACE/ADA consensus statement on inpatient glycemic control. [33] More stringent goals. [96] Algorithms are available for insulin infusions. stroke. In the absence of clear evidence for specific blood glucose goals in non–critically ill patients. regular insulin has been replaced by rapid-acting insulin (eg. a preprandial insulin dose can be added. or the need for renal replacement therapy. The emergency physician caring for patients with diabetes who require emergency surgery must notify the surgeon and the anesthesiologist of the patient’s condition.[99] Nevertheless.

(See Diabetes Mellitus and Pregnancy. their rate of developing diabetes increased to a rate similar to that seen in the placebo group. After the operation. fewer large-for-gestational-age infants. These include the Diabetes Prevention Trial–Type 1 (DPT-1) in the United States and the European Nicotinamide Diabetes Intervention Trial (ENDIT) in Europe and North America. repeat the preoperative dose of insulin when the patient recovers from the anesthesia.88 mmol/L). Glycemic Control During Pregnancy Because pregnant patients with type 1 DM are at risk for multiple poor maternal and fetal outcomes. injection of one third to one half of the total daily dose as NPH insulin or 80% of the dose as glargine or detemir insulin before surgery is often effective. treatment with a target antigen can modulate aggressive autoimmunity. retinopathy. good glycemic control before and during pregnancy.or 3-dose insulin schedule.2 g/m 2. obesity. 5. a trial of antigen-based immunotherapy with 2 or 3 doses of glutamic acid decarboxylase formulated with aluminum hydroxide (GAD-alum) vaccine for 4-12 weeks in patients with newly diagnosed type 1 DM did not alter the course of loss of insulin secretion during the first year. Both trials have reported disappointing results.[101] This finding suggests that better tools are needed to improve glycemic control in patients with type 1 DM. lispro. aspart. The infusion is continued through recovery. and administer regular insulin every 4-6 hours as needed to maintain the plasma glucose level in the range of 100-250 mg/dL (ie.to 4-hour intervals thereafter. These patients should be referred to obstetricians specializing in high-risk pregnancies. plus annual 4-day continuous IV infusions of insulin. Subjects in the treatment arm received oral modified-release nicotinamide in a dose of 1. but once therapy was stopped. parenteral insulin failed to delay or prevent type 1 DM in subjects at elevated risk (as indicated by family history and the presence of islet cell antibodies). Prevention Significant improvements in the prediction of type 1 DM have led to several trials of prevention. it is essential to provide these patients with prepregnancy counseling. Unless a change in dosage is indicated. and fewer neonatal care admissions than patients with type 1 DM.to 4-hour intervals. and more frequent congenital anomalies.Perioperative blood glucose management Surgical procedures—including the preoperative emotional stress and the effects of general anesthesia as well as the trauma of the procedure itself—can markedly increase plasma glucose levels and induce DKA in patients with type 1 DM.) High-risk possibilities include exacerbation of existing hypertension. and a complete medical evaluation. depending on the plasma glucose level.9% saline solution or water should be started at a rate of 1 L (50 g glucose) over 6-8 hours (or 125-150 mL/h). or glulisine) should be given if values exceed 140 mg/dL. multiparity. (SeePerioperative Management of the Diabetic Patient. fewer preterm deliveries. Postoperative IV insulin infusion after major surgical procedures is currently considered the standard of care in most hospitals. In DPT-1. Monitor plasma glucose and ketones at 2. Despite advanced age. an IV infusion containing 5% glucose in either 0. Blood glucose levels should be checked every 2 hours during the surgical procedure. and small doses of regular or rapid-acting insulin (eg.[105] . check plasma glucose levels and assess for a reaction to ketones. nicotinamide (which prevents autoimmune diabetes in animal models) did not prevent or delay the clinical onset of diabetes in people with a first-degree family history of type 1 DM. and social disadvantage. These subjects received low-dose subcutaneous Ultralente insulin twice daily. renal insufficiency. and continue the glucose infusion. Continue until the patient can be switched to oral feedings and a 2. [103] In the ENDIT study.[104] Slowing progress of recent-onset type 1 DM In animal models of autoimmunity. with insulin adjustments depending on the plasma glucose levels obtained in the recovery room and at 2. However. patients with type 2 DM were found to have better glycemic control. Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6-10 units of regular insulin to 1 L of 5% glucose in normal saline or water infused at 150 mL/h on the morning of the operation. At the same time.[102] DPT-1 subjects who received oral insulin experienced considerable delays in the onset of diabetes.) In patients going to surgery who have not received a dose of intermediate-acting insulin that day.55-13.

