Diabetes mellitus

Summary
Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia (elevated blood glucose levels). The two most common forms
are type 1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the destruction of insulin-producing β cells in the pancreas and results in
an absolute insulin deficiency. Type 2, which is much more common, has a strong genetic component as well as a significant association with obesity and sedentary lifestyles.
Type 2 diabetes is characterized by insulin resistance (insufficient response of peripheral cells to insulin) and pancreatic β cell dysfunction (impaired insulin secretion),
resulting in relative insulin deficiency. This form of diabetes usually remains clinically inapparent for many years. However, abnormal metabolism (prediabetic state or
impaired glucose intolerance), which is associated with chronic hyperglycemia, causes microvascular and macrovascular changes that eventually result in cardiovascular,
renal, retinal, and neurological complications. In addition, type 2 diabetic patients often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase
the risk of cardiovascular disease (e.g., myocardial infarction). Renal insufficiency is primarily responsible for the reduced life expectancy of patients with DM.
Because of the chronic, progressive nature of type 1 and type 2 diabetes mellitus, a comprehensive treatment approach is necessary. The primary treatment goals for type 2
diabetes are the normalization of glucose metabolism and the management of risk factors (e.g., arterial hypertension). In theory, weight normalization, physical activity, and a
balanced diet should be sufficient to prevent the manifestation of diabetes in prediabetic patients or delay the progression of disease in diabetic patients. Unfortunately,
these general measures alone are rarely successful, and treatment with oral antidiabetic drugs and/or insulin injections is often required for optimal glycemic control. In type
1 diabetes, insulin replacement therapy is essential and patients must learn to coordinate insulin injections and dietary carbohydrates. Both type 1 and type 2 diabetic
patients require regular self-management training to improve glycemic control, reduce the risk of life-threatening hypoglycemia or hyperglycemia, and prevent diabetic
complications.

Epidemiology
• Type 1:
• ∼ 5% of all patients with diabetes
• Childhood onset: typically < 20 years but can occur at any age; peaks at age 4–6 years and 10–14 years
• Highest prevalence in non-Hispanic whites
• Type 2:
• The estimated prevalence in the US is 9.1%.
• Adult onset: typically > 40 years ; mean age of onset is decreasing
• Highest prevalence in Hispanics, Native Americans, Asian Americans, African Americans, and Pacific Islanders
References:[1][2][3][4][5]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
• Type 1
• Autoimmune β cell destruction in genetically susceptible individuals
• HLA association. HLA-DR3 and HLA-DR4 positive patients are 4–6 times more likely to develop type 1 diabetes.
• Association with other autoimmune conditions
• Hashimoto thyroiditis
• Type A gastritis
• Celiac disease
• Primary adrenal insufficiency
• Type 2
• Hereditary and environmental factors
• Association with metabolic syndrome
• Risk factors
• Obesity, high-calorie diet
• High waist-to-hip ratio (visceral fat accumulation)
• Physical inactivity
• First-degree relative with diabetes
• Ethnicity
• Hypertension
• Dyslipidemia
• History of gestational diabetes

Classification
Classification according to the WHO and American Diabetes Association (ADA)
1 Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
• Autoimmune (type 1A)
• Idiopathic (type 1B)
2 Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
3 Other types of diabetes mellitus
• Genetic defects in the β cell function: MODY (maturity onset diabetes of the young)
• Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 years and are not associated with obesity or
autoantibodies
• 6 subtypes, the most common being MODY II and MODY III
• Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α, respectively
• In contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite
stable hyperglycemia and chronically elevated HbA1C levels
• All other subtypes require medical treatment, either with insulin or sulfonylureas
• Genetic defects in insulin function
• Diseases of the exocrine pancreas (pancreoprivic diabetes mellitus)
• Endocrinopathies: Cushing disease, acromegaly
• Drug-induced diabetes: e.g., corticosteroids
• Infections: e.g., congenital rubella infection
• Rare immunological diseases: stiff person syndrome
4 Gestational diabetes

