Glucagon

 

Glucagon

 Hyperglycemic – Glycogenolytic factor (HGF)

•    Produced by α-cells of islets of Langerhans of Pancreas and act antagonistic to insulin

•    Involved in 

– Rapid mobilization of hepatic glycogen to glucose

•    By Glycogenolysis

Chemistry:

•    Polypeptide hormone consisting of 29AA

– 15 different types of amino acids are present

•    Unlike insulin no cysteine, proline or isoleucine 

–      But tyrosine, methionine and tryptophan are present

–      Amino acid sequence is same in all species • Molecular wt. of glucagon is approximately 3500 D

•    Biosynthesis:

•    Synthesized as pro-glucagon in α-cells

•    Various peptidases hydrolyse pro-glucagon to glucagon and different inactive peptides

–      Carboxy peptidase B

–      Trypsin-like peptidase

•    Peptidases act on both C – & N – terminals

•    Regulation of Secretion:

•    Stimulated by 

–      low blood glucose level

–      Amino acid derived from dietary proteins

–      Low levels of epinephrine

•    Inhibited by elevated blood glucose level

•    Mechanism of Action:

•    Act by binding to G-protein coupled receptor on the membranes of hepatocytes and adepocytes

–      Activates adenylyl cyclase and increases cAMP

–      cAMP then activates protein kinases that regulate the actions of glucagon

•    cAMP also induce the synthesis of specific enzymes by increasing transcription of genes

–      E.g. Glucose-6-phosphatase enzyme Physiological Functions:

•    It influences the metabolism of carbohydrates, proteins and lipids

–      Typically acts opposite to insulin

i) Action on carbohydrates metabolism:

•    Overall it increases the blood sugar levels

–  Cause hyperglycemia

•    a) Increases Glycogenolysis in liver only

–  Muscle cells lack glucagon receptors

•    b) increase gluconeogenesis in liver

–  Protein kinase activity leads to the synthesis of new enzymes involved in gluconeogenesis

•    PEP carboxykinase

•    Pyruvate carboxylase

•    Fructose-1,6-bisphosphatase etc.

•    c) increase glucogenic aminoacids pool in liver

– Increased breakdown and decreased synthesis of proteins

ii) Action on Lipid metabolism:

•    a) Promotes lipolysis

–  Increase breakdown of TG

–  Increased level of FFA

•    FA undergo β-oxidation

–  Increased formation of ketone bodies

•    Thyroid hormones help in lipolytic action of glucagon probably by increasing glucagon receptors on adipocytes

•    b) Decreases lipogenesis

–  Increased FFA inhibits acetyl-CoA carboxylase

–  cAMP phosphorylate acetyl-CoA carboxylase and inactivates it

iii) Action on Protein metabolism:

•    a) Reduces protein synthesis

–  Decreases the incorporation of AA into peptide chains

–  Inactivation of ribosomal components by protein kinases regulated by cAMP

•    b) increase amino acid pool in liver for gluconeogenesis

–  Stimulate protein catabolism, specially in liver

–  Increased uptake of amino acid by liver

•    Lowers plasma amino acids level iv) Action on Heart:

–  Positive ionotropic effect without myocardial arrhythmias (advantage over nor-epinephrine)

–  Increased heart rate and heart contraction

v) Actions on mineral metabolism:

•    Increase K+ release from liver

–  May be due to glycogenolytic activity

•    Decrease plasma Ca²⁺ levels

–  Increase calcitonin release from thyroid gland vi) Calorigenic Actions:

•    Increased hepatic de-amination of amino acids

–  Thyroid activity is increased to utilize these deaminated residues

–  Overall heat of the body increases

•    Increase heat production

•    Raise basal metabolic rate (BMR)