Short-. Novolin R) . View full drug information Regular insulin (Humulin R. 5-15 minutes. They are usually combined with faster-acting insulins to maximize the benefits of a single injection. teplizumab. Short-acting and rapid-acting insulins are the only types that can be administered intravenously (IV). Human insulin currently is the only species of insulin available in the United States.A phase 3 trial using an anti-CD3 monoclonal antibody. They should also undergo a complete retinal examination by an ophthalmologist at least once a year. [107] Consultations Patients with type 1 DM should be referred to an endocrinologist for multidisciplinary management. Intermediate-acting insulins have a relatively slow onset of action and a relatively long duration of action. and the usual duration of action is 2-4 hours. when combined with faster-acting insulins. Antidiabetics. Insulins Class Summary Rapid-acting insulins are used whenever a rapid onset and short duration are appropriate (eg. The different types of insulin vary with respect to onset and duration of action. rash was almost 3 times more common in treated patients than in those receiving placebo. because of their need for frequent adjustments of premeal insulin doses. 5-15 minutes. and the usual duration of action is 2-4 hours. 5-15 minutes. In patients with type 1 DM. View full drug information Insulin glulisine (Apidra) Insulin glulisine has a rapid onset of action. intermediate-. and long-acting insulins are available. The peak effect occurs within 30-90 minutes. it is less antigenic than the previously used animal-derived varieties. Patients with significant foot involvement should see a podiatrist. short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 DM. View full drug information Insulin aspart (NovoLog) Insulin aspart has a rapid onset of action. However. Rapid-acting insulins are associated with less hypoglycemia than regular insulin. before meals or when the blood glucose level exceeds target and a correction dose is needed). Medication Summary Insulin injected subcutaneously is the first-line treatment of type 1 diabetes mellitus (DM). and the usual duration of action is 2-4 hours. However. Premixed insulin is usually not recommended in type 1 DM patients. The peak effect occurs within 30-90 minutes. which can restrict their use. They are used when a slightly slower onset of action or a greater duration of action is desired. Further studies are needed. they must be used in conjunction with a rapidacting or short-acting insulin given before meals. provide better glucose control for some patients. Insulin glulisine is FDA-approved for use in insulin pumps. View full drug information Insulin lispro (Humalog) Insulin lispro has a rapid onset of action. Those patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist. The peak effect occurs within 30-90 minutes. Long-acting insulins have a very long duration of action and. suggesting that T-cell activation lessens over time.[106] A study by Orban et al found that costimulation modulation of activated T cells with abatacept slowed reduction in beta-cell function over a 2-year period of administration. this effect was reduced after 6 months of treatment. Insulin aspart is approved by the US Food and Drug Administration (FDA) for use in insulin pumps. found an encouraging trend toward preservation of beta-cell function with reduction in daily insulin requirements in patients with recently diagnosed type 1 DM. Currently. Premixed insulins contain a fixed ratio of rapid-acting insulins with longer-acting insulin.

2 hours (high dose). Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract. View full drug information Glucagon (GlucaGen) Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). Insulin aspart is absorbed more rapidly than regular human insulin. Its peak effect occurs within 2-4 hours. Hypoglycemia Antidotes Class Summary Pancreatic alpha cells of the islets of Langerhans produce glucagon. and regulates food intake through centrally mediated appetite modulation. The drug inhibits lipolysis in adipocytes. and enhances protein synthesis. decreasing postprandial glucagon release. . which is a rapid-onset insulin. View full drug information Insulin aspart protamine/insulin aspart (NovoLog 70/30) The combination of insulin aspart protamine with insulin aspart includes 30% rapid-onset insulin (ie. Novolin 70/30 and Humulin 70/30) are available. Antidiabetics. View full drug information Insulin lispro protamine/insulin lispro (Humalog 75/25) The combination of insulin lispro protamine with insulin lispro includes 75% insulin lispro protamine. It has no pronounced peaks of action. 0. it also inhibits glucose output from the liver. Amylinomimetics Class Summary These amylinomimetic agents elicit endogenous amylin effects by delaying gastric emptying. Insulin detemir binds to insulin receptors and lowers blood glucose levels by facilitating cellular uptake of glucose into skeletal muscle and fat. and modulating appetite. which has a prolonged duration of action. View full drug information Insulin detemir (Levemir) Insulin detemir is indicated for once-daily or twice-daily subcutaneous administration in individuals with type 1 DM who require long-acting basal insulin for hyperglycemia control.5 hour. It slows gastric emptying. a naturally occurring hormone made in pancreatic beta cells that is deficient in people with type 1 DM.Regular insulin has a short onset of action. suppresses postprandial glucagon secretion. Its primary activity is regulation of glucose metabolism. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular human insulin (eg. because a small amount of insulin is gradually released at a constant rate over 24 hours.7 hours (low dose) to 23. View full drug information Pramlintide acetate (Symlin) Pramlintide acetate is a synthetic analogue of human amylin. and its usual duration of action is 5-8 hours. insulin aspart protamine). Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis. View full drug information Insulin glargine (Lantus) Insulin glargine stimulates proper utilization of glucose by the cells and reduces blood sugar levels. and insulin aspart protamine has a prolonged absorption profile after injection. insulin aspart) and 70% intermediate-acting insulin (ie. a polypeptide hormone. Its duration of action ranges from 5. A possible association of insulin glargine with an increased risk of cancer has been reported. It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. inhibits proteolysis. and 25% insulin lispro. The prolonged action results from slow systemic absorption of detemir molecules from the injection site. but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use.

