This presentation includes information about secretion of glucagon, inhibitors, regulation of secretion, mechanism of action & actions of glucagon. It also includes ways to prevention of occurrence of hyperglycemia.
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Glucagon
1. Glucagon
Dr. Rupali A. Patil
Associate Professor, Pharmacology Department
GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical
Education & Research, Nashik
2. GLUCAGON
• Peptide hormone secreted by pancreatic alpha cells.
• Glucagon is a polypeptide (29 amino acid) with a molecular weight of 3500.
• Counterregulatory hormone: opposes insulin action.
• Other counter-regulatory hormones: epinephrine, norepinephrine, cortisol, GH.
• Binds G-protein coupled receptors in specific tissues (i.e. liver).
3. GLUCAGON SECRETION
Pancreatic alpha cell
• Glucagon: single polypeptide chain
• Pre-proglucagon: cleaved to produce
diff. products in diff. tissues (i.e. intestinal GLP-1)
• Pre-proglucagon --> --> --> glucagon
Stored in dense granules
Released by Exocytosis.
Ca is needed for exocytosis.
4. PLASMA LEVELS
Circulating Glucagon – Unbound.
Basal level in Fasting – 100-150 pg/ml.
Half life – 6 min (5-9 min)
Secretion Rate 100 -150 μg/day.
Degradation – in liver & kidney
5. Activate secretion:
• Low blood glucose (primary stimulus)
• Stress hormones: (nor)epinephrine override alpha cell's response during
physiologic stress
• Amino acids: high protein meal stimulates glucagon secretion (counters insulin
secretion)
• Gi hormones (cck, gastrin)
• Cortisol, growth hormone
• Exercise
• Infections
• Adrenergic stimulus, ACh
11. Actions
• Hepatocytes: receptors for glucagon and epinephrine
• Counter regulatory hormones control same processes, but respond to other
stimuli (i.e. stress)
• Muscle cells: only receptors for epinephrine NOT glucagon
1. Binds G-protein coupled receptor on hepatic cell
2. Alpha subunit exchanges GDP for GTP
3. Alpha subunit activates adenylyl cylase, which activates PKA
4. PKA phosphorylates downstream enzymes
5. Activates glycogen & lipid breakdown, and gluconeogenesis
6. Inhibits glycogen, protein and lipid synthesis
Long-term response: increases transcription of gluconeogenic enzymes (~hrs/days)
13. Carbohydrate metabolism
Glycogen: Increases glycogenolysis in liver &
not in muscle
Glucose-1-Phosphate (inhibit Glycogen synthetase)
Glucose: Increases gluconeogenesis in liver.
Formation of Glucose from Lactate, Pyruvate,
Glycerol & amino acids.
14. Fat metabolism
Increases lipolysis – excess FFA oxidized – energy production -
ketogenesis in liver.
Increases release of FFA & Glycerol from adipose tissue and makes it
available for peripheral utilization.
Prevents synthesis of triglycerides
Thus Glucagon – Ketogenic & Hyperglycemic Hormone.
15. Protein metabolism
Increases Gluconeogenesis by increasing transport of Amino Acids into liver.
Lowers plasma amino acids.
CALORIGENIC EFFECT
• Due to increased hepatic deamination of amino acids
16.
17. Other actions
Inhibit renal tubular Na reabsorption –
• Natriuresis.
Increases Cardiac force of contraction – activation of myocardial Adenyl cyclase.
Stimulate secretion of growth hormone, insulin & Somatostatin
Regulation of appetite.
Increases secretion of bile.
Inhibits secretion of gastric juice.
20. CLINICAL CORRELATION
• Hypoglycaemia
• Acute drop in blood glucose levels to below 60 mg/dL
• Symptoms range from dizziness to coma and even death
• Brain and red blood cells depend on glucose for energy
21. PREVENTIONOF OCCURRENCE OF HYPERGLYCEMIA
Hyperglycemia after a carbohydrate meal or mixed meal is
prevented by 4-5 times increase in INSULIN secretion.
Increase uptake & utilization as chief fuel
Promotes store of glucose as glycogen in liver & TG in adipose tissue.
Inhibit Gluconeogenesis & Glycogenolysis.
22. PREVENTIONOF OCCURRENCE OF HYPERGLYCEMIA…..
• There is only one hormone to prevent Hyperglycemia – Insulin
• But 4 hormones to prevent Hypoglycemia
• Glycogen, Growth hormone, Glucocorticoids & Epinephrine.
• Organs cannot use any fuel other than glucose so vulnerable to
Hypoglycemia are –
Brain, Retina & Germinal Epithelium of gonads
23. PREVENTIONOF OCCURRENCE OF HYPERGLYCEMIA
Role of Glucagon – prevent hypoglycemia between meals (few hours).
Promotes Glycogenolysis & Gluconeogenesis.
Lipolysis in adipose tissue& use FFA as chief fuel.
Role of Epinephrine (Many hours) – stimulate sympathetic nervous
system through Hypothalamus
Supplement actions of Glycogen
Increase FFA production by lipolysis.
Role of growth hormones & Glucocorticoids(Few days) – decrease
peripheral use of Glucose.