Pancreatic Hormones

Question 1

Pancreas Structure

Answer 1

Exocrine cells lie in groups around a central duct.

Endocrine cells clustered in the Islets of Langerhans surrounding a capillary.

• Accounts for 1-2% of total weight
• Blood flows from the central capillary to the periphery
• Cells release their secretions which are carried out to the portal vein
  
  • Liver controls the appearance rate of the hormones in the systemic circulation
  • Pancreas in an optimal location to signal the liver
• The cells within each islet are connected by gap-junctions
  
  • Regulates each others secretory activity
• Islets innervated by sympathetic and parasympathetic fibers
  
  • Cholinergic stimulation increases insulin secretion

Question 2

Pancreatic

Endocrine Cells

Answer 2

• Beta-cells: produce insulin, C-peptide, and Amylin
• Alpha-cells: produce glucagon
• Delta-cells: produce somatostatin
• F-cells: produce Pancreatic polypeptide (PP)

Question 3

Amylin

Answer 3

• Peptide hormone which is co-secreted with insulin by pancreatic β-cells
• Exerts two main actions:
  
  1. Post-prandial inhibition of glucagon secretion
     
     • To mitigate the amount of glucose released by the liver into circulation
  2. Reduction of gastric motility
     
     • To allow for a slower rate of nutrient absorption from the intestinal tract
• Both effects aim to cooperate with the action of insulin and implement clearance of glucose from the blood

Question 4

Somatostatin

Answer 4

• Two forms of 14 AA & 28 AA peptide hormone
• Secreted by pancreatic delta-cells
• Inhibits the release of:
  
  • Insulin
  • Glucagon
  • PP
  • Gastrin
  • Vasoactive intestinal peptide (VIP)
  • TSH
• [Somatostatin] produced by delta cells would effectively inhibit release of insulin from beta-cells, however, blood flows from the centrally located β-cells out to the peripherally located δ-cells making it unlikely for somatostatin to locally affect insulin release via paracrine action.

Question 5

Pancreatic Polypeptide

(PP)

Answer 5

• Secreted by pancreatic F-cells
• Stimulated by:
  
  • Gastric distension
  • Vagal stimulation
  • Nutrients
• Inhibited by:
  
  • Hyperglycemia
  • Somatostatins
  • Others
• PP activates the Y4 receptor
  
  • Expressed by cells of the GI system in the stomach, small intestine, and colon.
• Activation reduces gastric emptying times & motility of the upper intestine

Question 6

Insulin & C-peptide

Biosynthesis

Answer 6

Produced by pancreatic β-cells.

1. Secreted as pre-pro-insulin
2. The connecting peptide (C-peptide) facilitates formation of interchain disulfide bonds between the A and B peptide chains allowing assembly into pro-insulin.
3. Pro-insulin transported from RER to Golgi where it is cleaved to form mature insulin.
4. C-peptide formed from initial connecting peptide plus two additional basic AA from the original A and B chains on insulin.
5. Insulin and C-peptide packaged into secretory vesicles until release.

Up to 50-60% of insulin secreted by the pancreas is extracted by the liver and never reaches systemic circulation.

Question 7

Clinical Significance

of

C-peptide

Answer 7

• C-peptide is co-secreted with insulin
• Due to hepatic degradation of insulin and possible exogenous insulin administration the peripheral measurement of insulin levels can be problematic
• Liver does not extract C-peptide
• As it is secreted in equimolar concentrations with insulin its immunodetection can provide reliable information about the rate and amount of insulin secretion

Question 8

A1c Test

Answer 8

• Measures a form of hemoglobin which is glycosylated by glucose in the plasma
  
  • Percentage of A1c modest in normal individuals with controlled plasma [glucose]
  • Increases significantly with DM
• Glycosylation is irreversible and life-span of RBC is ~ 3-4 months
• Gives an average plasma glucose level over the last 3 months
• Used to measure the effectiveness of treatment

Question 9

Insulin Secretion Kinetics

Answer 9

• Stimulation of insulin release by glucose is dose and method related.
• Significantly different release profiles observed if glucose given PO or IV.

Glucose by mouth

• Magnitude of insulin released is greater when glucose taken PO ⇒ incretin effect
  
  • Attributed to the fact that GI tract produces hormones that increase the sensitivity of β-cells to glucose.
• Fasting plasma [glucose] is the threshold for release

Glucose Intravenously

• Release of insulin less than observed with PO
• Follows biphasic kinetics
  
  • Acute phase with an initial rapid peak
    
    • Caused by sensing of the larger and immediate increase in plasma glucose by β-cells causing rapid release of stored insulin
  • Second slower and more prolonged increase
    
    • Chronic phase caused by secretion of newly synthesized insulin
  • Third phase has been described which starts 1.5-3 hours after glucose intake, declines to 15-25% of acute phase, and lasts for up to 48 hours

Question 10

Glucose Activation

of

β-cells

Answer 10

1. Glucose enters pancreatic β-cells via facilitated diffusion through an insulin-independent GLUT-2.
2. Glucose phosphorylated to glucose-6-phosphate by glucokinase.
   