which appears after the age of 35 and is frequently associated with other autoimmune endocrine diseases. Others genetics associations are weaker and depend on the population studied. which permits unrestricted use. Department of Medicine of Federal University of São Paulo. but it is influenced by genetic and metabolic factors. Glycemic intensive control and immunotherapeutic agents may preserve beta-cell function in newly diagnosed patients with T1ADM. . Type 1 diabetes classification Nowadays. we do not have precise methods to assess the beta cell mass. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.0). A combination of precipitating events may occur at the beginning of the disease. provided the original work is properly cited. idiopathic and double. IA2 and Znt8. They correspond to T1DM of the autoimmune polyglandular syndrome type 1A [3] and of IPEX syndrome (Immune Dysfunction. GAD65. Polyendocrinopathy. we may subdivide T1DM in three groups from the etiological point of view: autoimmune. Abstract Type 1A diabetes mellitus (T1ADM) is a progressive autoimmune disease mediated by T lymphocytes with destruction of beta cells. There is a silent loss of immune-mediated beta cells mass which velocity has an inverse relation with the age. which are important for glycemic stability and for the prevention of chronic complications of this disease. Department of Medicine of State University of Rio de Janeiro. Brazil For all author emails. The other subtype of this group is the latent autoimmune diabetes in adults (LADA)[2]. GB. licensee BioMed Central Ltd. We can predict the development of the disease primarily through the determination of four biochemically islet auto antibodies against antigens like insulin.dmsjournal. Up to now. 1:25 doi:10.com/content/1/1/25 Received: Accepted: Published: 10 July 2009 4 December 2009 4 December 2009 © 2009 Dib and Gomes. distribution.dib@unifesp. The goal of secondary disease prevention is halt the autoimmune attack on beta cells by redirecting or dampening the immune system. X-linked) [4].Etiopathogenesis of type 1 diabetes mellitus: prognostic factors for the evolution of residual β cell function Sergio A Dib1* and Marilia B Gomes2  *Corresponding author: Sergio A Dib sergio. please log on. Review We are presently going through a revaluation of the knowledge acquired in the last decades regarding the etiopathogenesis of type 1 diabetes mellitus (T1DM). Diabetology & Metabolic Syndrome 2009. The studies about its genetic susceptibility show strong association with class II antigens of the HLA system (particularly DQ). Enteropathy.1186/1758-5996-1-25 The electronic version of this article is the complete one and can be found online at:http://www. It is remains one of the foremost therapeutic goals in the T1ADM.org/licenses/by/2. It may be assessed through C-peptide values. Brazil Diabetes Division. corresponding to approximately 80-90% of all T1DM cases [1]. SP. "in vivo" or "ex-vivo". The third subtype includes called "monogenic" T1DM. Beta cell destruction is chronically progressive but at clinical diagnosis of the disease a reserve of these cells still functioning. The autoimmune group is represented by: type 1A. which is polygenic and it is the most frequent type of this disease. This article will summarize the etiopathogenesis mechanisms of this disease and the factors can influence on residual C-peptide and the strategies to it preservation.br Author Affiliations 1 2 Endocrinology Division. and reproduction in any medium.

