Glucoregulatory systems

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Glucoregulatory systems

• Ichiro Matsumura
• December 1, 2003

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How do tissues communicate about blood glucose
levels?

• Hormones
• Insulin
• Glucagon
• Nervous system
• Ephinephrine
• Cortisol
• Circulating substrates

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Insulin

• Produced by the beta cells of the pancreas
• Anabolic effects on metabolism
• Intravenous administration leads to immediate
  decrease in blood glucose
• Defects can lead to diabetes

duct
Islet of Langerhans cells produce insulin
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Structure of Insulin

• 2 polypeptide chains linked by disulfide bonds
• Disulfide bonds also link A chain together
• Insulin forms hexamer for greater stability

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Cellular Secretion of Insulin
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Production of insulin to treat diabetes

• Discovered in 1921 by Banting and Best
• (won Nobel prize in 1923)
• Porcine insulin
• Only differs from human by one amino acid
• (at the C-terminus)
• Replacement of amino acid allows production of
  human insulin
• Recombinant DNA technology
• 1985 began producing insulin in bacteria

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Recombinant DNA technology to produce insulin
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Making Insulin Better
Small changes in amino acid sequence that allows
the protein to be more stable as individual
proteins not hexamer (monomeric insulin)
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Stimulation of insulin secretion

• Glucose-most important stimulation
• Amino acids -especially arginine
• Secretin release after food ingestion
• May account for much greater increase in insulin
  seen with injestion of food than if given
  intravenously

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Inhibition of insulin secretion

• Decrease in dietary fuels or during periods of
  trauma
• Epinephrine release by adrenal medulla more on
  this later

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Metabolic effects of insulin

• Carbohydrate
• Lipid
• Protein

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Insulin induces glucose uptake
Increases glucose uptake through increased
glucose transporters
Glut4 protein in adipocytes
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Carbohydrate metabolism and insulin

• Affects liver, muscle and adipose tissue
• Inhibits gluconeogenesis and glycogenolysis
• Increases glycogenesis and glycolysis

Glycogen Glucose Pyruvate
Glycogenesis
Glycogenolysis
Insulin
Glycolysis
Gluconeogenesis
Insulin
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Lipid metabolism and insulin

• Decrease in triacylglycerol degradation
• Inhibits the action of hormone sensitive lipase
• Increase in triacylglycerol synthesis
• Increases glucose transport-providing
  glycerol3phosphate
• Increases lipoprotein lipase in adipose tissu,
  providing FA

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Protein metabolism and insulin

• Stimulation of entry of amino acids into cells
  and protein synthesis

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1.
Protein synthesis
2.
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Mechanism for insulin action

• Activation of the receptor leads to tyrosine
  phosphorylation
• Phosphorylation of other proteins leads to
  biological action of insulin

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Time course for insulin action

• Immediate increase in glucose uptake into cells
  (seconds)
• Changes in enzymatic activity (minutes)
• Increase in enzyme synthesis glucokinase, PFK1,
  pyruvate kinaase (hours to days)
• Changes in gene transcription

glu
Glucose transporter
PFK1
enzyme activity
Changes in gene expression
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Glucagon

• Opposes the action of insulin
• Leads to increase in glucose levels in the blood
• Most important effects are glycogenolysis and
  gluconeogenesis

Bruce Lee
Glycogen Glucose Pyruvate
Glycogenesis
Glycogenolysis
Glucagon
Glycolysis
Gluconeogenesis
Glucagon
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Glucagon protein structure

• Single polypeptide chain
• Same sequence in all mammalian species
• Produced by a cells of
• pancreatic islets
• Synthesized similar to insulin requires
  proteolytic cleavages

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Increases in glucagon synthesis

• Low blood glucose
• During overnight fasting prevents hypoglycemia
• Amino acids (inc. insulin and glucagon)
• Prevents hypoglycemia after a protein meal
• Epinephrine (stress causes inc. glucagon)

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Glucagon activated signal transduction
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Control of blood glucose levels
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Control of metabolism by the nervous system

• The nervous system requires glucose for energy
• Hypoglycemia can cause cerebral dysfunction and
  lead to brain death
• Glucagon and epinephrine release and decreased
  insulin release prevent hypoglycemia

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Hypoglycemia Symptoms

• Glucose levels below 45mg/dL
• Adrenergic symptoms anxiety, palpitation,
  tremor and sweating
• Mediated by epinephrine release
• Occur when blood glucose levels fall rapidly
• Neuroglycopenia impaired glucose deliver to the
  brain
• Headache, confusion, slurred speech, seizures,
  coma, and death
• Epinephrine response is not triggered

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Glucoregulatory systems activated by hypoglycemia

• Release of glucagon by pancreas
• Activation of glucoreceptors in the hypothalamus
• Secretion of epinephrine
• Release of hormones by the anterior pituitary

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Effects of Epinephrine on metabolism

• Lipolysis
• Inhibits insulin secretion
• Inhibits uptake of insulin

Glycogen Glucose Pyruvate
Glycogenesis
Glycogenolysis
Ephinephrine
Glycolysis
Gluconeogenesis
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Types of Hypoglycemia

• Postprandial
• Exaggerated insulin release following a meal
• Treatment is frequent small meals
• Fasting
• Alcohol related

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Alcohol Metabolism

• Aldehyde dehydrogenase is blocked by
  disulfiram-help control alcohol ingestion
• Massive increase in NADH
• Favors the production of lactate and malate
  intermediates in gluconeogenesis
• Reduced glucose synthesis because these
  intermediates are diverted into other pathways

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Main points of todays lecture

• Insulin stimulates anabolic pathways in
  metabolism
• Glucagon controls catabolic pathways in
  metabolism
• Nervous system also controls metabolic pathways
• Hypoglycemia can occur when metabolic pathways
  are not controlled