Pathophysiology
Normal insulin physiology
• Secretion: Insulin is synthesized in the β cells of the islets of Langerhans. The cleavage of proinsulin (precursor molecule of insulin) produces the C-peptide (connecting
peptide) and insulin, which consists of two peptide chains (A and B chains).
• Action: Insulin has a variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control.
• Carbohydrate metabolism: Insulin is the only hormone in the body that lowers the blood glucose level.
• Protein metabolism: stimulates protein synthesis Stimulates amino acid uptake into cells; inhibits proteolysis
• Lipid metabolism: maintains a fat depot and has an antiketogenic effect
• Electrolyte regulation: stimulates intracellular potassium accumulation
Type 1 diabetes
1 Genetic susceptibility
2 Environmental trigger (often associated with previous viral infection)
3 → Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid decarboxylase antibody (Anti-GAD), that target insulin-producing cells → progressive
destruction of insulin-producing β cells in the pancreatic islets by autoreactive T cells → destruction of 80–90% of β cells
4 → Absolute insulin deficiency → elevated blood glucose levels
Type 2 diabetes
Two major mechanisms:
1 Peripheral insulin resistance
• Numerous genetic and environmental factors
• Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
• Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1
for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake
2 Pancreatic β cell dysfunction
• Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production
• Initially, insulin resistance is compensated by increased insulin and amylin secretion.
• Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines.
• After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.

Clinical features
Type 1 diabetes Type 2 diabetes
Onset • Sudden; diabetic ketoacidosis is often the first • Gradual; the majority of patients are asymptomatic
manifestation • Symptoms of complications may be the first clinical sign of disease.
• Alternatively, children may present with acute illness and
classic symptoms (see “Characteristic features”
below)
Characteristic features • Classic
• Polyuria
• Secondary enuresis and nocturia in children
• Polydipsia
• Polyphagia
 • Nonspecific
• Fatigue
• Visual disturbances: blurred vision
• Calf cramps
• Poor wound healing
• Pruritus
• Weight loss; a thin appearance is typical for type 1 • Benign acanthosis nigricans
diabetic patients
Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), influenza,
genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.

Diagnostics
• Hyperglycemia: elevated blood glucose levels

Indication for testing

Symptomatic patients • Symptoms or signs of diabetes •
•

Asymptomatic patients • < 45 years of age who are obese and have one other risk factor •
for diabetes (see “Etiology” above)
• > 45 years of age
Results (venous blood plasma) Diabetes mellitus Prediabetes
Fasting plasma glucose (FPG) in mg/dL (mmol/L) ≥ 126 (≥ 7.0) 100–125 (5.6–6.9) = impaired fasting glucose
2-hour glucose value after oral glucose tolerance test (OGTT) in mg/dL (mmol/L) ≥ 200 (≥ 11.1) 140–199 (7.8–11.0) = impaired glucose toleranc
Hemoglobin A1C (HbA1c or A1C) in % ≥ 6.5 5.7–6.4
• Additional tests
• Specific autoantibodies for diabetes mellitus type 1
• Anti-GAD
• Anti-tyrosine phosphatase-related islet antigen (IA-2)
• Islet cell surface antibody (ICSA; against ganglioside)
• C-peptide
• ↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes
• ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes
• Urine analysis
• Microalbuminuria: an early sign of diabetic nephropathy
• Glucosuria: Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus.
• Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis)