the heterodimers HLA-DQ (alpha chains denominated DQA1 and beta chains. DRB1*1501 are negatively associated with type 1 A diabetes and are related in less than 1% of the majority of populations studied. Such syndrome. a large part of autoimmune regulation occurs at the thymus level. while DR3 as a recessive feature. Such locus codifies important proteins at the presentation and recognition of antigens by the immune system. as the presence of DQB1*0602 protects from diabetes. including Asians. most of the times. associated with the Autoimmune Polyglandular Syndrome Type 1 [10]. The most frequent manifestations of this syndrome are mucocutaneous candidiasis. It is interesting that in such patients. is not hyperglycemia. located in chromosome 11p15. DQB1) codified by the alleles DQA1*0301. Nevertheless. observed in Caucasians. In Caucasians. dyslipidemia) diabetes characteristics in the same individual [7]. the polygenic group type 1 A diabetes is the most frequent form of T1DM and it is accountable for approximately 90% of these cases. On the other hand. DQA1*0102. also as APECED (Autoimmune Polyendocrinopathy. ankylosing spondylitis and Hashimoto's thyroiditis. with rare exceptions. IIDM3. To date. they receive information about antigens to which they must react or not. but the autoimmune component is not detected [5]. However. the latest studies in populations of the Northeast [14] and Southeast[15] show higher frequency of antigens DRB1*03 and DRB1*04 in type 1 diabetes than in normal controls. also called idiopathic. presents the impairment of beta and alpha cells of the pancreatic islet and no autoimmune etiology [6]. the susceptibility for type 1 A diabetes associated with the genes of the HLA system may involve other alleles. so that when peripheral lymphocytes go through the thymus.Type 1B. For nearly 20 years. The latest studies using molecular biology techniques have demonstrated that the locus HLA-DQ is more narrowly associated with the susceptibility to type 1 A diabetes. 1. Bell et al[16] found out that variations in the number of nucleotide elements repeated (Variable Number of Tanden Repeats . A change in this gen results in autoimmune reactions to different antigens expressed in peripheral tissues due to a failure in regulating the presentation of such antigens in the thymus for its recognition as "self-antigens".DR4 and 55 . etc. even in the concomitance of alleles of the HLA system of high risk of the disease. but heterogeneous disease. celiac disease. enteropathy. are more related to the presence of enteropathy [3]. China and Korea. DQB1*0302 and DQA1*0501. Most of these data come from Caucasian populations from Europe and North-America.5 or double (type 1 plus type 2) diabetes has been proposed when we have the type 1A (autoimmunity) plus type 2 (obesity. Type 1 diabetes is observed in 13-20% of these patients. followed by homozygote DR4 or DR3. particularly molecules DR.regs) on this process is involved [9]. The data suggest that DR4 may offer this susceptibility in a dominant manner. Genotype DR3/DR4 offers higher risk for type 1 A diabetes. DQ and DP in chromosome 6p21. In these studies. In this review.5 and contributes with approximately 10% of this disease susceptibility. A failure of regulatory T cells (T. with a synergic mode of action. Another 1B subtype is the fulminant diabetes most described in Asian peoples. we will cover only autoimmune type 1A diabetes. Finally. because the first clinical manifestation. that in classical type 1A diabetes indicate pancreatic β cell lesion. approximately 95% of patients have class II antigens HLADR3 or . Genetic Predisposition Type 1 A diabetes is considered by some authors a polygenic and by others. dependent on exogenous insulin. located in chromosome 21. Such locis are denominated IDDM1. One of the subtypes of type 1A diabetes is the "monogenic" diabetes. Such cells are affected by a process involving specific cellular and humoral autoimmunity mechanisms against their antigens. Particularly in Brazil. This protection seems to have a dominant effect. In other ethnical groups. several loci in different chromosomes are related to the genetic susceptibility of this type of diabetes [12]. before to the first acute metabolic decompensation. its complete natural history has not been fully clarified yet. respectively.Candidiasis-Ectodermal Dystrophy) is more frequent in children and pre-puberal individuals and is associated with the mutation of the autoimmune regulatory gene (AIRE). As it is already known. an oligogenic. growth deficiency and early death in such children [4]. children present mutation in the gene which codifies the express of FOX-P3 in CD4+ and CD25+ cells. It is denominated IDDM2. One of the mechanisms . it is characterized by the onset of a different type of diabetes. insulin resistance. the selection criteria fail and these patients start to react against antigens to which they should not react. DQB1*0201 have the strongest association with type 1 A diabetes and are respectively not balanced at the connection to alleles HLADR4 and DR3. The most