Hormonal Regulation of Glucose

Question 1

Hormone secreting cells of pancreas

Answer 1

• 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

Question 2

Structure of insulin

Answer 2

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

Question 3

Stimuli of insulin release

Answer 3

• 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)

Question 4

Inhibitors of insulin release

Answer 4

• 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

Question 5

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

Answer 5

• 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

Question 6

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

Answer 6

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

Question 7

Actions of insulin on Muscle, Liver and Adipose tissue

Answer 7

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

Question 8

Insulin resistance (general)

Answer 8

• 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

Question 9

Incretin effect

Answer 9

• 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

Question 10

Effects of GLP-1

Answer 10

Question 11

Effects of the counter-regulatory hormones: glucagon

Answer 11

• 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

Question 12

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

Answer 12

• 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.

Question 13

Insulin resistance effects @ muscle, liver, adipose tissue

Answer 13

• 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.

Question 14

Effects of catecholamines

Answer 14

• 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

Question 15

Effects of glucocorticoids

Answer 15

• 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

Question 16

Effects of growth hormone

Answer 16

• 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)