Pediatric Diabetes 2009: 10(Suppl. 12): 17–32 doi: 10.1111/j.1399-5448.2009.00584.

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© 2009 John Wiley & Sons A/S

Pediatric Diabetes

ISPAD Clinical Practice Consensus Guidelines 2009 Compendium

Type 2 diabetes in children and adolescents
Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P, Klingensmith, G Type 2 diabetes in the child and adolescent. Pediatric Diabetes 2009: 10 (Suppl. 12): 17–32.
Corresponding author: Professor Emeritus Arlen L Rosenbloom Division of Endocrinology Department of Pediatrics, University of Florida College of Medicine, 1701 SW 16th Avenue Gainesville, FL 32608 USA. e-mail: rosenal@peds.ufl.edu Conflicts of interest: The authors have declared no conflicts of interest. Editors of the ISPAD Clinical Practice Consensus Guidelines 2009 Compendium: Ragnar Hanas, Kim Donaghue, Georgeanna Klingensmith and Peter Swift.
This article is a chapter in the ISPAD Clinical Practice Consensus Guidelines 2009 Compendium. The complete set of guidelines can be found at www.ispad.org. The evidence grading system used in the ISPAD Guidelines is the same as that used by the American Diabetes Association. See page 2 (the Introduction in Pediatric Diabetes 2009; 10 (Suppl. 12): 1–2).

Arlen L. Rosenblooma , Janet H. Silversteinb , Shin Amemiyac , Phil Zeitlerd and Georgeanna J Klingensmithe
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Division of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; c Division of Endocrinology, Department of Pediatrics, Saitama Medical University, Saitama, Japan; d Division of Endocrinology, Department of Pediatrics, The Children’s Hospital, University of Colorado Denver, Aurora, CO, USA; e Department of Pediatrics, The Children’s Hospital and Barbara Davis Center, University of Colorado Denver, Aurora, CO, USA.

Introduction
Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world (1–17). Because of the relatively recent recognition of the problem in this age group, many children with new onset T2DM may be misclassified as having T1DM. Conversely, as the population becomes heavier, overweight adolescents with autoimmune diabetes may be misdiagnosed as having T2DM. T2DM is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis, making normalization of blood glucose levels and diagnosis and treatment of hypertension and dyslipidemia important (18).

non-alcoholic fatty liver disease (NAFLD)] (20). Insulin secretion depends on disease status and duration, and can vary from delayed but markedly elevated in response to a glucose challenge, to absolutely diminished (19). Adults with symptoms have 50% reduction at the time of diagnosis, and may become insulin dependent within a few years (21). T2DM occurs: • in youth most often during the second decade of life, with a mean age of diagnosis of ∼13.5 years. This coincides with the peak of physiologic pubertal insulin resistance, which may lead to onset of overt diabetes in previously compensated adolescents. • in all races, but at a much greater prevalence in those of non-white European descent, e.g. those of black African descent, native North American, Hispanic (especially Mexican)-American, Asian, South Asian (Indian Peninsula), and Native Pacific islanders. The SEARCH for Diabetes in Youth population-based study found the proportion of physician diagnosed T2DM among 10–19-year-olds to vary greatly by ethnicity in the US: 6% for non-Hispanic whites, 22% for Hispanics, 33% for blacks, 40% for Asians/Pacific Islanders, and 76% for Native Americans (8). In Hong Kong > 90% of young onset diabetes is

Definition and classification of non-T1DM (non-immune mediated)
Type 2 diabetes (T2DM). T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance (19). Thus, T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism,

Update of guidelines previously published in Pediatric Diabetes 2008; 9: 512–526.

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half of those with T2DM had normal weight (< 120% ideal for height) (12). 30). It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells (26). in some asymptomatic individuals in high-risk populations during medical.Rosenbloom et al T2DM (10). in Taiwan 50% (11) and nearly 60% in Japan (Ogawa et al. resulting in more rapid development of insulin dependence. • • Atypical diabetes mellitus or ‘‘Flatbush’’ diabetes (32. • ADM is not associated with obesity beyond that in the general population and it is not associated with insulin resistance.23). Uncertainties of Classification Distinguishing T2DM from T1DM or monogenic diabetes The clinician is obliged to weigh the evidence in each individual patient to distinguish between T1DM and T2DM. which can be fatal (24. • Antibody positive young adult individuals with the T2DM phenotype are significantly less overweight and younger than antibody negative patients (21. 33) • Atypical diabetes mellitus (ADM) occurs throughout childhood. however. or sports examinations (22. including asymptomatic individuals identified through testing of family members. • the significant number of pediatric patients with T2DM demonstrating ketonuria or ketoacidosis at diagnosis (2). as many as 15–25% of newly diagnosed T1DM (or monogenic diabetes) patients may be obese. The reasons for this conundrum are: • with increasing obesity in childhood. including many who are not receiving insulin one year after diagnosis (27–30). It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. however (26). in the presence of ketosis/ketoacidosis. Monogenic diabetes (formerly referred to as maturity onset diabetes of the young or MODY) For more in depth information see the ISPAD Clinical Consensus Guidelines for Monogenic Diabetes (34). although diabetes control may be poor and ketoacidosis may recur without insulin. • ß-cell function is significantly less in antibody positive individuals. • Ketosis or ketoacidosis is typical at onset. It has only been described in young people of African descent. 31). occasionally with severe dehydration (hyperosmolar hyperglycemic coma. in > 75% of cases in youth in the USA there is a first or second-degree relative with T2DM. Neither the autoimmunity nor the diabetes is latent. hypokalemia) at presentation. one third or more of newly diagnosed patients (24). • Identified in families with multigenerational diabetes. e. but rarely begins past age 40. in youth in the USA and Europe with body mass index (BMI) above 85th percentile for age and sex. ∼30% of T2DM are not obese (17). personal communication). but an abnormal sex ratio (M : F = 1 : 3). In Japan.25) with a sex ratio (male:female) that varies from 1: 4–1:6 in native North Americans to 1:1 in Asians and Libyan Arabs without associated HLA specificities.g. • ADM is not associated with HLA specificities and islet autoimmunity does not occur. • Monogenic diabetes is not associated with obesity beyond that in the general population and it is not associated with insulin resistance • • • • • • Autoimmune T2DM • The pathophysiology of autoimmune ’T2DM’ is unclear. • There is a strong family history in multiple generations with an autosomal dominant pattern of inheritance. school. 27). the most dramatic difference being reported in younger adult patients (25–34 years). Interestingly. Pediatric Diabetes 2009: 10 (Suppl. • Youth and adults in US and Europe who are clinically diagnosed with T2DM are found to have T1DM-associated auto-antibodies in 15–40% of cases. without associated islet cell autoimmunity (see autoimmunity T2DM). usually by 3 years duration (27. in Asian Indian urban children. • The presence of islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults (27. • Hemoglobin (HbA1c) concentrations are significantly higher in young adults with T2DM who are antibody positive compared with those who are antibody negative (27). with illness or pregnancy. insulin is often not required for survival after treatment of acute metabolic deterioration. and half of Taiwanese children with T2DM were not obese (11). 12): 17–32 18 . • Insulin secretion is present but diminished and without long-term deterioration of function. This presentation is responsible for misclassification of T2DM patients as T1DM.