Differential diagnoses
DM type 1 vs. type 2
Type 1 Type 2
Relative frequency 10–20% 80–90%
Genetics Positive HLA association Negative HLA association; strong genetic predisposition
Pathogenesis Absolute insulin deficiency Insulin resistance
Association with obesity No Yes
Onset Acute decompensation, typically at age < 20 years Gradual; usually at age > 40 years
C-peptide (Insulin) Decreased or absent Initially elevated
Metabolism Unstable Stable
Risk of ketoacidosis High Low
Treatment Insulin therapy Lifestyle changes → oral antidiabetic drugs → insulin therapy
Glucagonoma
• Definition: a rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
• Clinical findings: nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea
(30%), deep vein thrombosis, and depression
• Necrolytic migratory erythema
• A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma
• Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities
• Develop into painful and pruritic crusty patches with central areas of bronze-colored induration
• Tend to resolve and reappear in a different location
• Skin biopsy shows epidermal necrosis
• Diagnostics: requires a high index of suspicion to make the diagnosis
• Laboratory findings: ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%)
• Imaging (CT): locate the tumor
• Treatment
• Glycemic control
• Octreotide (somatostatin)
• Pancreatic resection
Somatostatinoma
• Definition: a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
• Clinical findings
• Abdominal pain
• Weight loss
• Classic triad
• Glucose intolerance
• Cholelithiasis
• Steatorrhea
• Achlorhydria
• Diagnostics
• Laboratory findings: ↑ somatostatin, ↑ blood glucose levels
• Imaging: locate the tumor
• Treatment
• Octreotide → inhibition of somatostatin secretion
• Pancreatic resection: curative if no metastases are present
• Chemotherapy

Treatment
Aspects of treatment
Individual treatment targets
Lifestyle modification
Approach
• Blood glucose control and regular glycemic monitoring: A1C values
• Weight loss : Type 2 diabetic patients with a BMI of 27–35 benefit from a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight reduction
• Blood pressure control
• Improved blood lipid profile with statin therapy
• Low dose aspirin for men > 50 years and women > 60 years with cardiovascular risk factors
• ↑ Physical activity → ↓ blood glucose and ↑ insulin sensitivity
• Smoking cessation
• Balanced diet and nutrition
• Small, frequent meals
• Diet: ∼ 55% carbohydrates (replace simple carbohydrates such as glucose and sucrose with complex carbohydrates), 30% fat, 15% protein
• High-fiber diet
• Alcohol should (if possible) be consumed with carbohydrates to avoid hypoglycemia.

Self-management education • DSME/S programs

Medical treatment
Monitoring complications
• Oral antidiabetic drugs (see below)
• Insulin therapy (see below)
• Patients with prediabetes usually do not require medical treatment but do benefit from a healthy diet, weight loss, and exercise.
• Regular monitoring of weight, abdominal circumference, blood pressure, blood lipids, renal retention parameters (creatinine, electrolytes), injection s
therapy
• Yearly eye exam (type 1: after 5 years with diabetes mellitus or after the age of 11 years); more frequently in patients with abnormal findings or diagn
• Annual urine testing for microalbuminuria
• Foot exam for neuropathy and ulcers; advise patients to wear appropriate footwear and avoid injury
• Routine screening for psychosocial problems, including signs of depression and cognitive impairment
• Pneumococcal vaccines
Antihyperglycemic therapy algorithm for type 2 diabetes
• HbA1C target for adults: < 7% (53 mmol/mol)
• The guidelines for the treatment of DM recommend an individualized treatment strategy.
• If the target A1C is not reached within 3 months with conservative measures (e.g., diet, exercise), the next step in the therapeutic algorithm should be initiated.
Treatment algorithm Description
General measures Weight reduction, exercise , medical nutrition therapy, self-management education
Monotherapy The drug of choice is metformin.
Dual therapy • Metformin +
• A second oral antidiabetic drug: dipeptidyl peptidase-4 inhibitor, sulfonylureas, thiazolidinedione, meglitinides, SGLT-2 inhibitors, alpha
analogs
• GLP-1 receptor agonists (incretin mimetics)
• Basal insulin
Triple therapy Add a third oral antidiabetic drug, nightly basal insulin, or injectable GLP-1 receptor agonist
Combination injectable therapy Metformin + basal insulin + mealtime insulin or GLP-1 receptor agonist
Only consider the substitution of drugs in cases in which the drug is not tolerated or side effects occur.
Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated!

