PHSL 410 Endocrine

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PHSL 410 - Endocrine

• Lecture 4
• Endocrine Pancreas
• (Insulin/Glucagon)

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Islet of Langerhans

• 500,000-several million islets per pancreas.
• Insulin-dependent diabetes mellitus (IDDM, type 1
  diabetes) develops in 1 in 600 children in US
  and Europe, 1 in 10,000 in Asia.
• Before 1922, children with diabetes died within
  1-2 years of diagnosis
• Slowly starved and eventually died of acidosis.
• Remove pancreas from dogs
• 1923 extract of beef and pork pancreas used to
  treat diabetes.

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Glycogen Synthase and Glycogenolysis

• Glycogen synthesis
• Glycogen is the main form of carbohydrate storage
  in animals
• Glycogen is synthesized from glucose
• Glycogenolysis - the breakdown of glycogen to
  glucose.

Glucose-1-phosphate
Glucose
Glycogen Synthesis
Glycogenolysis
Glycogen
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Glycolysis and Gluconeogenesis
Muscle

• Glycolysis - conversion of glucose to pyruvate,
  generating ATP in the process.
• Stimulated by insulin
• Energy storage
• Gluconeogenesis - formation of glucose from the
  breakdown of lipids and proteins (pyruvate, amino
  acids, glycerol).
• Inhibited by insulin
• Energy utilization

proteolysis
FAT
lipolysis
Pyruvate
Pyruvate Carboxylase
ATP
Oxaloacetate
Phosphoenolpyruvate Carboxykinase
Gluconeogenesis
Phosphoenolpyruvate
Glycolysis
ATP
Glucose-6-phosphate
Glucose-6-phosphatase
Glucose
Glucose-1-phosphate
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Muscle
proteolysis
FAT
lipolysis
Pyruvate
Pyruvate Carboxylase
ATP
Oxaloacetate
Phosphoenolpyruvate Carboxykinase
Gluconeogenesis
Phosphoenolpyruvate

• Energy Storage
• Stimulated by insulin

Glycolysis
ATP
Glucose-6-phosphate
Glucose-6-phosphatase
Glucose-1-phosphate
Glucose
Glycogen Synthesis
Glycogenolysis
Glycogen

• Energy Utilization
• Inhibited by insulin

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Synthesis of Insulin

• Insulin is coded for by a single gene on human
  chromosome 11.
• Synthesis and secretion of insulin is stimulated
  when ??cells of the pancreatic islet are exposed
  to glucose.

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Synthesis of Insulin

• Insulin is synthesized as a pre-prohormone.
• Gene --gtmRNA --gtprotein --gtprocessed protein
  (mature hormone)
• Leader sequence cleaved in ER to form proinsulin
  (B, C, A)
• In trans-Goli, proteases cleave C peptide to form
  insulin (A, B).
• Insulin (A, B), proinsulin (B, C, A), and C
  peptide are packaged into secretory vesicles.

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Insulin, Proinsulin, and C peptide

• C peptide has no known biological activity
• Secreted in 11 ratio with insulin (A, B)
• Insulin is removed by liver (60), C peptide is
  not
• Therefore, C peptide is a good measure of insulin
  (A, B) secretion.
• Proinsulin (B, C, A) has modest insulin-like
  activity
• 1/20th as potent as insulin (A, B)
• ? cell secretes about 5 as much proinsulin as
  insulin (A, B).

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Glucose Tolerance Tests

• Oral glucose tolerance test (OGTT)
• Most commonly used
• 2 hours after glucose administration, blood is
  drawn and glucose levels analyzed
• Determine how quickly orally administered glucose
  is cleared from the blood
• Intravenous glucose tolerance test (IVGTT)
• Used to look at early insulin secretion
  abnormalities.

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Secretion of Insulin

• Glucose is the major regulator of insulin
  secretion
• Plasma glucose after o/n fast is 4-5mM, after
  a very large meal is 10mM.
• Small increases/decreases in plasma glucose
  cause large increases/decreases in insulin
  secretion

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Secretion of Insulin and Diabetes

• In type 1 diabetes due to destruction of
  pancreatic islets, causes little increase in
  insulin

Insulin Glucose
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Intravenous Glucose

• Earliest detectable metabolic defects in diabetes
  is loss of first phase, detected by glucose
  tolerance test.