(E). polydipsia. Three ways to diagnose diabetes are possible and each. T2DM and MODY at onset of diabetes and over the first year or so. and unexplained weight loss. • Diabetes is diagnosed when: • A fasting plasma glucose (FPG) is ≥ 7. by any one of the three methods given below. • Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes (E). using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. This overlap is due to the recovery phase of autoimmune-mediated T1DM (the honeymoon) and degree of glucotoxicity/lipotoxicity impairing insulin secretion at the time of testing in both T1DM and T2DM.1 mmol/l (200 mg. • In its most severe form. but are too high to be considered normal. The classic symptoms of diabetes include polyuria. Waiting another day to confirm the hyperglycemia may be dangerous in allowing ketoacidosis or hyperosmolarity to evolve.0 mmol/l (126 mg/dl) or • The post challenge plasma glucose is > 11. The diagnosis of diabetes.1 mmol/L). Diagnosis may require continued observation with fasting and/or 2-h postprandial BG levels and/or an oral glucose tolerance test (OGTT). There are individuals whose glucose levels do not meet the criteria for diabetes. random. coma. in some cases. • An OGTT should not be performed if diabetes can be diagnosed using fasting. Epidemiology. or postprandial criteria. death. as excessive hyperglycemia can result using a fasting OGTT in these circumstances. periodic re-testing should be undertaken until the diagnosis is established or refuted. ketoacidosis or hyperglycemic hyperosmolar state may develop and lead to stupor. should not be based on a single plasma glucose concentration.Type 2 diabetes • T2DM is common in the general adult population. In addition the insulin resistance of obesity raises residual C-peptide levels in obese adolescents with T1DM. Pediatric Diabetes 2009: 10 (Suppl. hyperglycemia detected incidentally or under conditions of acute infective. Such measurements are thus relatively valueless in the acute phase. in the absence of unequivocal hyperglycemia. and in absence of effective treatment. including T2DM. 12): 17–32 19 . circulatory. • IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation. must be confirmed. [The role of C peptide may be more helpful in established diabetes as persistent elevation of C-peptide above the level of normal would be unusual in T1DM after 12–24 months. Diagnostic criteria for diabetes are based on BG measurements and the presence or absence of symptoms (E) (38. • There is considerable overlap in insulin or C-peptide measurements between T1DM. with a random family history of ∼15% or greater in minority populations. treatment is urgent. or • Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl (11. usually presents with characteristic symptoms such as polyuria.39). if ketones are present in the blood or urine. • The diagnosis is usually confirmed quickly in symptomatic individuals by measurement of a marked elevation of the blood glucose level. • If doubt remains. on a subsequent day. In this situation. and weight loss. 36). polydipsia. or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. Diagnosis and Classification of Diabetes (37) Diagnostic criteria for type 2 diabetes in childhood and adolescence. Diagnostic criteria for impaired glucose tolerance and impaired fasting glycemia. traumatic. in association with glycosuria and. while IGT is a dynamic measure of carbohydrate intolerance after a standardized glucose load.] • Casual is defined as any time of day without regard to time since last meal. in the absence of symptoms. ketonuria. reducing the specificity of a positive family history. • positive family history for T2DM is increased for patients with T1DM as much as threefold over the non-diabetic population and T1DM is more frequent in relatives of patients with T2DM (35.dl) • performed as described by the World Health Organization (39). • Diabetes in children. IFG is a measure of disturbed carbohydrate metabolism in the basal state. Diagnosis of type 2 diabetes The criteria and classification of diabetes are presented in greater detail in the ISPAD Clinical Practice Consensus Guidelines: Definition. • In the absence of symptoms or presence of mild symptoms of diabetes. blurring of vision.