   • Glucokinase controls rate of glycolysis
   • Functions as main sensor for changes in blood [glucose]
3. G-6-P oxidized via glycolysis producing ATP.
   
   • [ATP]_in is the key factor controlling insulin secretion
4. When [ATP]_in increases, K⁺ channels on the plasma membrane close causing depolarization of the β-cell.
5. Deploarization causes opening of voltage-senstive Ca²⁺ channels allowing calcium to enter.
6. Increased intracellular [Ca²⁺] causes exocytosis of the insulin-containing secretory granules.

Question 11

Sulfonylureas

Answer 11

Tolbutamide

Glyburide

• These drugs block the ATP-sensitive K⁺ channels on the β-cell membrane inducing depolarization and subsequent insulin secretion.
• Administered orally to treat Type II DM

Question 12

Other Factors Affecting

Insulin Release

Answer 12

• Amino acid metabolism results in intracellular ATP production ⇒ stimulates secretion
• Lipids may impair the glucose-stimulated secretion of insulin especially long-term.
• Small intestine releases hormones which increase the sensitivity of β-cells GLUT2 transporter for glucose ⇒ potentiates insulin secretion ⇒ basis for the incretin effect
  
  • Glucose-dependent insulinotropic peptide (GIP)
  • Cholecystokinin (CCK)
• Activation of α-adrenoreceptors decreases intracellular [cAMP] and inhibits insulin release.
  
  • These receptors predominantly involved in the stress response when mobilization of glucose needed.
• Activation of β-adrenoreceptors induces cAMP production and stimulates insulin release.

Question 13

Insulin Receptor

Answer 13

Activation

• Integral tetrameric (2 alpha/2 beta) protein located on plasma membrane.
• Insulin binding causes conformational change ⇒ autophosphorylation ⇒ activation of β-subunits
• Activated β-subunits phosphorylate and either activate or inhibit several cytosolic transducers
  
  • Including activation of GLUT4 in muscle and adipose
• Main target tissues are:
  
  • Liver
  • Adipose
  • Skeletal muscle

Inactivation

• Insulin-receptor complex eventually removed and internalized.
  
  • Insulin removed.
  • Receptor either degraded or recycled.
• Protein Tyrosine Phosphatase 1B (PTP 1B) production triggered by insulin binding which dephosphorylates and inactivates the receptor.
• Insulin also decreases the rate of receptor synthesis

Insulin down-regulates its own receptor.

Partially responsible for reduced sensitivity of target tissues to insulin observed in obesity and Type II DM.

Question 14

Glucagon Secretion

Regulation

Answer 14

• Secreted by pancreatic α-cells as polypeptide precursor called proglucagon.
• Proglucagon cleaved by prohormone convertase 2 to produce glucagon in the pancreatic α-cells only.
• Stimulated by:
  
  • Hypoglycemia
  • Ingestion of proteins
  • Catecholamines
• Inhibited by:
  
  • Glucose
  • Insulin

Question 15

Metabolic Effects

of

Insulin and Glucagon

Answer 15

• Insulin secreted in times of nutrient abundance.
  
  • Main targets are liver, adipose, and skeletal muscle.
  • 70% of cells are insulin-sensitive.
  • Action responsible for returning plasma glucose levels to normal physiological range.
  • Facilitates the transport of plasma glucose into the cell.
  • Promote the storage of energy metabolites.
• Glucagon produced and released in response to and overall deficit in nutrient supply.
  
  • Main targets are liver and adipose tissue
    
    • Adipose only shows a significant response when insulin levels low
      
      • Insulin/glucagon ratio determines the net effect
  • Acts by increasing plasma glucose.
• Glucagon, epinephrine, glucocorticoids, and growth hormone are the counter-regulatory hormones.
  
  • Aims toward the metabolic goal of increasing the use of stored nutrients.

Question 16

Actions of Insulin

Answer 16

1. Increases glucose transport into cells
   
   • Primarily in muscle & adipose via GLUT 4 mobilization
2. Increases glucose utilization​
   
   • Stimulates glycolysis
     
     • Thus increases production of α-glycerol phosphate and fatty acids
   • Inhibits gluconeogenesis
3. Increases glycogen production
   
   • Stimulates glycogenesis by activting glycogen synthase
   • Inhibits glycogenolysis
4. Implements biosynthesis of triglycerides and fat deposition
   
   • Lipogenic effect on adipose and liver
   • Stimulates lipoprotein lipase (LPL) expressed by adipocytes
     
     • Promotes uptake of fatty acids and glycerol from the blood
5. Inhibits lipolysis
   
   • Inhibits hormone-sensitive lipase
     
     • Decreases triglyceride catabolism
   • Inhibits free fatty acid mobilization
   • Inhibits β-oxidation
6. Promotes protein synthesis
   
   • Stimulates amino acid uptake
   • Increases synthesis of ribosomes
   • Inhibits protein degradation
7. Inhibits cAMP
8. Increases cellular uptake of K⁺, Mg²⁺, and phosphate
9. Essential for normal growth of soft tissues and bone

Question 17

Insulin Control

of

Glucose Transport

Answer 17

Under normoglycemic conditions GLUT4 is continuously cycled between cytoplasm and plasma membrane with a predominant fraction in the cell interior.