important genes are located inside the major complex of histocompatibilty (MHC) in the region of class II of the HLA system.15].VNTR) of the 5' portion of the insulin gene were associated with the development of type 1 A diabetes.31 [13]. that it is important to the regulation of autoimmune mechanisms [3].60% of them are heterozygotes DR3/DR4. Such studies have been replicated and have demonstrated that the important locus is clearly limited to the insulin gene [17]. mainly Japan. has all the clinical features of type 1A. Afro-Americans and Mexican-Americans. One of the genes related to the protection is DRB1*11 in both Brazilian populations studied [14. These are called IDDM1 and are responsible for about 45% of the genetic susceptibility of type 1 A diabetes. among four common DR2 haplotypes. such as multiple sclerosis. The second "monogenic" subtype of type 1 A diabetes is a rare type of diabetes which occurs in children and is associated with changes in genes located in chromosome X [11]. Such changes lead to a disability of generating regulatory T cells and the development of early autoimmunity against several organs. In this type of diabetes. Type 1 A diabetes Type 1 A diabetes is a chronic inflammatory disease which leads to selective destruction of beta cells in pancreatic islets [8]. the denomination of mixed. characterized by a short clinical history. A longer group of repetitions was associated with a reduced risk of diabetes. DQB1*0602. When the individual suffers change in the AIRE gene. even though type 1 A diabetes is one of the most widely studied autoimmune diseases over the last decades. They are generally referred by other specialists. Many of these loci are also related to the predisposition to other autoimmune diseases. the glutamic acid decarboxylase antibodies (GADA). Addison's Disease and hypoparathyroidism [3]. IDDM2. Thus.

Another locus associated with a modulation of the immune response and with type 1 A diabetes. surpassing susceptibility. Recent data from literature have emphasized the importance of the intestinal barrier. these cells have acquiescence and may to keep the levels of C-peptide secretion for a additional period of time. diet components and psychosocial factors are being assessed in a longitudinal study with children since their first months of life up to the age of 15 (TEDDY study). such as viruses. Several environmental factors have already been associated with the development of type 1 A diabetes. but it is also glycotoxic. thus proteomics may be useful to describe the protein profile expression of cells and of their diabetic phenotype. the immune system and environmental factors in individuals genetically susceptible. where a group is related to susceptibility and another is related to a significant protection and. When proper glycemic control is instituted at the beginning of the disease. The gastrointestinal tract is likely the main system through which non-self antigens gain access. gene rearrangements by chance (e. Environmental Factors The incidence of type 1A diabetes has increased dramatically in many countries during the past four decades. necessary to establish self-tolerance during body growth and development. it is likely that some factors in the environment are changing. manipulation of the nutritional pattern of islets and of transplanted cells. up to now. data indicate that beta cells participate actively in their self-destruction during the development of T1DM. The remaining 50% probably occur due to additional inherited polymorphisms/mutations.21] have recently reported a novel protein.htm webcite. there are endless antigens which are activating the process. i.edu/TEDDY/index. vaccinations.e. Such protein may be assessed in the plasma and studies demonstrate that its serum concentration is increased in patients with type 1 A diabetes in relation to their relatives and to controls[22]. to predict levels of susceptibility and to monitor the disease progression and its response to therapies. bioindicators able to diagnose diseases in initial stage. It is supposed that. many times. Though these studies have revealed a complex and detailed scene of the protein expression profiles of these cells. IDDM1 and IDDM2 compete to approximately 50% of the family aggregation of type1 A diabetes. Considering the above mentioned. Autoimmune Process The selective destruction of beta cells of pancreatic islets in T1ADM is the result of a complex interrelation among beta cells. The influence of several environmental factors in the development of type 1 A diabetes.. the mechanisms which start the changes in this interrelation and lead to the development of T1DM are not yet fully clarified and. new-born weight).. which allows the passage of several antigens. the greater the beta cell lesion. Likewise. but at the end. would be characterized by a succession of relapses and remissions with interrelation between regulatory T cells (T-regs) and effectors cells. This proposal covers a new concept for the natural history of T1ADM which. related to a protein 4 of cytotoxic T lymphocytes (CTLA-4)[19]. suggesting that a possible link between genetic susceptibility. In early childhood. In this sense. through biologic samples. individuals produce different proteins. Proteins are involved in most cellular processes and the cumulative expression of certain proteins may reflect the specific activities of these cells. increased intestinal permeability. that modulates intestinal permeability by disassembling the intercellular tight junctions. In summary.usf. . there are no specific genes or proteins for most of the cases of T1ADM. Ultimately. their functional implications have not been clarified yet. Up to now. According to the suggestion of a recent article[24] in the beginning of the autoimmune process against pancreatic beta cells. Proteomics has been applied in studies of beta cell differentiation. antigens with the expression of different epitopes which were not detected initially. and regeneration of beta cells up to the moment when the percentage of beta cell destruction would no longer allow a proper insulin secretion. Fasano A et al [20. they will trigger an immune response which might result in a autoimmune process. which will reactivate the process. but there are serial reactions which favor the transition of dynamic stability of healthy beta cells to dynamic instability and eventual destruction of beta cells [23]. contributing to the process perpetuation. However. which is an entry door for viruses and proteins. we may infer that the T1DM prevention is difficult. it is important to emphasize that genes may have unique behavior among autoimmune diseases.g. Within this context. infections. the more antigens are expressed. in some populations. we may have three or more antigens. and when these antigens are presented to T lymphocytes by the antigen presenting cells (macrophages). is IDDM12 in chromosome 2q33. which is a stimulus metabolic factor to the insulin secretion. it seems that there is not any isolated protein responsible for the disease development. in its preclinical stage. such as birth-related factors (type of birth. People interested in such study may enroll through the electronic address http://Teddy. resulting in the expression of hyperglycemia. In a third place of this disease prediction is a lymphocyte specific phosphatase (PTPN22) gene[18]. in the autoimmune process evolution. rearrangements in T cell receptors) or to environmental factors. environmental exposure to non-self antigens and development of autoimmune disease. certain constituents of diet and preservatives food. such barrier is immature. The lack of 100% concordance in identical twins could be due to somatic mutations.suggested for the susceptibility and resistance associated with IDDM2 is related to the influence of VNTR in the transcription of insulin in the thymus. exposure of islets to cytokines. zonulin. the study of proteomics and metabolomics is an area which seeks the development of methods able to characterize. Studies using recent techniques for identifying genes and the formation of cooperative study groups must increase the speed of appearance of susceptibility genes for type 1 A diabetes. it becomes important to mention the low capacity of regeneration/neogenesis of beta cells mainly when they are exposed to hyperglycemia.epi.

Th2 (humoral immune response). it was possible to characterize three evolution profiles: 1. this patient evolution is an exception. One report [40]. while approximately 10% of patients who develop T1ADM have antibodies reacting against IA2. persisting weakly positive (± 2 U/ml) and anti-insulin and IA2 autoantibodies which were initially positive became negative later. In such individuals. it was possible to increase the autoimmune T1DM diagnosis from 80-85% to 98. insulin and pro-insulin are the only specific antigens of beta cells (all the other antigens described can also to be founded at other cells). . Four years after de clinical diagnosis the reevaluation of this patient showed an improvement in the C-peptide secretion and normal glucose tolerance. 2.After presenting the antigen by the macrophages to T lymphocytes. This was confirmed by the publication of T1DM cases in individuals who did not produce antibodies through congenital agamaglobulinemia [25. anti-insulin and anti-IA2). to some degree. So far. The use of vaccines constituted from fragments 9-23 of the insulin B chain. shown a patient (male. glutamic acid decarboxylase antibodies (GADA). Nowadays. anti-tyrosine-phosphatase (IA2/ICA512) antibodies and anti-insulin autoantibodies. The analysis concerning the evolution profiles of individuals with multiple anti-islet autoantibodies was assessed in the DAISY study [39]. Thus. 13 years old) with a classical T1DM(low C-peptide secretion. has been tested in experimental T1ADM models to verify their immunomodulate power in the natural history of the disease [37].g. Nowadays. It is important to confirm these antibodies at least two times in three different occasions. 