• 2-h postload glucose 7. in the absence of diabetes (55).1 mmol/l (140–199 mg/ dl)= IGT. Several events in development may be associated with increased risk for the insulin resistance syndrome.6–6. • FPG 5.6 mmol/L (100 mg/dL)= normal fasting glucose. • FPG ≥ 7. Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth (41) and also at increased risk for premature adrenarche. 42–50). race/ethnicity. and protein metabolism. Hypertension is estimated to account for 35–75% of diabetes complications. While visceral adiposity is important in insulin resistance in adults. Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM. ketosis/ketoacidosis). including effects on 20 .9 mmol/L (100–125 mg/dL)= IFG. which includes obesity (especially abdominal or visceral obesity). (E) Diabetes autoantibody testing also should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss. Diabetes is only one manifestation of the insulin resistance syndrome or the MS (22. (iii) Hypertension. dyslipidemia of the high-triglyceride and/or low-high density lipoprotein type. stage of sexual maturation. • Individuals who meet the criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near-normal glycated hemoglobin levels. and hypertension. lipid. glucose. muscle. In addition.0 mmol/L (126 mg/dL)= provisional diagnosis of diabetes (the diagnosis must be confirmed. insulin resistance (40). and those with IGT may manifest hyperglycemia only when challenged with an OGTT. After the diagnosis of diabetes is established.8 mmol/l (140 mg/dl)= normal glucose tolerance. Other associations include: (i) Obesity: Obesity has deleterious associations with morbidity and cardiovascular risk independent of effects related to insulin resistance and diabetes (51–54). These include premature adrenarche in girls (pubic hair appearing before the age of 8 years) and being born small for gestational age. and increased small dense LDL particles. Proteinuria and focal segmental glomerular sclerosis have also been reported in African-American adolescents with severe obesity. autoantibody testing should be considered when diagnosing and treating T2DM. Decreased lipoprotein lipase activity. Insulin resistance occurs in most tissues including liver. age. (60. (ii) Nephropathy: Albuminuria (either micro. elevated lipoprotein(a). there is a possible genetic predisposition to hypertension in T2DM related to the associated angiotensin converting enzyme genotype (58). and fat tissue and is influenced by sex. Hypertension in T2DM is due to volume expansion and increased vascular resistance (59) related to reduced (NO)-mediated vasodilatation and increased activity of the renin-angiotensin system. and total adiposity. (iv) Dyslipidemia: Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are the hallmarks of T2DM dyslipidemia. some of whom may have T2DM (E) T2DM and the insulin resistance syndrome Insulin resistance is an impaired response to the physiologic effects of insulin. The corresponding categories for IGT when the OGTT is used are as follows: • 2-h postload glucose < 7. the specific contribution of visceral adiposity to insulin resistance in the pediatric population remains uncertain. • 2-h postload glucose > 11. and on vascular endothelial function.8–11. as described above).Rosenbloom et al • Patients with IFG and/or IGT are now referred to as having ‘pre-diabetes’. Girls with a history of premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS and thus. Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise ‘‘typical’’ T2DM. 12): 17–32 Categories of fasting plasma glucose (FPG) are defined as follows: • FPG < 5. elevated LDL-c. Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (57). both microvascular and macrovascular (56). indicating the relatively high risk for development of diabetes in these patients (38). increased lipoprotein glycation and increased lipoprotein oxidation render the lipoproteins more atherogenic. as described above under ‘Diagnostic criteria for type 2 diabetes’).61) Pediatric Diabetes 2009: 10 (Suppl. • IFG and IGT may be associated with the metabolic syndrome (MS). Additional findings include elevated very low-density lipoprotein (VLDL).or macro-) is present at the time of diagnosis in a substantial number of adolescents with T2DM and prevalence increases with duration of diabetes (24).1 mmol/l (200 mg/dl)= provisional diagnosis of diabetes (the diagnosis must be confirmed with additional testing.

hypertension and albuminuria are more common in type 2 diabetes compared to type 1 diabetes and may be present at diagnosis and should be assessed after blood glucose control has been optimized.Type 2 diabetes (v) Ovarian hyperandrogenism and premature adrenarche (62): PCOS is being increasingly recognized in adolescents as part of the insulin resistance syndrome. Decreasing insulin resistance may improve ovarian function and increase fertility. glycation of vascular proteins. • Confirmed hypertension (BP> 95% for age. repeat lipid profile should be performed in 6 months and dietary intervention to decrease total and saturated fat initiated. 72)(E). Additional health problems related to obesity include Obstructive sleep apnea (OSA) with associated pulmonary hypertension (65). Likewise. • If LDL-C is borderline (2. 71) (B). 64). are increasingly common and associated with progression to cirrhosis (24. gender and height) or albuminuria should be treated with an ACE inhibitor or.100–129 mg/ dl). Comorbidities characteristic of the insulin resistance syndrome are commonly seen at diagnosis or appear early in the course of T2DM and should be tested for sooner than in T1DM. where these disorders are complications of the diabetes rather than comorbid conditions (70. along with oxidative stress. Evaluation for NAFLD should be done at diagnosis and annually thereafter (24)(E). and predictive of cardiovascular events (68) (B) and occurs in obese children relative to their level of obesity and degree of insulin resistance (69) (B). may be present at the time of diagnosis and albuminuria should be evaluated at diagnosis and annually thereafter (55. Dyslipidemia. hypertension may be present at.6 mmol (100 mg/dl) (68). orthopedic problems resulting in diminishing physical activity (66.61) E • Goal is LDL-C < 2.4 mmol. 12): 17–32 21 . or elevated ( 3. (72). 130 mg/dl).6-3. hyperkalemia. Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter. • Either micro. A more complete discussion of testing for complications/co-morbidities is Pediatric Diabetes 2009: 10 (Suppl. major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in nondiabetic women (74). pancreatitis. The aggregation of risk factors for cardiovascular disease in the presence of insulin resistance and diabetes may result in a high risk for coronary events and increased mortality in young adulthood (A) Testing for Co-morbidities and Complications. (a) Side effects are cough. if not tolerated. there is a strong association between level of hyperglycemia and increased risk of macrovascular disease. cholecystitis and pseudotumor cerebri. It is an early sign of increased risk for cardiovascular disease. Defective endothelium dependent vasodilatation is an additional factor accelerating atherosclerosis in T2DM. Hyperglycemia. such as non-alcoholic steatohepatitis.4 mmol. Specific complications are more common in type 2 diabetes and need special attention. In adults. Hypertension and albuminuria. Adolescents with PCOS have ∼40% reduction in insulin-stimulated glucose disposal compared to body composition matched non-hyperandrogenic control subjects (59). In addition. dyslipidemia. • Combination therapy may be required if hypertension or albuminuria does not normalize on single agent treatment (E). Inquiries about puberty. Dyslipidemia is more common in type 2 diabetes and in family members.or macro-albuminuria. presented in the ISPAD Clinical Practice Guidelines for microvascular and macrovascular complications (72). (vii) Systemic inflammation: elevated C-reactive protein. and hypertension are contributors to the acceleration of atherosclerosis in T2DM. (vi) NAFLD: Hepatic steatosis is present in 25–45% of adolescents with T2DM and more advanced forms of NAFLD. or prior to diagnosis of diabetes and each individual should be evaluated at every visit for hypertension. inflammatory cytokines and white blood cell counts in obese adolescents have been associated with increased risk for cardiovascular disease in adults (54). Treatment of comorbidities/complications Additional information is available in the ISPAD Clinical Practice Guidelines on complications. and abnormalities of platelet function and coagulation. menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65)(E). (60.67). headache and impotence (73). an angiotensin receptor blocker (E). Dyslipidemia.61) and should be screened for when metabolic stability is achieved. NAFLD now represents the most common cause of cirrhosis in children and the most common reason for liver transplantation in adults in the US. (60.