• Intravenous glucose administration increases
  plasma glucose very rapidly
• Causes 2 phases of insulin secretion
• First phase
• lasts 2-5 minutes
• Secretion of preformed insulin
• Second phase
• Lasts as long as glucose levels are elevated
• Secretion of preformed and newly synthesized
  insulin

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Diabetes

• A number of disorders that cause defects in
  regulation of the synthesis, secretion, or action
  of insulin.
• Causes hyperglycemia
• 2 types of diabetes
• Type 1 (insulin-dependent diabetes)
• Type 2 (insulin-independent diabetes)
• Chronic elevated glucose levels cause tissue
  damage, particularly in the eyes, kidneys, and
  peripheral nerves.

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Type 1 Diabetes

• Insulin-dependent
• Primarily affects children
• Usually due to autoimmue disorder that targets ?
  cells of the pancreas.
• Loss of insulin production, no effect on glucagon
  production
• Essentially causes starvation because glucose is
  necessary to utilize glucose
• Liver produces ketones and glucose at higher rate
  than can be used
• High glucose and ketone levels provide high
  solute level and causes osmotic diuresis
  (increased urination)
• Keto acids eventually cause metabolic acidosis
• Without insulin patients will die of diabetic
  ketoacidosis

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Type 2 Diabetes

• Non-insulin-dependent diabetes
• More complex syndrome
• Insulin resistance
• Down-regultion of insulin receptors
• Due to insulin receptor mutations (10)
• Antibodies to insulin receptor
• Defect in glucose transporter
• Have enough insulin activity that severe
  ketoacidosis does not develop

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Insulin

• Fasting use fat and muscle to make glucose
• Glucose levels low
• ? cells of pancreas produce less insulin
• ? cells produce less glucagon
• Lipids mobilized for fuel
• Protein degraded and amino acids exported
• Feeding store glucose as fat and glycogen
• Glucose levels high
• ? cells produce more insulin
• ? cells produce more glucagon
• Lipids synthesized
• Protein preserved

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Insulin

• Regulates the concentration of glucose in the
  plasma very closely.
• Provides the central nervous system with constant
  supply of glucose.
• Plasma glucose concentration below 2-3 mM
  (hypoglycemia) results in confusion, seizures,
  and coma.
• Persistent elevation of glucose (hyperglycemia)
  is characteristic of diabetes.

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How does Insulin Regulate Glucose Concentration?

• Activates glucose transporters
• Activates enzymes involved in lipid metabolism
  (energy storage)
• Activates transcription of genes that promote
  glycogen synthesis (energy storage)

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Insulin activates glucose transporters

• Insulin binds its receptor - receptor tyrosine
  kinase
• Receptor phosphorylates insulin-receptor
  substrates (IRS-1, 2, 3, 4)
• Phosphatidyl inositol 3-kinase (PI-3-K) is
  activated by IRS, resulting in activation of
  PI-dependent kinase (PDK)
• PDK phosphorylates and activates protein kinase B
  (PKB) resulting in GLUT4 glucose transporters
  inserting into membrane

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Insulin stimulates glycogen synthesis

• Insulin --gt receptor --gt IRS-1 --gt PI-3-K --gt PDK
  --gt PKB
• PKB can phosphorylate glucose synthase kinase-3
  (GSK-3) which will inactivate it
• This keeps GSK-3 from phosphorylating and
  inactivating glycogen synthase (GS).
• Results in increase glycogen synthesis (glucose
  storage).

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Insulin promotes protein synthesis

• Insulin --gt receptor --gt IRS-1 --gt PI-3-K --gt PDK
  (PI-dependent kinase)
• PDK phosphorylates and activates mTOR (mammalian
  target of rapamycin).
• mTOR is a ser/thr kinase
• mTOR phosphorylates the binding protein PHAS-1,
  releasing a translational initiation factor (IF)

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Insulin promotes protein synthesis

• Insulin --gt receptor --gt IRS-1 --gt PI-3-K --gt PDK
  --gt mTOR
• mTOR also phosphorylates p70-S6 kinase which
  phosphorylates the ribosomal S6 protein which is
  necessary for translation