Insulin and Glucagon

Snapshot

• A 15-year-old high school student presents with sudden weight loss, increased urination and increased thirst.  He is an otherwise healthy individual who plays soccer on his schools team.  On physical exam you see a lean young man with dry mucous membranes.  Fingerstick glucose reveals a blood glucose of 469 mg/dL.

Insulin Overview  

• Synthesis/Release  
  • synthesized as proinsulin in β cells of pancreas
    • proinsulin = insulin + C-peptide
    • C-peptide secreted with insulin 
    • detection in serum is a mechanism to determine origin of hyperinsulinemia
      • present with endogenous insulin, but absent with exogenous administration  
  • hyperglycemia, GH, and cortisol ↑ insulin while hypoglycemia and somatostatin ↓ insulin secretion
  • released in response to increased glucose levels 
    • processed into ATP by oxidative phosphorylation
    • ATP-sensitive potassium channel causes depolarization
    • voltage sensitive calcium channel leads to calcium influx
    • calcium leads to exocytosis of insulin-containing vesicles
  • β agonists ↑ release of insulin while α agonists ↓ insulin secretion 
  • cleared by the kidneys 
    • dose adjustments may be required in patients with renal failure
• Function 
  • ↓ glucagon release by α cells of pancreas
  • ↑ Na+ retention (kidneys)
  • ↑ glycogen synthesis and storage
  • ↑ triglyceride synthesis and storage
    • major mechanism underlying weight gain with insulin treatment 
  • ↑ protein synthesis (muscles)
    • recall babies of diabetic mothers are macrosomic
  • ↑ cellular uptake of K⁺
    • recall used with glucose to treat hyperkalemia
  • ↑ glucose transport into skeletal muscle and adipose      
    • see Glucose transport topic 
• Pathology
  • a patient with an insulinoma will secrete abnormally high levels of insulin as well as C-peptide and will not produce anti-insulin antibodies
• these patients will have severe hypoglycemia

Glucagon Overview

• Production 
  • secreted by the pancreas (alpha cells)
  • major stimulus for secretion is hypoglycemia
  • major inhibition of secretion is hyperglycemia
    • also inhibited by insulin and somatostatin
• Function 
  • increase blood glucose
    • glycogenolysis
    • gluconeogenesis 
    • stimulation of insulin release
  • increase blood levels of other energy forms
    • lipolysis
    • ketone body production
  • increase protein kinase A activity
    • used in treatment of beta-blocker overdose 
• Pathology
  • a glucogonoma is a tumor that secretes excess glucagon leading to hyperglycemia as well as the characteristic rash of necrolytic migratory erythema