2/10 mmol/L) refer to self-monitoring plasma BG values of 90-130 mg/dL (5-7. • Statin therapy has been shown to be safe and effective in children as in adults and should be the first pharmacologic intervention (72) although long term safety data are not available. when parental influence is predominant. HBA1C > 9%.2 mmol/L) fasting or preprandial and peak postprandial values of <180 mg/dL (10 mmol/L). is only needed for those individuals who are overweight and inactive. T2DM in North America and Europe disproportionately affects those with fewer resources. metformin premeal BG 90-130 mg/dL peak postprandial BG <180 Diet and exercise monthly review 3 monthly HbA1c BG >130/180 HbA1c >7% BG <130/180 HbA1c <7% Attempt to wean off insulin Metformin monthly review 3 monthly HbA1c BG >130/180 HbA1c>7% BG <130/180 HbA1c <7% Check compliance consider adding sulfonylurea glitazone DPP-IV inhibitor insulin glargine alone or + meglitinide + amylin + GLP-1 mimetic blood glucose values < or >130/180 (7. the emphasis is on lifestyle modification and secondarily on glucose monitoring and medication. The failure of these family members to control weight and glycemia is common. 22 Pediatric Diabetes 2009: 10 (Suppl. diet & exercise. less educated parents. whereas T2DM occurs typically in adolescence. • Lower socioeconomic status. Only ∼5% of families with a child with T1DM have family experience with the disease. Whereas T1DM is distributed throughout the population proportionate to socioeconomic distribution. OR KETOSIS OR KETOACIDOSIS DIAGNOSIS MILDLY SYMPTOMATIC. less well insured. WITHOUT KETOSIS ASYMPTOMATIC Insulin. This socioeconomic bias has not been described for Asian T2DM.75). SYMPTOMS. Fig. Negative effects of technology. pharmacotherapy is warranted (72). T1DM occurs throughout childhood. The emergence of T2DM in children and adolescents has required that specialists familiar with the management of T1DM in children and adolescents recognize the vast differences between the treatment challenges of these two disorders. e.Rosenbloom et al • If LDL-C remains elevated after 3-6 months of attempting to optimize blood glucose control and diet. with resultant complications in the family members and a feeling of fatalism and resignation in the child. In all youth with T2DM. levels. when peer influence predominates. 12): 17–32 . Special attention should be paid to symptoms associated with muscles and connective tissues. as there is an increased risk of rhabdomyolysis (72. Technological advancements have revolutionized the management of T1DM (insulin purity and delivery systems. while 75% or more of families of the child with T2DM have such experience. Older age. lower income • • GLUCOSE (BG) > 250 MG/DL.g. More family experience. beyond insulin administration and glucose monitoring. Treatment decision tree for type 2 diabetes in children and adolescents. lifestyle modification. blood • • Treatment of T2DM Management differences Between Type 2 and Type 1 Diabetes. Different treatment priorities. 1. In most T1DM.

