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 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.

• 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 (Scandinavian heritage)
• 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 (e.g., Tokelau, Marshall Islands, Micronesia)

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)

1. Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
   • Autoimmune (type 1A)
     • Variant: LADA
   • 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 HbA_1C 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
   • Other genetic syndromes that may be associated with diabetes mellitus (e.g., Down syndrome)
4. Gestational diabetes

References:^[11][12]

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][13][14][15]}

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:^{[16][7][17][18]}

• Hyperglycemia: elevated blood glucose levels

• 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)

References:^[19][20][21]

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 > 500 μg/mL; , ↑ 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][22][20][23][24][25][26]}

The differential diagnoses listed here are not exhaustive.

References:^{[27][28][21][29]}

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][41][42][43][44][45][46][47]}

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