Understanding Diabetes Complications and Mechanisms

Oct 7, 2024

Notes on Diabetes Complications and Molecular Mechanisms

Overview

  • Focus: Molecular mechanisms leading to diabetes complications.
  • Complications of diabetes can be acute and chronic.

Acute Complications

  • Diabetic Ketoacidosis (DKA):
    • Common in Type 1 Diabetes, but can occur in Type 2.
    • Characterized by hyperglycemia, dehydration, ketosis, ketonemia, ketonuria, metabolic acidosis (increased anion gap), hyperventilation, fruity odor (acetone), hyponatremia, hyperkalemia.
  • Hyperosmolar Hyperglycemic State (HHS):
    • More common in Type 2 Diabetes.
    • Features include hyperglycemia, dehydration, increased plasma osmolarity, no ketosis, normal anion gap, no significant acidosis.

Chronic Complications

  • Macrovascular Complications:
    • Affect large vessels (arteries/veins):
      • Coronary heart disease.
      • Cerebrovascular disease.
      • Peripheral vascular disease.
    • Diabetes as a risk factor for atherosclerosis.
    • Leads to increased glycated LDL, oxidized LDL, small dense LDL, decreased HDL.
  • Microvascular Complications:
    • Affect small vessels (capillaries):
      • Diabetic retinopathy (eye).
      • Diabetic nephropathy (kidney).
      • Diabetic neuropathy (nervous system).
  • Other Complications:
    • Cataracts, glaucoma, infections, foot ulcers, gangrene, skin and fungal infections.

Molecular Mechanisms of Complications

  • Endothelial Dysfunction: Principal mediator for both macro and microvascular complications.
  • Mechanisms Involved:
    • Hyperglycemia-induced activation:
      • Release of growth factors (e.g., VEGF, angiopoietins).
      • Release of cytokines.
      • Oxidative stress and reactive oxygen species formation.
      • Epigenetic changes influencing disease progression.

Key Metabolic Pathways Activated by Hyperglycemia

  1. Glyoxylation Pathway:
    • Formation of advanced glycation end products (AGEs).
    • AGEs bind to RAGEs on cells (macrophages, T cells, endothelial, smooth muscle cells).
    • Results in cytokine/growth factor release, ROS production, LDL trapping, increased coagulant activity, smooth muscle proliferation, ECM synthesis.
  2. Protein Kinase C (PKC) Pathway:
    • Hyperglycemia increases diacylglycerol levels.
    • Leads to increased endothelin, growth factors, nuclear factor kappa B.
    • Decreases nitric oxide synthase, affecting vascular permeability.
  3. Polyol Pathway:
    • Converts glucose to sorbitol via aldose reductase.
    • Sorbitol accumulates in tissues like the eye lens, kidney, nervous tissue (lacking sorbitol dehydrogenase).
    • Leads to cataract, nephropathy, neuropathy due to osmotic activity.
  4. Hexosamine Pathway:
    • Glucose converted to glucosamine 6-phosphate, leading to UDP-N-acetylglucosamine production.
    • Causes protein glycosylation, altering expression of genes involved in TGF-beta, endothelial nitric oxide synthase modification.

Summary

  • Diabetes leads to numerous complications through complex molecular pathways.
  • Acute and chronic complications arise, notably characterized by endothelial dysfunction.
  • Understanding these mechanisms is key in managing and potentially mitigating diabetes-related vascular complications.