psychologist and/or social worker (77). • As in any behavioral change. Education in insulin therapy and hypoglycemia may not be required immediately. including individualized counseling for weight reduction. Dietary Management. reduced total and saturated fat intake. together with an economic environment that makes calorically dense food increasingly available. Management Goals. Overall goals • • • • Weight loss Increase in exercise capacity Normalization of glycemia Control of comorbidities. Lifestyle (diet and activity) modification for the entire family and for the patient in an age appropriate manner. have led to the emergence of T2DM in children and complicate its therapy. reading. technological advances in entertainment. a changing and sustainable reward system is essential for success. regardless of the ‘type’ of diabetes. exercise. Referral to a nutritionist/dietitian with knowledge and experience in nutritional management of children with DM is necessary. and physical activity. as suggested by the United Kingdom Prospective Diabetes Study (21). The family should be encouraged to make dietary changes consistent with healthy eating recommendations. Behavioral Change. including guidance about healthy dietary and activity habits Emphasizing healthy rearing patterns related to diet and activity by teaching parental modeling of healthy habits. and psychological needs of youth with T2DM • Education should be provided in a culturally sensitive and age appropriate manner • Because the majority of youth with T2DM are adolescents. preferably as a family unit. in one place. and should be provided to all caregivers (78. and especially diligent attention to comorbidities. Lifestyle change is the corner-stone of treatment of T2DM • The family and child should understand the medical implications of obesity and T2DM. • • Dietary management should include: Initial focus on eliminating sugar-containing soft drinks and juices in large quantities. Pediatric Diabetes 2009: 10 (Suppl. and avoiding using food for reward Recommending that meals should be taken on schedule. and inexpensive. dietary and physical activity changes than is generally required for T1DM. sensitive to family resources.Type 2 diabetes glucose monitoring. See also the ISPAD Clinical Practice Guidelines for diabetes education (76). Complete elimination of these drinks and substituting water. • The patient and family should be trained to monitor the quantity and quality of food. and artificial sweeteners for beverages can result in substantial weight loss and is one of the most important dietary/behavioral changes for successful weight loss. transportation. desirable. The anxiety can be minimized by emphasizing the importance of normalizing blood glucose metabolism using whatever therapy is appropriate to the metabolic circumstances of the specific individual. Reduction in the rate of complications may require more stringent control in insulin resistant T2DM than in T1DM. Initial and on-going education for T2DM will focus on behavioral changes (diet and activity). increased fiber intake. dyslipidemia. diet soft drinks. • Clinicians must have an understanding of the health beliefs and behaviors of the family/community to design an effective behavioral plan. Food and snacks should be served in a plate or bowl and not eaten directly from a box or can. the ISPAD Guidelines for Adolescent Care are appropriate to the education of youth and families with T2DM • The entire family will need education to understand the principles of treatment of T2DM and to understand the critical importance of the lifestyle changes required to manage T2DM • Care providers should acknowledge that the initial uncertainty in the diagnosis i. • The education and treatment team for T2DM ideally should include a nutritionist. Dietary recommendations should be culturally appropriate. • Changes should be made in small achievable increments and with the understanding that these changes need to be permanent. with no other activity (television. • Education in T2DM will place a greater emphasis on behavioral. avoiding overly strict dieting. • Education should be given by team members with special expertise and knowledge of the dietary. type 1 vs type 2. playing). and hepatic steatosis. labor saving devices. including hypertension. nephropathy. in a minority of patients can be confusing and anxiety provoking for the youth and family. Portion control. and increased physical activity (80). Education.e. 79). insulin analogues). In contrast. Patient and family education for youth with type 2 diabetes is as important as it is in type 1 diabetes. More specific dietary recommendations are given in the ISPAD Guidelines for dietary management (81). 12): 17–32 • • • • 23 . studying. eating behavior.

other oral agents are described below with the understanding that some adolescents may benefit from their use. diarrhea. nausea) may occur. Pharmacologic therapy. (ii) HbA1c concentration should be determined at least twice a year and quarterly if insulin is being used or metabolic control is unsatisfactory. Frequency of SMBG should be individualized. or a DPP-IV inhibitor (Fig. Exercise management. may be the most effective initially (82) (A). The first medication used should be metformin. During acute illness or when symptoms of hyper. Exercise management should include: • Developing and encouraging an achievable daily exercise program is essential to breaking the vicious cycle of increased weight-increased torpordecreased activity-increased weight. Pedometers may be motivating to patients and family members. Furthermore. 12): 17–32 24 . weight is either decreased or remains stable. Combination formulations may improve compliance in these older patients. Metformin acts on insulin receptors in liver. Available hypoglycemic agents. such as using stairs instead of elevators. • Encouraging positive reinforcement of minor achievement (e. no or minimal weight gain. 1). walking or bicycling to school and to shop. Frequent follow up to determine success with the dietary and exercise changes is important to the success of the program. • Thiazolidinediones may be used in older adolescents but these are not approved in those under 18 years. more frequent testing should be recommended for adjustment of therapy. 1). Lifestyle change should be continued in addition to pharmacologic therapy (Fig. (i) Self monitoring of blood glucose (SMBG) should be performed regularly. The aim of pharmacologic therapy is to decrease insulin resistance. and fat tissue. • Only metformin and insulin are approved for use in children/adolescents in the majority of countries. and doing house and yard work (E). • Physical activity needs to be promoted as a family. and should be provided to all caregivers. The side effects may be attenuated by the use of extended release formulations. Pediatric Diabetes 2009: 10 (Suppl. such as turning off the TV and decreasing the time spent in computer related activities. Sulfonylureas are approved for use in children in some countries. negotiated and enjoyable exercise prescriptions should be developed for each patient and family that are sensitive to family resources and environment. Patients on insulin or sulfonylureas need to monitor for asymptomatic hypoglycemia (E). These can be eliminated in most patients with slow dosage titration over 3–4 weeks. This should include daily efforts to be physically more active. • Patients at-risk for pregnancy should be counseled on the effects of diabetes and oral agents on conception and fetal development. increase insulin secretion. or to slow postprandial glucose absorption. and LDL-C and triglyceride levels decrease during treatment. No oral agent should be used during pregnancy.or hypoglycemia occur. It has the advantage over sulfonylureas of similar reduction in HbA1c without the risk of hypoglycemia. sulfonylurea. • Hepatic glucose production is reduced by decreasing gluconeogenesis • Insulin stimulated glucose uptake is increased in muscle and fat • An initial anorexic effect may promote weight loss • Long-term use is associated with a 1–2% reduction in HbA1c. including increases in daily activities (E).g. teach them to encourage and praise physical activity. If values rise into the impaired glucose tolerance range. Biguanides. a GLP-1 mimetic. and instructions to always take the medication with food. or insulin alone or in combination with meglitinide. Once glycemic goals have been achieved. amylin. • Educate parents for healthy behavior reinforcement. Approaches aimed primarily at reducing sedentary time. several fasting values a week and daily post prandial values. with a predominant action on the liver. muscle. and include a combination of fasting and postprandial glucose measurements. • Intestinal side effects (transient abdominal pain. Specific. high caloric density food and drink in the home. patients should perform more frequent testing and be in contact with their diabetes care team for advice (E). A family member or friend should be identified who is available to participate in physical activity with the patient. Glycemic Monitoring. Failure of monotherapy with metformin over 3 months indicates the need to add a Glitazone. reduction in high caloric drinks) and avoiding blame for failure. taken after the biggest meal are satisfactory while the values remain within the target range (E). • Maintaining food and activity logs as beneficial for raising awareness of food and activity issues and for monitoring progress.Rosenbloom et al • Limiting availability of high-fat. the reading of labels and control of purchasing.