Insulin:

Promotes the sub-cellular trafficking of GLUT-4 to the plasma membrane allowing glucose entry.

Also reduces GLUT-4 internalization.

Question 18

Actions of Glucagon

Answer 18

Liver and Adipose

1. Increases blood glucose
   
   • Induces glycogenolysis in liver
   • Induces gluconeogenesis in liver
     ​
2. Increases fat breakdown
   
   • Promotes lypolysis in liver and adipose tissue
   • Promotes release of fatty acids into blood
3. Promotes ketogenesis
   
   1. Used as fuel by muscle and heart sparing glucose for brain
   2. Brain can also use ketone bodies during prolonged starvation

When infused systemically also promotes:

1. Fatty acid and glucose mobilization
2. Stimulation of β-oxidation in all tissues
3. Positive inotropic effect on the heart
4. ​Increases amino acid and glycerol transport

Question 19

Insulin/Glucagon Ratio

(I/G)

Answer 19

• The I/G determines the net physiological effects exerted by insulin and glucagon.
• Ratio can vary 100-fold according to the nutritional state of the individual
  
  • In fed state: ~ 30.
  • After overnight fast: ~ 2
  • Periods of prolonged starvation: ~ 0.5
• With Type I DM, there is a significantly reduced or even absent secretion of insulin which creates an imbalance of the I/G ratio
  
  • Effects of glucagon will predominate over the pathways stimulated by insulin
• Release of insulin and glucagon are both promoted by intracellular increase of cAMP.
  
  • Stimulation of glucagon receptors on the β-cells of pancreas stimulates cAMP production
  • Stimulation of insulin receptors on α-cells inhibits cAMP production
  • Therefore, glucagon promotes insulin release but insulin obstructs the release of glucagon

Question 20

Diabetes Mellitus

Answer 20

• The most common debilitating metabolic disease in humans
• Two forms observed
  
  • Type 1: affects mostly children
  • Type 2: generally observed in adulthood
• Most typical sign is hyperglycemia
• Normal renal absorption rate of glucose is ~ 180 mg/dL
  
  • Any excess glucose is excreted in urine
  • Leads to:
    
    • Polyuria
    • Dehydration
    • Polydipsia
• Results in alterations in the metabolism of carbohydrates, lipids and proteins.
  
  • Causes increased food consumption but weight loss
• Complications:
  
  • Alterations of the cardiovascular system are the most common complication
  • May lead to renal failure
  • Erectile dysfunction
  • Blindness
  • Microvascular and peripheral nerve lesions

Question 21

Type I DM

Answer 21

Also called Insulin-dependent DM (IDDM)

• Most common form caused by autoimmune destruction of pancreatic β-cells (Type-1A)
• An autoimmune-indepedent form recently described where inflammation of endocrine pancreas is not associated with detection of auto-antibodies (T_ype-1B_)
  
  • Genetic and environmental factors are determinant for pathogenesis of disease
• Other pancreatic cells spared leading to abnormally low I/G
• Hyperglycemia leads to osmotic diuresis
• Lack of glucose for peripheral tissues induces hepatic proteolysis and lipolysis as energy substrates
  
  • Produces ketone bodies
  • Worsens solute load for kidneys
• If untreated, ketoacidosis will eventually lead to death
• Long term management involves a balance between appropriate and timely administration of insulin, diet, and exercise.

Question 22

Type 2 DM

Answer 22

Aka Non-Insulin Dependent DM (NIDDM)

1. Initially, normal insulin secretion in response to glucose.
2. Emergence of reduced sensitivity of insulin receptors on target tissues.
   
   • Compensated for by increasing the release/availability of insulin (panel B) either autonomously by the pancreas or therapeutically by sulfonylureas.
3. Hyperglycemia eventually develops
4. In response to hyperglycemia, pancreas increases the release of insulin (hyperinsulinemia)
5. Down-regulation of the insulin receptor on target tissues and emergence of reduced responsiveness to insulin.
   
   • Condition cannot be reversed by increasing pancreatic insuline release or therapeutic availability of insulin (panel A)

• Results in insulin resistance.
• Clinical manifestations include:
  
  • Decreased glucose transport and metabolism by adipocytes and skeletal muscle
  • Impaired suppresion of hepatic glucose output
• There is a clinical correlation between obesity and incidence of Type II DM.
  
  • There are 2 theories why:
    
    • Lipotoxicity: when adipose tissue exceeds its storage capacity, fat accumulates in muscle and liver, compromising the functioning of insulin receptor.
    • Inflammation: adipose cells of overweight/obese individuals secrete inflammatory cytokines and other signaling molecules named adipokines which induces insulin resistance.
• Severe ketoacidosis rarely observed because sufficient insulin is produced for most of the disease duration
• Complications:
  
  • Microvascular lesions
    
    • Retinopathy
    • Blindness
    • Alterations to blood flow to extremities which may lead to skin ulcerations or amputation
  • Peripheral neuropathy
    
    • Leads to diminished sensation in the feet and legs
    • Impaired sensory nerve function