0201. that was initially treated with insulin but it was discontinued after eleven months. but a high percentage of those who show another anti-islet cell antibody evolve to T1ADM after 10 years of age. Such antigen was characterized through the microarray technique and showed specificity of approximately 80% and high clonal pancreatic frequency. The insulin molecule epitope recognized by the liquid phase essays seems to be homogeneous [31].26]. approximately 60% of T1DM with less than 6 months of clinical diagnosis present residual C-peptide secretion (baseline > 0. peripancreatic T lymphocytes play an important role in the transmission of local reactions in islets to systemic cells [27].Non-diabetics (individuals persistently positive for autoantibodies who do not develop the disease) and 3. T1DM is considered a T. In our experience.Positive transitory (individuals transitorily positive for antibodies who do not develop the disease). the IA-2β essay is unnecessary. Antigens ICA512 (IA-2) and later IA-2 β (fogrin-phosphatase of insulinoma granules) were isolated independently by different investigators [28-30].2%. one of the therapeutic goals in T1DM is the preservation of the residual C-peptide secretion that is detected in a significant percentage of patients at diagnosis and which potentially may influence the clinical course of the disease. values above 2000 nU/ml are almost exclusively present in children who develop this disease before the age of 5 and less than 50% of the individuals who develop T1ADM after the age of 15 years old may have these autoantibodies. At the same time.reg cells). 0401[33]. The immunological assessment showed that GADA were initially positive. as recently performed with GAD-65. genetically determined and associated with DR4 [33]. studies has been shown that this epitope is between the positions 23 and 30 in the insulin beta chain. T lymphocytes of Th1 response with Th17 which do not obey the regulation of T. The presence of autoimmunity against the pancreatic islets is considered when the individual has one or more antibodies persistent for at least 3 to 6 months. a few years ago. it is also known that during the pathogenetic process. but not IA-2β. demonstrating the important role of these cells in the process. Such antibody value is. The last of antigens described in the autoimmune process against pancreatic beta cells was one of the bivalent cation (zinc) transporters [38].Pre-diabetics (individuals persistently positive for multiple autoantibodies who develop the disease).reg disease. Anti-insulin antibody values correlate inversely with the age when T1ADM develops. the Th2 response was absent and thus there was no antibody production. The anti-insulin antibodies react with conformational molecule epitope (not against chains A or B separately) [32]. Among T1ADM relatives children who are persistently positive only to anti-insulin antibodies rarely develop clinical T1DM [33]. However. both by its decrease or by its function alteration (e. The anti-islet antibodies circulating also express the inflammatory lesion taking place in the pancreas. In T1ADM the most studies autoantibodies are classical anti-islet (evaluated through the indirect immunofluorescence method and using as substract cry preserved human pancreas sections). In this study where children are assessed consecutively since birth regarding these autoantibodies and glucose tolerance. Usually. 4 developed T1ADM below the age of 3 years old [35]. When this new antibody were analyzed together the antibodies previously described (GADA. the lymphocyte response to proinsulin showed elevated concentration of interleukin 10. antiinsulin antibodies are the first to appear in children who develop T1DM [34-36]. At the same time. There are data suggesting that the anti-insulin antibody value among individuals with positive ICA is inversally related to time of their evolution to the clinical disease [34]. Preservation of the residual C-peptide secretion Today. but the concentration was low (± 10 U/ml). Almost all antibodies which react with IA-2β also react with IA-2. Th17 (cellular immune response potentialization) and T-regs (which take the control of immune cellular reactions). Thus. following the start of glycemic instability. which is one of the protective interleukins for the autoimmune T1DM process and trophy for Treg cells. DQA1*0102.0501). during the routine.. The beta cell recovery function after the clinical diagnosis of the disease is extremely rare.0301. DQ8 [32]. at least four types of answer may be induced in the immune system: Th1 (cellular immune response). mainly in children below 1 year of age. From five children with early (around 8 months old) high anti-insulin antibodies titers. Adolescents and adults present low concentration of anti-insulin antibodies. as in most cases there is a progressive decline in C-peptide secretion during the natural history of this disease.6 ng/ml) but which presents a significant drop after 2 to 3 three years of diagnosis and only 3% of individuals over 5 years of diagnosis present positive C-peptide secretion. Essays for anti-insulin antibodies have more specificity for the disease than the ones against proinsulin. DQB1*0303.