5–1. was almost as effective as three times a day rapid insulin analog (83). regulation of insulin receptor activity. • The frequent side effect of flatulence makes these agents unacceptable to most adolescents. Metformin should not be given to patients with renal impairment. a single daily injection of insulin glargine. Sulfonylurea and meglitinide/repaglinide (may not be approved for use in those < 18 years) • Increase insulin secretion. and is only approved for use in the US for patients with T1DM and T2DM who are taking insulin) • Amylin is administered by subcutaneous injection before meals. • Liver enzyme elevations were found in ∼1% of those taking the original member of this group. including cell growth. • Side effects include edema. hepatic disease. • In adults with inadequately controlled T2DM from multiple centers in Europe and Australia. Metformin should be temporarily discontinued during a gastrointestinal illness (A). which can be prolonged. • The side effects of insulin are hypoglycemia. This reduces the postprandial rise of plasma glucose. miglitol) reduce the absorption of carbohydrates in the upper small intestine by inhibiting breakdown of oligosaccharides. used for rapid enhancement of insulin secretion. Insulin. Thiazolidinediones are not recommended in combination with insulin because of increased risk for fluid retention with the combination. The newer thiazolidinediones (rosiglitazone and pioglitazone) appear not to have hepatotoxicity in adults. Pediatric Diabetes 2009: 10 (Suppl. thereby delaying absorption in the lower small intestine. relatively small doses of supplemental insulin are often effective. or who are receiving radiographic contrast materials. • Metformin may normalize ovulatory abnormalities in girls with PCOS and increase pregnancy risk (A).5-1% reduction in HbA1c (86). thus most useful when there is residual beta cell function • Sulfonylureas bind to receptors on the K + /ATP channel complex causing K+ channels to close. and possible increased risk of heart disease in adults (84. pre-meal meglitinide is a good initial choice. anemia. adipose cell differentiation. including arterial walls smooth muscle. activating peroxisome proliferator activator receptors (PPAR gamma). and weight gain. which has not been common in T2DM treated with insulin. Despite hyperinsulinemia and insulin resistance. • TZDs bind to nuclear proteins. If there is inadequate glycemic control on oral agents. Clinical trials have been. and glucose transport into the cell. • TZDs increase insulin sensitivity in muscle. The binding of the thiazolidinediones to PPARgamma receptors is ubiquitous. e. and weight gain. Metformin should be continued to improve insulin sensitivity. troglitazone. 25 . • Long-term treatment in adults is associated with a reduction in HbA1c of 0. before meals • Major adverse effects of sulfonylureas are hypoglycemia. weight gain.85). 12): 17–32 Amylin (amylin is not approved for those under 18 years. cardiac or respiratory insufficiency. • Long-term therapy is associated with 0. resulting in insulin secretion • Meglitinide and repaglinide bind to a separate site on the K + /ATP channel complex • Sulfonylurea sites equilibrate slowly and binding persists for prolonged periods. rapid or short acting insulin can be substituted. • Thiazolidinediones have differing effects on lipid profiles. with a greater effect on muscle glucose uptake than biguanides. with fatalities resulting in its withdrawal. or are underway in children with this class of drugs. and liver tissue. which are ubiquitous orphan steroid receptors particularly abundant in adipocytes. thus.g. If post-prandial hyperglycemia persists. a long acting (24 hours) analog with little or no peak action. thus. adipose.Type 2 diabetes • The risk of lactic acidosis with metformin is extremely low. affecting muscle cell growth and migration in response to growth factors.3%. Glucosidase inhibitors (these drugs are only approved for use in adults) Alpha glucosidase inhibitors (acarbose. a substantial problem in this population if dietary measures are not attended to. • If post-prandial hyperglycemia occurs. TZDs (only approved for use in adults). traditional sulfonylureas have prolonged effects • Meglitinide/rapaglinide have an intermediate equilibration and binding duration and are. a long-acting insulin analogue without peak effects may provide satisfactory therapy without meal related therapy. This activation ultimately increases formation of proteins involved in the nuclear based actions of insulin.