Insulin therapy
Principles of insulin therapy
Total daily requirement of insulin • On average, the body requires 40 USP units of insulin daily.
• 20 units for basic metabolism → basal insulin
• 20 units for calorie consumption → bolus insulin
Insulin correction factor • 1 unit of insulin lowers the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L)
Carbohydrate counting • 10 g of carbohydrates increases the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L).
Insulin-to-carbohydrate ratio • On average, 1 unit of insulin is required for 15 g carbs = 1 carb serving (carb unit); however, this varies greatly from patient to patient
• Insulin sensitivity fluctuates over the course of a day → Insulin-to-carbohydrate ratio changes over the course of a day.
• Morning hours: 2 units insulin, lunchtime: 1 unit, evening hours: 1.5 units
Type 1 diabetes • Insulin replacement therapy: The exogenous insulin requirement depends on the residual insulin production of the pancreas.
• The initial total daily dose (TDD) of insulin should be 0.6–1.0 U/kg.
• After beginning insulin treatment, there is often a temporary reduction in exogenous insulin demand.
Type 2 diabetes • Residual endogenous insulin production is augmented with exogenous insulin, depending on the extent of insulin resistance (which in
obesity).
• The TDD of insulin should be 0.1–0.2 U/kg.
Indications for insulin therapy
• Newly diagnosed patients with significantly elevated A1C levels (> 8.5%) or symptomatic diabetes: Initiate insulin therapy with or without an antidiabetic drug.
• Patients with insufficient glycemic control (target A1C not reached) over a 3-month treatment period with metformin or another antidiabetic drug:
• Initiate basal insulin supported oral therapy (BOT).
• Consider initiating insulin therapy.
• Pregestational and gestational diabetes
• Patients with end stage renal failure (oral antidiabetic drugs are contraindicated in this case)
Regimens of insulin therapy
Conventional insulin therapy
• Fixed regimen of insulin injections: usually twice daily injection of insulin (mixture of 30% regular insulin and 70% intermediate insulin) with self-monitoring of blood
glucose levels
• Advantages: simple regimen, requiring minimal patient education, not very time-consuming
• Disadvantages: patients must adhere to a rigid diet and exercise plan. Snacks may be required between meals to avoid hypoglycemia.
Intensive insulin therapy
• The goal is to simulate physiological glucose metabolism by keeping fasting blood glucose levels < 100 mg/dL (5.6 mmol/L) and postprandial blood glucose levels < 140
mg/dL (< 7.8 mmol/L)
• Intensified conventional therapy
• Basal-bolus regimen: basal insulin 1–2 times daily, + bolus insulin injection 30–45 minutes before meals adjusted to preprandial blood glucose measurements
• The bolus insulin dose depends on the preprandial blood glucose level, meal size and time of day
• Indication: type 1 diabetes; insulin-dependent type 2 diabetes with a high degree of compliance
• Insulin pump
• Continuous subcutaneous insulin infusion (regular or rapid-acting insulin analogs)
• Basal and bolus insulin may be managed individually
• Indication: type 1 diabetes, children, pregnancy, dawn phenomenon (see “Problems” below)
• Advantages
• Optimal glycemic control and reduced risk of complications in patients with good compliance
• More flexibility in the daily diet and exercise plan
• Disadvantages
• Complex and time-consuming therapy; requires frequent blood glucose measurements
• High risk of hypoglycemia
• Patients require intensive education and must be motivated and committed.
Basal supported oral therapy (BOT)
• Alternative to conventional or intensive insulin therapy
• Indication: combination therapy for type 2 diabetic patients with persistently elevated A1C levels despite oral antidiabetic regimen
• Regimen: long-acting insulin injection (e.g., glargine) before bedtime combined with an oral antidiabetic drug regimen
Types of insulin (see insulin)
Problems: early-morning hyperglycemia
• Dawn phenomenon
• A common problem (especially in young type 1 diabetic patients)
• Definition: early-morning hyperglycemia occurs because of the physiological increase of growth hormone levels in the early morning hours, which stimulates
hepatic gluconeogenesis. The subsequent increase in insulin demand cannot be met in insulin-dependent patients, resulting in elevated blood glucose levels
 in the morning.
• Treatment: measurement of nocturnal blood glucose levels before initiating insulin therapy. The long-acting insulin dose may be given later (around 11 p.m.) or
increased under careful glycemic control. Treatment with an insulin pump may be considered in children.
• Somogyi effect
• Rare
• Definition: early-morning hyperglycemia because of a counterregulatory secretion of hormones that is triggered by nocturnal hypoglycemia secondary to an
evening insulin injection
• Treatment: reduction of the evening dose of the long-acting insulin
• For additional side effects, see insulin.

