What is the pathophysiology of diabetes?

Pathophysiology of Diabetes

Diabetes mellitus is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, with different pathophysiological mechanisms underlying the various types of diabetes. 1

Classification of Diabetes

Diabetes is classified into four major categories:

1. Type 1 diabetes: Autoimmune β-cell destruction leading to absolute insulin deficiency
2. Type 2 diabetes: Progressive loss of β-cell insulin secretion often on the background of insulin resistance
3. Gestational diabetes mellitus (GDM): Diabetes diagnosed during pregnancy
4. Specific types due to other causes: Including monogenic diabetes, diseases of the exocrine pancreas, and drug-induced diabetes 1

Type 1 Diabetes Pathophysiology

• Primary mechanism: Autoimmune destruction of pancreatic β-cells 1
• Autoimmunity markers: Presence of autoantibodies to insulin, glutamic acid decarboxylase (GAD), islet antigen 2 (IA-2), or zinc transporter 8 (ZnT8) 2
• Staging process:
  • Stage 1: Multiple islet autoantibodies with normoglycemia (presymptomatic)
  • Stage 2: Islet autoantibodies with dysglycemia (presymptomatic)
  • Stage 3: Overt hyperglycemia with clinical symptoms 2
• Genetic factors: Strong genetic predisposition involving multiple genes 3
• Environmental triggers: May include viral infections, dietary factors, and other environmental exposures 3

Type 2 Diabetes Pathophysiology

• Primary mechanisms: Progressive loss of β-cell insulin secretion combined with insulin resistance 1
• Conventional paradigm: Insulin resistance as the primary defect, leading to compensatory hyperinsulinemia and eventual β-cell exhaustion 2
• Alternative model: Hyperinsulinemia as the primary event, which may promote obesity and insulin resistance, creating a negative feedback loop 2
• Genetic basis: Multiple risk susceptibility genes, each with relatively small effect (odds ratios below 1.2 in most cases) 4
• Ethnic variations: Different pathophysiological mechanisms across populations:
  • In Black Africans: Hyperinsulinemia (due to increased insulin secretion and reduced hepatic insulin clearance) appears to be the primary defect 2
  • This differs from the conventional model based primarily on studies in populations of European descent 2

Pathophysiological Mechanisms in Type 2 Diabetes

• Insulin resistance: Decreased sensitivity to insulin in muscle, liver, and adipose tissue 5
• β-cell dysfunction: Inability to compensate for insulin resistance with increased insulin secretion 5
• Adipose tissue dysfunction:
  • Changes in adipose tissue distribution and function
  • Release of inflammatory mediators and adipokines
  • Increased lipolysis leading to elevated free fatty acids 2
• Hepatic glucose production: Increased gluconeogenesis contributing to hyperglycemia 5
• Ectopic fat deposition: Accumulation of lipids in liver, muscle, and pancreas, exacerbating insulin resistance 2
• Incretin effect: Reduced incretin effect contributing to decreased insulin secretion 5

Unique Factors in Different Populations

• Black African populations:

  • Hyperinsulinemia as a characteristic feature, even with normal glucose tolerance
  • Lower insulin clearance and higher insulin secretion compared to White Europeans
  • Different body fat distribution patterns (lower visceral adipose tissue, higher gluteo-femoral subcutaneous adipose tissue) 2

• Gender differences:

  • Men may present with lower BMI, lower insulin secretion, and earlier β-cell failure
  • Women show stronger relationships between obesity and diabetes risk 2

• Socioeconomic and environmental factors:

  • Early life undernutrition may contribute to diabetes risk
  • Rapid urbanization and nutrition transition affecting disease patterns
  • Malnutrition-related diabetes in some populations 2

Complications of Chronic Hyperglycemia

• Microvascular complications: Retinopathy, nephropathy, and neuropathy
• Macrovascular complications: Cardiovascular disease, cerebrovascular disease, and peripheral arterial disease
• Other complications: Increased susceptibility to infections, impaired wound healing 6

Clinical Implications

• Accurate classification of diabetes is essential for appropriate management
• Treatment approaches differ based on underlying pathophysiology
• Understanding ethnic and population differences may lead to more personalized approaches to prevention and treatment
• Regular reassessment of diabetes classification is important, especially when treatment response is suboptimal 1

The pathophysiology of diabetes is complex and continues to evolve as our understanding of the disease improves. Recognizing the heterogeneity of diabetes and its varied pathophysiological mechanisms across different populations is crucial for developing effective prevention and treatment strategies.