Diabetes mellitus

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 undiagnosed for many years. However, abnormal metabolism (prediabetic state or impaired glucose tolerance), which is associated with chronic hyperglycemia, causes microvascular and macrovascular changes that eventually result in cardiovascular, renal, retinal, and neurological complications. In addition, patients with type 2 diabetes mellitus 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 and 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 patients with diabetes mellitus. 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. Patients with both type 1 and type 2 diabetes mellitus require regular self-management training to improve glycemic control, reduce the risk of life-threatening hypoglycemia or hyperglycemia, and prevent diabetic complications.

• 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.

• 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

References:^{[6][7][8][9][10]}

Classification according to the WHO and American Diabetes Association (ADA) ^[11]

• Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
  • Autoimmune (type 1A)
  • LADA: Latent autoimmune diabetes in adults, a variant of diabetes characterized by a late onset of type 1 (autoimmune) diabetes that is often mistaken for type 2 diabetes.
  • Idiopathic (type 1B)
• Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
• Gestational diabetes
• 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 HbA_1C levels
    • All other subtypes require medical treatment, either with insulin or sulfonylureas
  • Genetic defects in insulin function
  • Diseases of the exocrine pancreas
  • Endocrinopathies: Cushing disease, acromegaly
  • Drug-induced diabetes: e.g., corticosteroids
  • Infections (e.g., congenital rubella infection)
  • Glucocorticoid therapy (steroid diabetes)
  • Rare immunological diseases: stiff person syndrome

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.

References:^{[1][6][7][12][13][14]}

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.

References:^{[7][15][16][17]}

• Hyperglycemia: elevated blood glucose levels

• Additional tests
  • Specific autoantibodies for diabetes mellitus type 1
    • Anti-GAD antibodies
    • 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)

References:^[18][19][20]

DM type 1 vs. type 2

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

References:^{[2][19][21][22][23][24][25]}

The differential diagnoses listed here are not exhaustive.

References:^{[20][26][27][28]}

• 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.

Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated!

References:^[7][20]

Principles of insulin therapy

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

References:^{[6][29][30][31][32][33][34][35][36][37][38][39]}

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

References:^{[1][7][40][41][42][43][44][45][46]}

We list the most important complications. The selection is not exhaustive.

Diabetic nephropathy is a major cause of end stage renal disease (ESRD).

• Pathophysiology ^[47]
  • Seen in patients with diabetes for > 10 years
  • Chronic hyperglycemia → glycation (also called non-enzymatic glycosylation or 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, increase in renal size, and glomerular scarring (glomerulosclerosis) → worsening of filtration capacity
• Pathology: Three major histological changes can be seen on LM. ^[48]
  • Mesangial expansion
  • Glomerular basement membrane thickening
  • Glomerulosclerosis (later stages)
    • Diffuse hyalinization (most common) or
    • Pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) :
      • Glomerular capillary hypertension and hyperfiltration → increase in mesangial matrix → eosinophilic hyaline material in the area of glomerular capillary loops
      • Can progressively consume the entire glomerulus → hypofiltration (↓ GFR) ^[49]
• Clinical features
  • 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 ^[50][51][52]
  • Initially moderately increased albuminuria (microalbuminuria) ,
  • Eventually significantly increased albuminuria (macroproteinuria): 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 patients with diabetes.
    • 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!

References:^{[2][20][48][53][54][55][56][57]}

• 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

References:^{[58][59][60][61][62][63]}

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

References:^{[58][64][65][66][67][68][69][70]}

In about ⅓ of patients with diabetic foot, the underlying cause is both ischemic and neuropathic.

References:^{[67][71][72][73]}

• 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).

References:^[7]

References:^{[3][4][74][75][76][77][78][79]}

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