Conditions that require insulin adjustments

• Physical activity: decreases insulin by 1–2 units per 20–30 minutes activity
• Illness, stress, and changes in diet
• Increase in insulin demand: many illnesses are associated with elevated blood glucose levels due to an acute stress reaction. The subsequent increase in insulin
demand cannot be met by patients with insulin deficiency. A higher insulin dose is required.
• Decrease in insulin demand: vomiting and diarrhea lead to decreased glucose uptake, increasing the risk of hypoglycemia.
• Surgery: ⅓–½ of the usual daily requirement with frequent monitoring
Insulin purging
• Definition: attempting to lose weight by purposefully not injecting insulin after meals
• Population: young patients with type 1 diabetes with eating disorders use insulin purging as an alternative to fasting, vomiting, and other methods of weight loss
• Result: self-induced insulin deficiency reduces insulin-dependent glucose uptake in cells and reduces the anabolic effect of insulin.
• Poor glycemic control
• Increased risk of hyperglycemic coma

Complications
Acute • Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a coma
• Hyperosmolar hyperglycemic state (HHS)
• Diabetic ketoacidosis (DKA)
• Life-threatening hypoglycemia: secondary to inappropriate insulin therapy
Long-term • Macrovascular disease
• More common in patients with type 2 diabetes
• Pathophysiology: The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be
development of macrovascular disease.
• Manifestations
• Coronary heart disease (CHD)
• Cerebrovascular disease
• Peripheral artery disease (PAD)
• Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD)
 • PAD diagnostic tools are unreliable in patients with Mönckeberg's arteriosclerosis
• Microvascular disease
• Onset: typically arises 5–10 years after onset of disease
• Pathophysiology: Chronic hyperglycemia is the primary factor influencing the development of microvascular disease; results in glycation of proteins and lip
protein and cell membrane function and tissue damage
• Manifestations
• Diabetic nephropathy
• Diabetic retinopathy
• Diabetic neuropathy
• Diabetic foot
• Diabetic cardiomyopathy
• Diabetic fatty liver disease
• Hyporeninemic hypoaldosteronism
• Limited joint mobility (formerly known as diabetic cheiroarthropathy)
• Sialadenosis
• Increased risk of infection
Strict glycemic control is crucial in preventing microvascular disease.
Other complications
• Necrobiosis lipoidica
• Definition: inflammatory granulomatous disorder of the skin; characterized by collagen degeneration and lipid accumulation in the surface of the skin.
• Epidemiology
• > 60% association with DM
• ♀ >> ♂
• Symptoms
• Rash: circumscribed, erythematous plaques with atrophic centers and irregular margins
• Common sites: pretibial region
• Usually asymptomatic
• Ulcerations with subsequent scarring may occur
• Histopathology: necrobiotic palisading granuloma
• Lymphohistiocytic infiltration with plasma cells, foam cells, and giant cells
• Wall thickening and occlusion of small blood vessels
• Destruction of collagen fibers in the entire corium
• Treatment: Corticosteroids may be effective (e.g., intralesional corticosteroid injections).

