Glucagon – A hormone from pancreas Lecture NO:1st BDS Dr Muhammad Ramzan

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, opposite to the action of Insulin by ↑ hepatic Glycogenolysis

Glucagon – the back ground Both, Insulin ad Glucagon play a central role in glucose homeostasis - 90 - 110mg/dl Glucagon induces the liver/ other tissues 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

Glucose Homeostasis – Insulin/ Glucagon

Glucagon – the Target tissue - 2 No receptors for muscles These are the tissues with Glucagon receptors Hepatocytes and Adipocytes Muscles have no receptors for Glucagon and do not contribute in ↑blood glucose level in hypoglycemia

Glucagon – the biosynthesis 2 sources There are 2 sources for Glucagon synthesis α – cells in Islets of Langerhans L- Cells – Intestinal mucosal cells

Glucagon – the biosynthesis 1 α – Islets cells Glucagon is secreted as a Prohormone having 160 AAs in RER of α - Islet cells It is cleaved in the RER of α - cells to 4 peptides including 29 Amino acids Glucagon Is packed in Golgi complex and stored as secretary vesicles in α- cell cytoplasm It is released in response to a stimulus - Hypoglycemia

Glucagon – Biosynthesis in L- Cells

Glucagon – the biosynthesis 2 L- cells in intestinal mucosa Glucagon is also secreted in the L- cells of small intestine These are mucosal cells with granules of hormones such as Glucagon - like peptide 1 Processing results in the formation of different glucagon like peptides, some with physiological importance

Glucagon – the structure

Glucagon – regulation of secretion hypoglycemia is major stimulator Regulation of Glucagon secretion is complex and depends upon fed/fasting state and nutrients like : CHOs (glucose, Ketone) ; Lipids,(FA) and Proteins (AA) Hormones levels and interaction - Insulin and Glucagon Autonomic nervous system Physical factors :trauma,surgary and infections Some may stimulate, while others suppress its secretion

Glucagon secretion – the stimulators Hypoglycemia ≤ 70mg/dl – the major one Hypoglycemia: Fasting/starvation, exercise and period B/W the diet Diet : protein rich diet – AAs (Leucine) Hormones: GIT hormones like Gastrin and Cholicystokinin Neurotransmitters like Catecholamine and Acetylcholine Parasympathetic Nervous System

Glucagon secretion – the inhibitors Hyperglycemia and Insulin Diet : CHO and fat rich diet including: Glucose, Ketone and fatty acids Hyperglycemia (≥ 160mg/dl Hormones like Insulin

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 theI slet α – cell

Glucagon – The mechanism of action Activation G - Protein and enzyme It results in the replacement of the α -GDP molecule that 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.

GPRC activation

Glucagon– mechanism of action Formation of c - AMP Adenylate Cyclase produces c AMP from ATP which activates cAMP dependent protein kinase A It Phosphorylates activates 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

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 hypoglycemia - ≤ 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

Glucagon – major metabolic role Liver is the key player

Glucagon - Effects on CHO metabolism Glycogenolysis In hypoglycemia, Glucagon stimulates hepatic Glycogenolysis and glucose is released to ↑ its level It inhibits hepatic Glycogenesis by inhibiting hepatic Glycogen Synthase 1 It stimulate Gluneogenesis – a process of converting amino acids to glucose 2

Glucagon- Glycogenolysis

Glucagon – effects on CHO metabolism Liver is a major shareholder

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

Glucagon - Effects on protein metabolism promotes Gluconeogenesis Glucagon promotes Proteolysis (of skeletal muscles) and releases AAs into the circulation The free 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

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

Comparison B/W Insulin and Glucagon