Diabetes Mellitus: Regulation of Insulin Secretion

Regulation of Insulin Secretion

• Glucose is the primary physiologic stimulant of insulin release, entering β cells via glucose transporter (GLUT 2)
• Glucokinase, an enzyme regulated by glucose, controls the first step in glucose metabolism
• Stimulators of insulin release include:
  • Vagal stimulation
  • β-adrenergic stimulation
  • GLP1
  • Amino acids
• Inhibitors of insulin release include:
  • Catecholamines
  • α-adrenergic stimulation
  • Somatostatin

Diabetes Mellitus

• Defined as a heterogeneous disorder characterized by hyperglycemia
• Criteria for diagnosis:
  • Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L)
  • Symptoms of DM plus a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L)
  • Plasma glucose ≥ 200 mg/dL after OGTT
• Classification:
  • Normal fasting plasma glucose: 70-99 mg/dL (3.4-5.5 mmol/L)
  • Impaired fasting glucose (IFG): 100-125 mg/dL (5.6-6.9 mmol/L)
  • Impaired glucose tolerance (IGT): plasma glucose 140-199 mg/dL (7.8-11 mmol/L) after 2-hour OGTT
  • Prediabetes: IFG or IGT
  • Diabetes: symptoms of hyperglycemia and casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L)

Etiology of Diabetes Mellitus

• Functional deficiency of insulin action → hyperglycemia
• Decreased insulin secretion by β cells of pancreas (DM 1)
• Decreased response to insulin by target tissues → insulin resistance (DM 2)
• Increase in counterregulatory hormones that oppose the effects of insulin (DM in endocrinopathies, gestational DM)

Types of Diabetes Mellitus

• Type I DM
  • Selective destruction of over 90% of pancreatic β cells with severe insulin deficiency
  • Immune-mediated (autoimmune DM 1) → 90%
  • Idiopathic → 10%
• Type II DM
  • Insulin resistance with relative insulin deficiency
  • Genetic predisposition stronger than in DM 1
  • Polygenic origin of disease
• Gestational Diabetes Mellitus (GDM)
  • Any hyperglycemic state that occurs or is recognized for the first time during pregnancy
  • Occurs in 4% of pregnant women
  • May recur with subsequent pregnancies (in ~30%)
  • Tends to resolve at parturition
  • Associated with obesity

Complications of Diabetes Mellitus

• Acute Complications

  • Diabetic ketoacidosis
  • Hyperosmolar coma
  • Hypoglycemia

• Chronic Complications

  • Macrovascular:
    • Atherosclerosis
    • Stroke
    • Heart disease
    • Hypertension
  • Microvascular:
    • Retinopathy
    • Nephropathy
    • Neuropathy### Morphology of Steatofibrosis/Cirrhosis

• Gross findings: nodular surface, greenish color

• Microscopic findings:

  • Central vein sclerosis
  • Perisinusoidal scarring
  • Central portal fibrous septa
  • Continual subdivision of nodules (micronodular cirrhosis)
  • With abstinence, regeneration occurs, forming macronodules

Clinical Features of Alcohol-Related Fatty Liver Disease

Steatosis

• Asymptomatic, but may present with hepatomegaly
• Mild increase in serum bilirubin and alkaline phosphatase
• Resolves with abstinence

Steatohepatitis

• Weeks to months of heavy alcohol consumption
• Possible acute onset
• Symptoms: malaise, anorexia, tender hepatomegaly, fever
• Laboratory findings:
  • Hyperbilirubinemia
  • Increased serum alkaline phosphatase
  • AST & ALT < 500 U/mL
  • AST : ALT > 2:1
• Increased risk of cirrhosis and death

Chronic Liver Failure/Cirrhosis

Pathogenesis of NAFLD

• Contributing factors:
  • Diabetes type II
  • Central obesity
  • Dyslipidemia (high TG & LDL, low HDL)
  • Hypertension
• Mechanisms:
  • Insulin resistance → increased activity of lipoprotein lipase → increased release of free fatty acids
  • Decreased production of adiponectin by adipocytes
  • Decreased oxidation of FFA by skeletal muscle
  • Increased uptake of FFA by hepatocytes
  • Activation of inflammasome (release of IL-1)
  • Products of lipid metabolism → hepatocytes injury → stellate cell activation → fibrosis

Clinical Features of NAFLD

• Transaminase elevation (AST : ALT < 1)
• Steatosis: usually asymptomatic
• Steatohepatitis: asymptomatic or presents with fatigue, malaise, discomfort in right upper quadrant
• Low progression to NASH / cirrhosis