• Mucormycosis (zygomycosis)
• Definition: rare fungal infection, primarily affecting immunocompromised patients and patients with diabetes mellitus
• Etiology: fungi of the order Mucorales, most commonly Rhizopus oryzae; ubiquitous fungi found in vegetation and soil
• Pathophysiology: Inhalation of the spores into the nose and maxillary sinus (diabetic ketoacidosis stimulates fungal growth) causes sinusitis, tissue necrosis, and
 contiguous spread to the orbit, brain, and palate. Inhalation of the spores into the pulmonary system may lead to contiguous spread to the mediastinum and
heart.
• Risk factors
• Diabetes mellitus, particularly type 1 (ketoacidosis)
• Immunosuppression: hematologic malignancies, stem cell or solid organ transplantation, treatment with glucocorticoids, AIDS
• Iron overload or treatment with deferoxamine
• Symptoms and clinical findings
• Rhino-orbital-cerebral mucormycosis: the most common form; presents with sinusitis, fever, headache
• Pulmonary mucormycosis: aggressive infection of the bronchioli and alveoli, presenting with fever and hemoptysis
• Disseminated mucormycosis: (rare) invasion of the vasculature with subsequent dissemination; may affect any organ
• Diagnostics
• Biopsy: broad, nonseptate hyphae, with right-angle branching on microscopy
• Imaging: assess the extent of tissue damage and organ involvement
• Treatment
• Antifungal treatment: amphotericin B, step-down therapy with oral azole
• Surgical debridement
• Elimination of risk factors, aggressive blood glucose control
• Complications: palatal eschars , cerebritis, mediastinitis, cardiac involvement

Diabetic nephropathy
• A major cause of end stage renal disease (ESRD)
• Pathophysiology: chronic hyperglycemia → non-enzymatic glycosylation (NEG) of the basement membrane (protein glycation) → increased permeability and thickening of
the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure → progressive glomerular
hypertrophy and increased renal size → worsening of filtration capacity
• Pathology
• Three major histological changes occur:
• Mesangial expansion
• Glomerular basement membrane thickening
• Glomerulosclerosis (later stages): may be diffuse (most common) or pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)
• Clinical findings
• Often asymptomatic; patients may complain of foamy urine
• Progressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)
• Arterial hypertension
• Urine analysis
• Proteinuria
• Initially moderately increased albuminuria (microalbuminuria) ,
• Eventually significantly increased albuminuria (macroalbuminuria): nephrotic syndrome may develop.
• Differential diagnoses: other causes of chronic kidney disease (e.g., hypertensive nephropathy) and nephrotic syndrome
• Prevention and management
• Stringent glycemic control
• Antihypertensive treatment: ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in diabetic patients.
• Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockers
• Dietary modification: daily salt intake < 5–6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction
Microalbuminuria is the earliest clinical sign of diabetic nephropathy. The extent of albuminuria correlates with the risk of cardiovascular disease!
Early antihypertensive treatment delays the progression of diabetic nephropathy!

