What is the pathophysiology of type 2 diabetes?

Pathophysiology of Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is characterized by two primary defects: insulin resistance in peripheral tissues and progressive pancreatic β-cell dysfunction leading to relative insulin deficiency, which together result in hyperglycemia and metabolic dysregulation. 1

Core Pathophysiological Mechanisms

Insulin Resistance

• Occurs primarily in skeletal muscle, liver, and adipose tissue
• Present before clinical diagnosis, often associated with obesity, particularly visceral adiposity 1
• Mechanisms include:
  • Free fatty acid (FFA)-induced reactive oxygen species (ROS) production that impairs insulin signaling 2
  • Downregulation of insulin-responsive glucose transporter 4 (GLUT-4) 2
  • Impaired PI3K-Akt signaling pathway 2
  • Chronic inflammation in adipose tissue with increased cytokine production 2

β-Cell Dysfunction

• Progressive decline in β-cell function and mass over time 2
• Initially compensatory hyperinsulinemia occurs to overcome insulin resistance 2
• Eventually, β-cells fail to maintain adequate insulin secretion 2
• Abnormal insulin kinetics, including impaired first-phase insulin release in response to rising glucose levels 2

Hepatic Glucose Production

• Increased hepatic glucose output due to insulin resistance 2
• Enhanced gluconeogenesis driven by increased FFA oxidation 2
• Development of hepatosteatosis from lipid overabundance 2

Incretin System Dysfunction

• Abnormalities in gut hormones (GLP-1, GIP) that normally enhance insulin secretion 2
• Reduced incretin effect contributes to inadequate insulin response to meals 2

Pancreatic α-Cell Dysfunction

• Hyperglucagonemia despite hyperglycemia 2
• Inappropriate glucagon secretion further promotes hepatic glucose production 2

Disease Progression Continuum

1. Early Stage: Insulin resistance with compensatory hyperinsulinemia

   • Normal glucose tolerance maintained through increased insulin secretion 1
   • Often associated with obesity, physical inactivity, and genetic predisposition 1

2. Intermediate Stage: Prediabetes

   • Impaired fasting glucose (100-125 mg/dL) and/or impaired glucose tolerance (2-hour OGTT 140-199 mg/dL) 2
   • Early endothelial dysfunction and vascular inflammation begin 2
   • Progressive decrease in insulin sensitivity with rising glucose levels 2

3. Established Type 2 Diabetes:

   • Overt hyperglycemia (fasting glucose ≥126 mg/dL or 2-hour OGTT ≥200 mg/dL) 2
   • Relative insulin deficiency despite insulin resistance 2
   • Multiple metabolic derangements affecting carbohydrate, fat, and protein metabolism 2

Molecular Mechanisms

Oxidative Stress

• Mitochondrial dysfunction with increased ROS production 2
• Activation of protein kinase C (PKC) by hyperglycemia 2
• Upregulation of NADPH oxidase contributing to further ROS generation 2

Endothelial Dysfunction

• Decreased nitric oxide (NO) production due to impaired eNOS phosphorylation 2
• Vascular remodeling with increased intima-media thickness 2
• Activation of NF-κB leading to increased expression of inflammatory adhesion molecules 2

Chronic Inflammation

• Adipose tissue inflammation with macrophage infiltration 2
• Increased production of pro-inflammatory cytokines 2
• Impaired insulin signaling due to inflammatory mediators 2

Risk Factors and Genetic Influences

• Obesity (especially visceral adiposity) is the strongest modifiable risk factor 1
• Physical inactivity contributes to insulin resistance 1
• Genetic predisposition with strong familial association 1
• Aging increases risk through multiple mechanisms 1
• Ethnic variations in susceptibility (higher risk in African Americans, Hispanic/Latino individuals, Native Americans, and Asian Americans) 1

Clinical Implications

• Type 2 diabetes accounts for 90-95% of all diabetes cases 1
• Hyperglycemia develops gradually, often with minimal symptoms initially 2
• Both microvascular complications (retinopathy, nephropathy, neuropathy) and macrovascular complications (cardiovascular disease) result from chronic hyperglycemia and metabolic disturbances 2
• Metabolic memory phenomenon suggests early glycemic control has long-lasting effects on complications 2

Distinguishing Features from Other Types of Diabetes

• Unlike type 1 diabetes, which results from autoimmune destruction of β-cells causing absolute insulin deficiency 2
• Different from monogenic forms of diabetes (MODY) that have specific genetic defects 2
• Distinct from gestational diabetes, which is diagnosed during pregnancy 2

Understanding these pathophysiological mechanisms is crucial for developing targeted therapeutic approaches that address the multiple defects in type 2 diabetes rather than focusing solely on lowering blood glucose.