Patients who do not have these genes would keep a better beta cell function and higher C-peptide secretion [41]. Two other genetic factors related to residual C-peptide secretion are PTPN-P22 (protein tyrosine phosphatase non-receptor type 2[42] and one of the vitamin D receptor polymorphism (Fok1)[43]. The residual C-peptide secretion follow-up on the first 12 months of the disease in T1DM patients showed that it decreased in patients who had alterations in such gene [42]. where it was possible to assess this factor in a pancreas sample from an 89-year-old patient. after T1ADM diagnosis. it has been discussed if such effect was obtained through the removal of glycotoxicity or through the insulin immunomodulate effect. stage II which used a heat-shock protein peptide (Diapep27) [52]. it was observed that even through both groups present the same residual C-peptide secretion at diagnosis and after the 1st followup year. Regarding immunomodulators. It is classically known that children and adolescents (0 to 17 years old) present at T1DM diagnosis a lower C-peptide response to a mixed meal than adults [45]. This is easily verified when we compare T1DM in children and LADA [49]. At the same way. It was demonstrated through this study.001) and negative with the disease duration (r = -0. This last effect could be demonstrated when a residual insulin secretion was compared in two groups of T1DM with the same clinical features during the first two years from clinical diagnosis. we evaluated nicotinamide in a double blind study during the 1styear of T1DM diagnosis. p = 0. In a recent case report. In this study although the fasting C-peptide did not change. Duplicating beta cells were detected in the pancreatic tissue through immunohistochemical analysis and potassium channel indicators [47]. T1DM (GADA. apart from the autoimmune insult. However. depends on genetic factors. In this way. recently diagnosed T1DM patients received 20 μg GAD-alum on the 1stand 30th days of the protocol. Such case study shows that a potential pancreatic beta cell regeneration is a possibility to be considered while we are discussing the residual C-peptide secretion in T1DM. known as LYP. In this study.029) of our population. One of the first these clinical trials was a double-blind study. A24 +DQA1+03+ and DR9+ have been associated to a higher velocity of C-peptide levels decrease. PTPN22 gene codifies a lymphoid specific phosphatase synthesis. while in the placebo group.652. At T1DM diagnosis. which is important to inhibit T lymphocites activation. which also cooperates to decrease C-peptide secretion. Another study in this way used monoclonal anti-CD3 [53] antibody. p < 0. These last actions should be related to a higher stability of glycemia in these individuals and to possible actions which would be intermediated through the insulin receptor or a specific C-peptide receptor. FOK-1. where we verified a positive correlation with the age of the patient at clinical diagnosis (r = 0. we assess the relation of the frequency of one of vitamin D polymorphism receptor. However. which was also able to cooperate to C-peptide preservation during the 1st year of diagnosis. that the fasting C-peptide was significantly higher than the placebo group on the 10 th and 30th month of the study. there are recent literature data which demonstrates that. the number of anti-islet antibodies and the residual C-peptide secretion. A change in the LYP function leads to an alteration in regulatory T cells CD4+CD25+. the dropping speed after diagnosis is similar in young patients [46]. there was a progressive reduction in the fasting-C peptide since the 1st month of diagnosis. disease duration as the exposure to hyperglycemia time are also important to the maintenance of residual C-peptide secretion. Since a few years ago. despite this initially higher C-peptide reserve in adults. in a group of T1DM with 7 years average period of diagnosis and we verified that the patients who had this polymorphism presented lower residual C-peptide secretion [44].Several studies have been demonstrated that residual C-peptide secretion. Regarding genetic factors. some studies have been conducted using as immunomodulators the antigens involved in the autoimmune process against beta cells. submitted to surgery to neo pancreatic duct.001) and with the HbA1c value (r = -0. apart from patients' age. In this study. we did not see any differences between patients who used this vitamin and placebo [51]. the first ones studied were from the HLA system.176. C-peptide receptor and protein kinase C (PKC) and MAPK and nuclear transcription factors [58]. making the system less powerful to suppress immune response against autoantigens. Such "hormone" would supposedly act through G protein. The secondary prevention of T1DM has acquired increasing importance in the last few years due to the insufficiency of the latest large studies [54. Similar data we found in a univariated analysis study (with fasting C-peptide as depending variable) on a T1DM group. Among unconventional actions of this vitamin is its immunomodulating function [43].55] for primary prevention and to the positive effect of the C-peptide residual secretion to prevent hypoglycemia[56] and the prevention of diabetic microangiopathy (nephropathy and neuropathy)[57]. circulatory and neural clinical actions have been related to the C-peptide [59]. intensive insulin therapy and immunomodulators drugs may be useful in this direction. one submitted to intensive insulin therapy and other under conventional therapy [50]. Another widely discussed aspect in literature is the ability of pancreatic beta cells to regenerate. The most recent study for the denominated "secondary prevention of T1DM" used vaccine with GAD-65[54].270. . Among these. It was demonstrated that the group which received this vaccine presented significantly higher residual C-peptide secretion from the 7thmonth and this result was until the end of the study (10 th month). the patient's age at the diabetes diagnosis. beta cells are being submitted to hyperglycemia itself by the glycotoxic effect. by the end of the 2nd year it was significantly higher in the intensive therapy group. So it was demonstrated that. p = 0. In this study recently diagnosed T1DM patients received this peptide at their clinical diagnosis. The number of anti-islet auto-antibodies during the pre-diabetic stage and at diagnosis of T1DM shown a inverse relation with the residual beta cell [48]. for patients who received this vaccine up to 6 months after clinical diagnosis. and 1 to 6 months later. Renal. IA2 positive and lower fasting C-peptide) of recent diagnosis.

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