Diabetic retinopathy
• Epidemiology
• After 15 years with disease, approx. 90% of type 1 diabetic patients and approx. 25% of type 2 diabetic patients develop diabetic retinopathy.
• The most common cause of visual impairment and blindness in patients aged 25–74 years in the US
• Symptoms: asymptomatic until very late stages of disease
• Visual impairment
• Progression to blindness
• Ophthalmological findings and classification of diabetic retinopathy
• Nonproliferative retinopathy (mild, moderate, severe): accounts for most cases of diabetic retinopathy
• Findings: intraretinal microvascular abnormalities (IRMA), including microaneurysms; caliber changes in venous vessels; intraretinal hemorrhage; hard
exudates retinal edema, and cotton-wool spots
• Visual loss, most commonly due to macular edema
• Proliferative retinopathy
• Findings: Preretinal neovascularization is the hallmark of PDR , fibrovascular proliferation , vitreous hemorrhage, traction retinal detachment , rubeosis
iridis → secondary glaucoma. Additionally, findings of nonproliferative retinopathy are usually present.
• Visual loss may be due to vitreous hemorrhage, retinal detachment, or neovascular glaucoma.
• Macular edema
• Findings: clinically significant retinal thickening and edema involving the macula, hard exudates, macular ischemia
• May occur in all stages of NPDR and PDR
• Treatment
• Nonproliferative retinopathy
• Laser treatment: focal photocoagulation
• Intravitreal anti-vascular endothelial growth factor (VEGF) injection
• Proliferative retinopathy and severe nonproliferative retinopathy
• Laser treatment: panretinal photocoagulation over the course of numerous appointments
• Risks associated with laser treatment: night vision impairment, visual field loss, further fibrosis of the vitreous body with risk of retinal detachment
• Vitrectomy in case of traction retinal detachment and vitreal hemorrhage
• Macular edema
• VEGF inhibitors
• Focal photocoagulation
Diabetic neuropathy
Distal symmetric polyneuropathy
• Pathophysiology: Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple
peripheral nerves
• Epidemiology: Diabetic polyneuropathy is the most common form of polyneuropathy in Western countries.
• Clinical features
• Early: progressive symmetric loss of sensation in the distal lower extremities
• A "stocking-glove" sensory loss pattern with proximal progression is typical
• Dysesthesia (burning feet) may occur
• A similar sensory loss pattern may occur in the upper extremities.
• Late: pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia
• Special types:
• Mononeuropathy
• Cranial mononeuropathy
• Peripheral mononeuropathy
• Mononeuropathy multiplex: asymmetric neuropathy, affecting the multiple peripheral and cranial nerves
• Diabetic truncal neuropathy
• Diabetic lumbosacral plexopathy
• Screening
• Tuning fork: decreased vibration sense
• Monofilament test: decreased pressure sense
• Pinprick (pain assessment) or temperature assessment: decreased sensation
• Treatment
• Optimal glycemic control
• Pain management
• Anticonvulsants: pregabalin (most effective; usually first-choice), gabapentin, and sodium valproate
• Antidepressants
• Tricyclic antidepressants: amitriptyline
• SNRI: duloxetine, venlafaxine
• Miscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate spray
• Opioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone
Autonomic neuropathy
Urogenital system • Erectile dysfunction (most common)
• Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary stream
Cardiovascular system • Silent myocardial infarction
• Decreased heart variability or fixed rhythm
 • Orthostatic hypotension
• Persistent sinus tachycardia
• Ventricular arrhythmia
Gastrointestinal system • Gastroparesis (→ delayed gastric emptying, risk of postprandial hypoglycemia): nausea, abdominal bloating, loss of appetite, early satiety
• Diarrhea, constipation, incontinence
• Treatment involves prokinetic agents (e.g. metoclopramide (1st line), erythromycin, cisapride).
Other manifestations • Sweat gland dysfunction associated with heat intolerance
• Pupillary dysfunction
• Risk of hypoglycemia due to absence of hormonal counterregulation (secretion of cortisol, glucagon, and catecholamines)

Neuropathic diabetic foot Ischemic diabetic foot

Clinical features • Warm, dry skin, foot pulses are palpable • Cool, pale foot with no palpable pulses
Additional info • Diagnostics • Prevention
• Neurological examinations: evaluation of peripheral neuropathy • Glycemic control
• Foot ulcer risk assessment (see “Screening” for diabetic • Regular foot examinations
polyneuropathy above) • Self-monitoring and proper foot care
• Complications
• Malum perforans: painless neuropathic ulcers (usually located on
the plantar pressure points of the foot: over the head of the
metatarsal bones or the heel)
• Complex, multifactorial pathophysiology. Major risk factors
include peripheral sensory neuropathy, autonomic
neuropathy, microvascular changes , as well as
macrovascular disease.
• Secondary infection of foot ulcers may lead to cellulitis and
acute or chronic osteomyelitis.
• Diabetic neuropathic arthropathy (Charcot foot): deformation of
joints and bones
• Tarsus and tarsometatarsal joints most commonly affected
• Coexisting ulcers common
• Acute: swelling, warmth, erythema
• Chronic: painless bony deformities, midfoot collapse,
osteolysis, risk of fractures
Treatment of foot • Surgical debridement
ulcers • Regular wound dressing
• Mechanical offloading: fitting of therapeutic footwear or total contact cast
• Antibiotic therapy if foot ulcers become infected
 • Interventional or surgical revascularization: in patients with underlying peripheral artery disease
• Amputation if all else fails or severe life-threatening complications arise

In about ⅓ of patients with diabetic foot, the underlying cause is both ischemic and neuropathic.
• Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are myocardial infarction and end stage renal failure.
• One of the leading causes of blindness, nontraumatic lower limb amputation, end stage renal failure, and cardiovascular disease
• The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia).