prompting the manufacturer to recommend decreasing the insulin dose by 50% when treatment with amylin is initiated (87). metformin is the treatment of choice (E) a. severity of hyperglycemia. They are rapidly degraded by dipeptidyl peptidaseIV (DPP-IV). increase to 250 mg BID. The principal adverse effects are hypoglycemia and nausea. when insulin is eliminated (E) 6. • They are administered orally with metformin or a thiazolidenedione once daily. prolonging gastric emptying. It lowers BG by decreasing glucagon release. they have no effect on gastric emptying. suppressing glucagon. including T2DM (90). resulting in higher concentrations of GLP-1 producing effects similar to those of GLP1 mimetics. GASTRIC SURGERY • Bariatric surgery may be considered for adolescents with obesity-related comorbidities. and promoting satiety. those with symptoms. As in T1DM. include gastric banding and vagal nerve stimulators. if tolerated. • Gastric bypass. this treatment is still uncommon in children and should be undertaken only in centers with an established program designed to collect outcome data (E). The nausea decreases over time. without serious complications (92). 12): 17–32 DPP-IV Inhibitors (89) (these drugs are only approved for use in adults) • DPP-IV inhibitors inhibit the enzyme that breaks down GLP-1. If metabolically stable. Begin with 250 mg daily x 3–4 days. • Clinical trials in adults have shown reduced fasting and post-prandial BG. • There is a reported study of amylin use in children with T1DM (88) 1. Pediatric Diabetes 2009: 10 (Suppl. the diagnosis of T2DM should be reconsidered and lifestyle changes reinforced (E) Incretin mimetics (glucagon-like peptide-1 receptor agonists) (exenatide) (89) (these drugs are only approved for use in adults) • Incretin mimetics are given as a twice-daily subcutaneous injection. initial medical treatment: Initial treatment modality is determined by symptoms. • Unlike GLP-1 mimetics. If the glucose values are in the diabetic range. can deteriorate rapidly and need urgent assessment and treatment (E) 26 . the taper should be slowed until values stabilalize. and dyspepsia. Transition can usually be achieved safely by titration of the metformin as in # 1 above. usually 1-2 weeks after diagnosis (E) 4. 2. GLP-1 is rapidly secreted by L-cells in the small intestine into the circulation in response to food. Insulin may be decreased by 10–20% each time the metformin is increased with a goal of eliminating insulin therapy (E) 5. • Modest weight loss or weight stabilization is generally seen with amylin treatment.Rosenbloom et al • Amylin peptide is co-secreted with insulin from pancreatic beta cells in response to food. weight loss. titrate in this manner over 3–4 weeks until the maximal dose of 1000 mg BID is reached. • Although the morbidity and mortality rates in adults have decreased over the last 5 years. Newer techniques. • Treatment produces mild reductions in HbA1c. both native GLP-1 and the injected mimetic have a half life of 2 minutes. diarrhea. In normal physiology. and presence or absence of ketosis/ketoacidosis. particularly vomiting. Blood glucose testing may be decreased to twice a day. A Swedish study of over 2000 subjects undergoing a variety of bariatric surgery procedures found persistence of weight loss after 10 years and reduced mortality compared to conventionally treated obese patients (91). the glucose values rise into the impaired range. headache. which appear to be safer. and lower HbA1c. vomiting. and infrequent dizziness. can have significant complications including nutrient malabsorption and even death. • A randomized controlled trial of gastric banding versus conventional treatment for recent onset T2D in a small population of obese individuals from Australia achieved a 73% remission rate which correlated with weight loss and lower baseline HbA1c. fasting and 2-3 hours after the largest meal. Insulin may be required for metabolic stabilization (A) 3. satiety or weight loss. with nausea occurring in up to 44% of patients. the traditional surgical procedure for weight loss. Adverse effects include nausea. Transition from insulin to metformin can usually be made over 2-6 weeks beginning when metabolic stability is reached. increasing insulin secretion proportionate to BG concentrations. If at any time during the insulin taper. usually with breakfast and dinner. slowing gastric emptying and decreasing food intake.

