Glucagon – A hormone from pancreas Lecture NO: 2 nd MBBS

1. Glucagon – A hormone from pancreas Lecture NO: 2nd MBBS Dr Muhammad Ramzan

2. Glucagon – the definitionhyperglycemic agent • A peptide hormone secreted by the α - cells of the islets of Langerhans in response to hypoglycemia • It increases plasma glucose levelby ↑hepatic Glycogenolysis opposite to the action of Insulin • www.dictionary.com

3. Glucagon – the back groundA catabolic hormone • Both, Insulin ad Glucagon play a central role in glucose homeostasis at - 90 - 110mg/dl • Glucagon induces the liver to deliver glucose through: Glycogenolysis and Gluconeogenesis • It is a major player in providing glucose to the brain in hypoglycemia - the only nutrient for the neurons and RBC • www.webster – merrium.com

4. Glucose Homeostasis – Insulin/ Glucagon

5. Glucagon – the Target tissues - 2No receptors for muscles • These are the tissues with Glucagon receptors and are encoded by a receptor gene • Target tissues are 1Hepatocytes and 2 Adipocytes • Muscles have no receptors for Glucagon and do not contribute to↑blood glucoselevel in hypoglycemia • www.onlinelibrary.wiley.com – www.nibi.nlm.nih.gov/gene

6. Glucagon – the biosynthesis 2 major sources • There are 2 major sources for Glucagon synthesis • α – cells in Islets of Langerhans • L- Cells – Intestinal endocrine cells of the : • small/large intestine • It is also synthesized in brain and salivary glands

7. Glucagon – the biosynthesis 1α – Islets cells • Glucagon is produced as a Prohormone with 160 AAs in RER of α - Islet cellsby a single gene • It is cleaved in the RER of α - cells to 4 peptidesincluding29 Amino acids as Glucagon • It Is stored as secretary vesicles in α- cell cytoplasm • It is released in response to a stimulus - Hypoglycemia

8. Glucagon – the biosynthesis 2 • Glucagon is also produced by the L- cells of small intestine • These are intestinal epithelial /endocrine cells of the small and large intestine that produce : • GLP-1 and GLP-2 - Glucagon like peptides • GLP – 1 Promotes Glucose homeostasis and • GLP- 2 intestinal epithelial growth • www.clinicalgate.com

9. Structure of Glucagon

10. Glucagon – regulation of secretionhypoglycemia is major stimulator • Regulation of Glucagon is complex and depends upon hypoglycemia and nutrients like : • 1. CHOs (glucose) , Lipids,(FA) and Proteins (AA) • Hormonal interactions - Insulin and Glucagon

11. Glucagon regulators cont.stimulators/inhibitors • Autonomic nervous system • Physical factors : Trauma, surgery and infections • Some are stimulators, while others are inhibitors for the Glucagon secretion

12. Glucagon secretion – the stimulatorsHypoglycemia - the major one • Hypoglycemia: major (≤ 70mg/dl) Fasting/starvation/exercise • Diet : Protein rich diet – AAs (Leucine) • Hormones: GIT - Gastrin and Cholicystokinin • Neurotransmitters like Catecholamine and Acetylcholine • Parasympathetic Nervous System

13. Glucagon secretion – the inhibitorsmajor 2 - Hyperglycemia and Insulin • Diet : CHO and fat rich diet including Glucose, Ketone bodies and fatty acids • Hyperglycemia (≥ 160mg/dl) • Hormones like Insulin

14. Glucagon – the mechanism of action GPCR • Glucagon is a protein hormone with the action similar to the rest of the ones • Glucagon binds to its receptor/ GPCR and produces conformation changes in the membranous portion • This activates Cytoplasmic G proteins which has α, β, and γ subunits in the Islet α – cell

15. Glucagon – The mechanism of action Activation G - Protein and enzyme • It results in the replacement of the α -GDP molecule with a α-GTP molecule. • This substitution causes the release of α - subunit from the β and γ subunits. • The α GTP subunit activates the membranous enzyme Adenylate Cyclase.

16. GPRC activation

17. Glucagon– mechanism of actionFormation of c - AMP • Adenylate Cyclase produces c AMP from ATP which • activates cAMP dependent protein kinase A • It Phosphorylates a no of proteins/enzymes including Glycogen Phosphorylase converting it to Phosphorylase A • An enzyme responsible for the release of Glucose – 1- phosphate from Glycogen to↑blood glucose level

18. Glucagon – the metabolic roleon CHO, fats and proteins • The major role of Glucagon is on glucose metabolism • Glucagon ↑ blood glucose level when it is too low : • ≤ 70mg/dl and to maintain it at normal level - 90- 110mg/dl • It has got minor effect on fat metabolism • With no significant action on protein metabolism

19. Glucagon – major metabolic roleLiver is the key player

20. Glucagon - Effects on CHO metabolismGlycogenolysis • Glucagon stimulates Glycogenolysis in hypoglycemiaand glucose is released to↑ its blood level • It promotes Gluconeogenesis- AAs to glucose • It inhibits synthesis of glycogen in liver • Antagonistic to insulin secretion and actions

21. Glucagon – effects on CHO metabolismLiver is a major shareholder

22. Glucagon - Effects on lipid metabolismLipolysis – β oxidation and Ketogenesis • Glucagon has got minor effects on fat metabolism • Promotes Lipolysis and↑ FA level by releasing TG from the adipose tissues • It ↑ β oxidation of FAs and hepatic Ketogenesis to conserve glucose in hypoglycemia • It reduces Lipogenesis

23. Glucagon - Effects on protein metabolismProteolysis /Gluconeogenesis • Glucagon promotes Proteolysis(of skeletal muscles) and releases AAs into the circulation 1 • These AAs are not usedfor Proteogenesis but for hepatic Gluconeogenesis 2 • This serves to ↑the blood glucose level through the action of Glucagon to relieve hypoglycemia

24. Glucagon - secretion abnormalitiesDeficiency - Hypoglycemia • Diseases associated with high or low secretion of Glucagon are rare • Excess of Glucagon is due to α – cell hyperplasiaand carcinoma thatleads to wasting syndrome • Glucagon deficiencyproduces low hepatic glucose production and fasting hypoglycemia

25. Comparison B/W Insulin and Glucagon