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

2. Glucagon – the definition hyperglycemic agent
A peptide hormone secreted by the α - cells of the islets of Langerhans in response to hypoglycemia
It increases plasma glucose level by ↑hepatic Glycogenolysis opposite to the action of Insulin

3. Glucagon – the back ground A catabolic hormone
Both, Insulin ad Glucagon play a central role in glucose homeostasis at mg/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
– merrium.com

4. Glucose Homeostasis – Insulin/ Glucagon

5. Glucagon – the Target tissues - 2 No 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 glucose level in hypoglycemia –

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 1 α – Islets cells
Glucagon is produced as a Prohormone with 160 AAs in RER of α - Islet cells by a single gene
It is cleaved in the RER of α - cells to 4 peptides including 29 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

9. Structure of Glucagon

10. Glucagon – regulation of secretion hypoglycemia 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 stimulators Hypoglycemia - 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 inhibitors major 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 action Formation 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 role on 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 mg/dl
It has got minor effect on fat metabolism
With no significant action on protein metabolism

19. Glucagon – major metabolic role Liver is the key player

20. Glucagon - Effects on CHO metabolism Glycogenolysis
Glucagon stimulates Glycogenolysis in hypoglycemia and 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 metabolism Liver is a major shareholder

22. Glucagon - Effects on lipid metabolism Lipolysis – 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 metabolism Proteolysis /Gluconeogenesis
Glucagon promotes Proteolysis (of skeletal muscles) and releases AAs into the circulation
These AAs are not used for Proteogenesis but for hepatic Gluconeogenesis
This serves to ↑the blood glucose level through the action of Glucagon to relieve hypoglycemia

24. Glucagon - secretion abnormalities Deficiency - Hypoglycemia
Diseases associated with high or low secretion of Glucagon are rare
Excess of Glucagon is due to α – cell hyperplasia and carcinoma that leads to wasting syndrome
Glucagon deficiency produces low hepatic glucose production and fasting hypoglycemia

25. Comparison B/W Insulin and Glucagon