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Hormone secreting cells of pancreas

  • Cells in Islets of Langerhans:
    • B cells (60%)
      • Secrete insulin
      • Arranged in a central core
    • a-cells (25%)
      • Secrete glucagon
    • Delta cells
      • Secrete somatostatin.
    • F cells or PP cells
      • Secrete pancreatic polypeptide


Structure of insulin

  • Derived from proinsulin by cleavage of central peptide (C peptide) leaving A and B chains joined by disulfide bonds.
  • MW 6000


Stimuli of insulin release

  • Exposure of islet cells to high glucose concentrations for 20 minutes or longer
    • Results in rapid surge of insulin followed by decline
    • Then rise that is sustained as long as glucose remains high
  • Initiators stimulate insulin release on their own
    • Glucose, amino acids, drugs like sulphonylureas
  • Pontentiators increase insulin secretion only in presence of glucose
    • Glucagon, GI peptides, VIP, ACh
  • Incretins stimulate insulin response when secrete in response to food (amino acids and fats) in GI tract
    • Gastrin, pancreozymin, secretin, GLP-1, glucose dependent insulinotropic peptide (GIP)


Inhibitors of insulin release

  • Scarcity of dietary fuels
  • Periods of stress like fever or infection
  • Inhibitors
    • Somatostatin, a-adrenergic agents (epinephrine, diazoxide)
  • More long term fatty acids
    • Possibly enhance failure of islet cell function
  • Stimulation of splanchnic nerve
    • Release catecholamines
  • Alloxan and streptozotocin
    • Used to create experimental diabetes in mice


Cellular mechanisms leading to the secretion of insulin in response to an increase in serum glucose (glucose-related)

  • Glucose, leucine and other nutrients enter the cell and are metabolized to a compound that stimulates insulin release, now thought to be ATP
  • Metabolism of glucose depolarizes the ß cell by closing ATP regulated potassium channels.
    • When these channels are blocked by ATP, action potentials are generated


Mechanisms for insulin signaling within target cells for metabolic and mitogenic actions

  • Key intermediate in mitogenic pathway: MAP kinase
  • Key intermediates in metabolic pathway: PI3K and AKT
  • See figure:


Actions of insulin on Muscle, Liver and Adipose tissue

  • Overall insulin action:
    • Increases glucose uptake, glycogen synthesis, protein synthesis, fat synthesis
    • Decreases gluconeogenesis, glycogenolysis, lipolysis


Insulin resistance (general)

  • Condition in which body produces insulin but does not use it properly
  • Or steps in insulin receptor signaling that lead to increased glucose uptake in skeletal muscle and adipose tissue at the cellular level


Incretin effect

  • Insulin secretion stimulated much more by oral intake of glucose than by IV infusion of glucose
  • Responsible for 50-70% of insulin response to oral glucose ingestion
  • Caused mainly by GLP-1 and GIP


Effects of GLP-1


Effects of the counter-regulatory hormones: glucagon

  • Glucagon: most important modulator of glucose production in fasting state
  • Increases cellular levels of cAMP when bound to GPCR
  • Results in increases in glycogenolysis and gluconeogenesis in liver --> increase glucose output by liver
    • Provides source of glucose in fasting state to maintain normal blood glucose levels


Cellular mechanisms leading to the secretion of insulin in response to an increase in serum glucose (~neuro-chemical related)

  • Depolarization:
    • Leads to opening of voltage-dependent calcium channels in the plasma membrane
    • The attendant rise in intracellular calcium brings about exocytosis of insulin granules
  • Acetylcholine:
    • Stimulates insulin release --> increase in cytosolic calcium in absence of extracellular calcium
    •  Thought to act by generating ITP --> increases intracellular calcium stores.


Insulin resistance effects @ muscle, liver, adipose tissue

  • Muscle:
    • Increases membrane transport of amino acids, increases protein synthesis, and decreases protein catabolism --> stops amino acid release into plasma
  • Liver
    • During fed state, causes glycogen, lipid, and protein to be stored 
  • Adipose tissue:
    • Causes triglycerides to be stored as fat.


Effects of catecholamines

  • Generally - increase blood glucose concentrations
  • Inhibit insulin release, increase glycogenolysis, increase insulin resistance of muscles, stimulate lipase and thus lipolysis
  • Response by body to fix hypoglycemia


Effects of glucocorticoids

  • Cortisol released in response to stressful stimuli
  • Inhibition of insulin action at insulin receptor (post-receptor) --> increased insulin resistance
  • Increases the supply of amino acids available as substrates for gluconeogenesis by promoting protein breakdown, particularly in muscle
  • Potentiation of the actions of glucagon and epinephrine (permissive effect)
  • Stimulates lipolysis, ketogenesis, and proteolysis


Effects of growth hormone

  • Increased in response to hypoglycemia and other forms of stress
  • Long-term metabolic effects:
    • Promotion of lipolysis and stimulation of protein synthesis
  • Also has anti-insulin effects
    • Produces insulin receptor defect in insulin action
    • Tends to decrease insulin sensitivity (diabetogenic)