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Glucoregulatory systems

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Increases glycogenesis and glycolysis. Glycogen. Glucose ... Glycogenesis. Glycogenolysis. Gluconeogenesis. Glycolysis. Ephinephrine. Types of Hypoglycemia ... – PowerPoint PPT presentation

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Title: Glucoregulatory systems


1
Glucoregulatory systems
  • Ichiro Matsumura
  • December 1, 2003

2
How do tissues communicate about blood glucose
levels?
  • Hormones
  • Insulin
  • Glucagon
  • Nervous system
  • Ephinephrine
  • Cortisol
  • Circulating substrates

3
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
4
Structure of Insulin
  • 2 polypeptide chains linked by disulfide bonds
  • Disulfide bonds also link A chain together
  • Insulin forms hexamer for greater stability

5
Cellular Secretion of Insulin
6
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

7
Recombinant DNA technology to produce insulin
8
Making Insulin Better
Small changes in amino acid sequence that allows
the protein to be more stable as individual
proteins not hexamer (monomeric insulin)
9
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

10
Inhibition of insulin secretion
  • Decrease in dietary fuels or during periods of
    trauma
  • Epinephrine release by adrenal medulla more on
    this later

11
Metabolic effects of insulin
  • Carbohydrate
  • Lipid
  • Protein

12
Insulin induces glucose uptake
Increases glucose uptake through increased
glucose transporters
Glut4 protein in adipocytes
13
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
14
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

15
Protein metabolism and insulin
  • Stimulation of entry of amino acids into cells
    and protein synthesis

aa
1.
Protein synthesis
2.
16
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17
Mechanism for insulin action
  • Activation of the receptor leads to tyrosine
    phosphorylation
  • Phosphorylation of other proteins leads to
    biological action of insulin

18
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
19
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
20
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

21
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)

22
Glucagon activated signal transduction
23
Control of blood glucose levels
24
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

25
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

26
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

27
Effects of Epinephrine on metabolism
  • Lipolysis
  • Inhibits insulin secretion
  • Inhibits uptake of insulin

Glycogen Glucose Pyruvate
Glycogenesis
Glycogenolysis
Ephinephrine
Glycolysis
Gluconeogenesis
28
Types of Hypoglycemia
  • Postprandial
  • Exaggerated insulin release following a meal
  • Treatment is frequent small meals
  • Fasting
  • Alcohol related

29
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30
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

31
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
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