or family history of diabetes (90). Random opportunistic glucose measurements may be appropriate. as in adults. from Europe. These new data indicate that screening to identify diabetes in asymptomatic youth has a low yield and further research is required to determine the optimal strategy for testing. using urine tests for initial screening indicate a very low yield (∼0. including the frequency of testing. • Several studies. Japan. However. • An intervention is available to prevent or delay disease onset or to more effectively treat the condition detected in the latency phase. but albuminuria and dyslipidemia may already be present. not evidence-based • although the fasting plasma glucose was considered preferable because of lower-cost and greater convenience. (C/E) In populations with high incidence of T2DM. the US. A large screening program identified only < 1% of high risk children with type 2 diabetes (22). 12): 17–32 Studies in the 7 years following publication of these criteria. Taiwan. 94) (C) • These studies emphasize the limitation of fasting glucose determination for testing purposes in obese youngsters. Because abnormal glucose tolerance may be present in 2–3% of high risk groups and additional findings of insulin resistance may be also be present prior to overt diabetes. • Studies of large numbers of school children in Japan and Taiwan.4% had diabetes in a Native American population (23). and Israel. The cost of this if the yield is low must be considered in any screening program.02%) of diabetes and an unjustifiable cost-benefit ratio in most populations (11. including all ethnicities have also noted the high frequency of detection of nonglycemic features of the insulin resistance syndrome in children and youth with BMI greater than 85th percentile (95). (B) Whether this is sufficiently frequent in adolescents to justify testing those with high-risk ethnicity or family history is still unclear (E). Children with BMI > 95th percentile. Concerns about these criteria are: • they were established without a database and. regardless of family history or associated features. if resources are available. • Some studies demonstrate a relatively low yield of identifying cases even in high risk populations using an OGTT. Unquestionably true of T2DM in adolescents because of the association with increased cardiovascular risk factors and renal dysfunction. dyslipidemia. have provided a data base for refining casefinding recommendations (11. in many populations screening outside of a research setting is not cost effective. or • if there are signs of insulin resistance (acanthosis nigricans. currently some clinicians may favor screening while awaiting more information on optimal screening strategies. Concerns have been raised about these recommendations as more information has accumulated since this publication. 0. early cardiovascular disease. predominantly overweight US population (22) and 0. • The condition tested for is serious in terms of morbidity and mortality. and are likely to be sensitive. during which abnormality can be detected.1% were found to have a 2 hour post glucose > 200 mg/dl (11 mmol/l) in a primarily nonwhite. The American Diabetes Association issued a Consensus Statement in 2000. a high index of suspicion should be maintained and at risk children should be advised on approaches to prevent T2DM (see subsequently). India. hypertension.22. indicative of a period of dysmetabolism and potentially a long latency period for overt type 2 diabetes. • A test is available that is sensitive (few false negatives) and accurate with acceptable specificity (minimal number of false positives). The fasting plasma glucose and 2-hour plasma glucose have been applied to high risk populations and are exceptionally sensitive and specific.Type 2 diabetes Testing (case finding) for T2DM Justification for case finding in a population at risk (93): • The condition tested for is sufficiently common to justify the investment. recommending screening youth for type 2 diabetes based broadly on known risk factors (2) (E). therefore. sensitivity is compromised because the 2-hour plasma glucose increases earlier in the course of development of T2DM • while some ethnicities may be overrepresented in populations of affected individuals. In the face of an apparent rapid increase in type 2 diabetes in US youth. 43–49. Impaired glucose tolerance in youth has been detected in asymptomatic adolescents. PCOS) Asian children regardless of BMI. 93). not being a member of such a group is not protective and therefore may be a spurious basis for selection of individuals to be tested Pediatric Diabetes 2009: 10 (Suppl. • The condition tested for has a prolonged latency period without symptoms. 27 . Children at risk for T2DM diabetes and metabolic syndrome include (C/E): • Children with BMI 85–95th percentile: • if there is an immediate family history of T2DM. if history of abnormally low or high birth weight (89). 23. In these studies 2–3% had impaired glucose tolerance or impaired fasting glucose.

and communities that have resulted in excess caloric intake and marked decrease in energy expenditure by children and adults. • Because of the multitude of cardiovascular risk factors associated with insulin resistance. and the promotion of breast-feeding. – Normal BP levels for age. can deteriorate rapidly and need urgent assessment and appropriate treatment. obesity is increasing in all segments of the population. Recommendation for initial medical treatment of type 2 diabetes* (98): * Preadolescent children are unlikely to have T2DM. As in T1DM. as in adults. • Inquiries about puberty. those with symptoms. 72) (E). Pediatric Diabetes 2009: 10 (Suppl. particularly vomiting. be associated with micro. Hypertension is defined as an average systolic or diastolic BP 95 percentile for age. 95). – Elevated levels of urine albumin should be confirmed on 2 of 3 samples • Blood pressure should be monitored at every visit according to standardized techniques specific for children ( (72). and height are available at the above website. 12): 17–32 Recommendations: Autoantibody testing when diagnosing and treating T2DM: • Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise ‘‘typical’’ T2DM: • Antibodies will indicate an earlier need for insulin. sex. and presence or absence of ketosis/ketoacidosis.8) * Antibody determination is the only way to definitively determine the presence of autoimmune diabetes (T1DM) Initial treatment modality is determined by symptoms. severity of hyperglycemia.(E) 28 .pdf – Elevated BP should be confirmed on 2 additional days. T2DM is likely to be associated with earlier severe complications than T1DM in childhood (E). schools. • Studies have shown that relatively minimal weight loss can decrease rate of diabetes in at risk populations (96. • The insidious onset in much of T2DM. the lipid dysmetabolism. menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65) (E). • The societal changes required are of such magnitude that enormous community and governmental commitment is required (E).or macro-albuminuria. (A) • Primary prevention of T2DM is directed toward the obesity pandemic and involves reversing eating and entertainment trends in homes. ubiquitous. The epidemic of obesity and its complications accounts for a substantial and increasing proportion of direct and indirect health care costs. • The challenge is huge. Prevention of T2DM requires prevention of obesity in those who are not overweight and treatment of obesity in those who have a BMI > 85th percentile (or even less in non-European populations) (11.61) E • Evaluation for NAFLD should be done at diagnosis and annually thereafter (24) (E). even if obese (8) * Overweight adolescents should have both T1DM and T2 DM considered in the diagnosis (4. ketosis/ketoacidosis). sex and height percentiles.nih. should be performed at the time of diagnosis and annually thereafter (55.Rosenbloom et al Prevention of T2DM • Worldwide. optimizing the fetal environment in pregnancy. • Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter (60. (E). Lifestyle changes in diet and exercise are essential and should be recommended for all individuals with T2DM Complication testing specific to T2DM in young people: • Testing for either micro.and macrovascular disease already present at diagnosis (E).gov/health/prof/heart/hbp/hbp_ ped.97) (A. of countering eating and entertainment trends that provide popular social outlets and are highly attractive. some of whom may have T2DM (E) • C–peptide measurements should be considered in overweight/obese children > 13 years of age who have worsening levels of control on oral agents to confirm those requiring insulin therapy and to reconsider the diabetes classification. and the unknown duration of IGT preceding diagnosis may.C) • Intervention in adult populations reflects difficulty in altering lifestyle and dietary habits (98). with high normal BP being 90 to < 95percentile . E) On-line instructions are available at: www. and heavily promoted (E).nhlbi. (E) • Antibodies will indicate the need to check for thyroid autoimmunity and to consider other associated autoimmune disorders. (E) • Diabetes autoantibody testing should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss.

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