What is the pathophysiology of diabetes?

Diabetes Pathophysiology

Core Pathophysiological Mechanisms

Diabetes mellitus results from progressive loss of pancreatic β-cell mass and/or function combined with insulin resistance, leading to chronic hyperglycemia and disturbances in carbohydrate, fat, and protein metabolism. 1

The pathophysiology differs fundamentally between diabetes types:

Type 1 Diabetes

• Autoimmune destruction of pancreatic β-cells leads to absolute insulin deficiency 1
• Characterized by presence of islet autoantibodies (insulin, GAD, IA-2, or ZnT8) 1
• Progresses through three stages: Stage 1 (multiple autoantibodies, normoglycemia), Stage 2 (autoantibodies with dysglycemia), and Stage 3 (overt hyperglycemia with symptoms) 1
• Both genetic predisposition (HLA antigen associations) and environmental triggers (possibly viral infections) contribute to pathogenesis 2

Type 2 Diabetes - Conventional Paradigm

The traditional model posits insulin resistance as the primary defect, triggering compensatory hyperinsulinemia that eventually leads to β-cell exhaustion and diabetes. 1, 3

The conventional sequence involves:

• Insulin resistance in liver, skeletal muscle, and adipose tissue reduces glucose uptake and increases hepatic glucose production 4, 5
• Obesity, particularly visceral adiposity, drives insulin resistance through adipocyte hypertrophy, oxidative stress, inflammation, and ectopic fat accumulation in liver and muscle 3, 5
• Compensatory β-cell hypersecretion maintains normoglycemia initially, but progressive β-cell dysfunction and failure ultimately result in hyperglycemia 1, 6
• Genetic factors (at least 83 identified variants, many affecting β-cell function) interact with environmental factors (urbanization, physical inactivity, dietary changes) 6, 4

Alternative Paradigm - Hyperinsulinemia as Primary Event

Emerging evidence suggests hyperinsulinemia itself may be the initial pathophysiological event, driven by either β-cell hypersecretion or reduced hepatic insulin clearance, which then promotes insulin resistance. 1, 3

This alternative model is particularly relevant for:

• Black African populations, who demonstrate hyperinsulinemia characterized by higher insulin secretion and lower insulin clearance compared to White Europeans, independent of adiposity differences 1, 3
• The hyperinsulinemia creates a negative feedback loop, reducing skeletal muscle insulin sensitivity and exacerbating both hyperinsulinemia and obesity, eventually leading to β-cell failure 1

Population-Specific Pathophysiology

Sub-Saharan African Populations

Black Africans exhibit distinct pathophysiological features: hyperinsulinemia due to combined increased insulin secretion and reduced hepatic insulin clearance appears to be the primary defect, rather than insulin resistance alone. 1

Key characteristics include:

• Unique fat distribution pattern with low visceral adipose tissue (VAT) but high gluteo-femoral subcutaneous adipose tissue (SAT), particularly in women 1
• Lower hepatic fat content despite obesity, associated with reduced de novo lipogenesis 1
• Skeletal muscle insulin resistance characterized by changes in lipid intermediates and subspecies rather than increased intramyocellular lipids 1
• Sex differences: men present with lower insulin sensitivity, secretion, and β-cell function compared to women, often with low BMI (<25 kg/m²) phenotype 1
• Malnutrition-related diabetes represents ~30% of cases in SSA, presenting in individuals with low socioeconomic status, low BMI, and relative β-cell impairment 1

Environmental and Social Determinants in SSA

• Hypercaloric, high-carbohydrate diets in the context of hyperinsulinemia drive obesity increases, particularly in women 1
• Childhood undernutrition followed by catch-up growth or adult obesity amplifies type 2 diabetes risk 1
• Higher education levels paradoxically associate with increased diabetes risk in SSA, contrasting with European patterns 1
• Infectious disease exposure may further influence pathogenesis and diabetes risk 1

Cellular and Molecular Mechanisms

Oxidative Stress and Mitochondrial Dysfunction

• Hyperglycemia-induced reactive oxygen species (ROS) overproduction leads to oxidative stress, accompanied by reduced antioxidant response and impaired DNA repair 7
• Mitochondrial dysfunction closely correlates with insulin resistance and β-cell dysfunction 7

Endoplasmic Reticulum Stress and Inflammation

• ER stress and chronic inflammation contribute to both insulin resistance and β-cell failure 7
• Adipose tissue as endocrine organ secretes adipocytokines (leptin, TNF-α, resistin, adiponectin) implicated in insulin resistance and β-cell dysfunction 5

Ectopic Fat Deposition

• Triglyceride accumulation in muscle, liver, and pancreatic cells (ectopic fat storage syndrome) impairs insulin action 5
• Elevated non-esterified fatty acids from adipose tissue lipolysis contribute to hepatic and peripheral insulin resistance 1, 5

Clinical Implications

The pathophysiology determines clinical presentation and progression: individuals may exhibit impaired insulin secretion and resistance years before diabetes onset, with abrupt β-cell decompensation occurring in the final 2 years before diagnosis 6. This understanding emphasizes the importance of early detection through oral glucose tolerance testing, which captures both fasting and post-load glucose abnormalities 1, and supports targeted prevention strategies addressing the specific pathophysiological defects present in different populations 1.