Special patient groups

Gestational diabetes mellitus Pregestational diabetes mellitus
Definition • Impaired glucose tolerance diagnosed during pregnancy; associated with an increased risk • Diabetes mellitus (type 1 or type 2) that is present prior
of maternal and fetal morbidity associated with a significantly increased risk for ma
pregnancy and delivery, and congenital malformat
Epidemiology • Occurs in 5-7% of all pregnancies • Observed in 1% of all pregnancies
• Usually in the second and third trimesters (less common in the first trimester)
Pathophysiology • The insulin requirement varies during pregnancy. • As for diabetes mellitus type 1 or 2
• In the first trimester, insulin sensitivity increases and there is a tendency towards
hypoglycemia.
• In the second and third trimesters, hormonal changes trigger progressive insulin resistance
that results in hyperglycemia, particularly after mealtimes.
Risk factors • Major risk factors for type 2 diabetes (see “Etiology” above) • As for diabetes mellitus type 1 or 2
• Obstetric
• Gestational diabetes in prior pregnancy
• Recurrent pregnancy loss
• At least one birth of a child diagnosed with fetal macrosomia
Clinical features • Mothers are usually asymptomatic • As for diabetes mellitus type 1 or 2
• May present with edema; warning signs include polyhydramnios or large-for-gestational age
infants (> 90th percentile)
Screening and • First and second trimester (the first 24 weeks of pregnancy): the diagnosis of diabetes • Maternal baseline HbA1c, renal function (creatinine clea
diagnostics mellitus and gestational diabetes is confirmed with two independent measurements ≥ cardiac and ophthalmic testing
126 mg/dL and 92–125 mg/dL respectively • Monitoring fetal development
• Third trimester (at 24–28 weeks) • Weeks 18–24: ultrasound to determine fetal age
• Recommended in all pregnancies! for congenital anomalies
• Initial screening: 50-g, one-hour oral glucose challenge test • Weeks 32–36: close surveillance with ultrasound
• blood glucose level should be < 135 mg/dl • Week > 36: at least once weekly ultrasound; con
• Confirmation test: 100-g, three-hour oral glucose tolerance test (oGTT) to be induced prior to 39 weeks of gestatio
• blood glucose level should be < 140 mg/dl
Treatment • Glycemic control • Stringent glycemic control (exercise, diet, insulin therapy
 • Dietary modifications and regular exercise (walking) • Delivery and postpartum
• Strict blood glucose monitoring (4x daily) • Consider early delivery if the patient has poor gl
• Insulin therapy if glycemic control is insufficient with dietary modifications • Consider C-section if estimated fetus weight > 4
• Metformin and glyburide in patients who refuse insulin therapy • Intrapartum IV insulin and dextrose to avoid blo
• Regular ultrasound to evaluate fetal development (maintain normoglycemia 80–100 mg/dL; h
• Consider inducing delivery at week 39–40 if glycemic control is poor or if complications measurements
occur
Complications • Maternal • Maternal
• Gestational hypertension • Diabetic ketoacidosis (in type 1), hyperosmolar h
• Preeclampsia, eclampsia, and HELLP syndrome (in type 2)
• Urinary tract infection • Gestational hypertension
• Fetal: Diabetic fetopathy • Preeclampsia, eclampsia, and HELLP syndrome
• Urinary tract infection
• Increased risk of premature birth
• Spontaneous abortions
• Postpartum hemorrhage
• Polyhydramnios
• Fetal
• Diabetic embryopathy (first trimester)
• Diabetic fetopathy (second and third trimester)
Prognosis • In most cases, gestational diabetes resolves after pregnancy. • As for diabetes mellitus type 1 or 2
• Increased risk of gestational diabetes recurring in subsequent pregnancies (∼ 50%)
• Increased risk of developing type 2 diabetes mellitus (up to 50% over 10 years)→ screen for
DM 6–12 weeks postpartum (75 g 2-hour GTT); repeat every 3 years