Biochemistry of Insulin & Glucagon PDF

BIOCHEMISTRY OF INSULIN & GLUCAGON BBM1233 MEDICAL BIOCHEMISTRY 2  Learning Objectives At the end of this lecture, the student will be able to: Explain the biosynthesis of insulin and glucagon Explain the mechanisms that regulate secretion of insulin and glucagon Exp...

BIOCHEMISTRY OF INSULIN & GLUCAGON BBM1233 MEDICAL BIOCHEMISTRY 2  Learning Objectives At the end of this lecture, the student will be able to: Explain the biosynthesis of insulin and glucagon Explain the mechanisms that regulate secretion of insulin and glucagon Explain the mechanism of action of insulin and glucagon Describe the effects of insulin and glucagon upon carbohydrate, protein and lipid metabolism  Insulin Protein synthesized and secreted by the β-cells of the islets of Langerhans of the pancreas Responsible for regulating blood glucose levels Normal insulin level in blood: 5-15 mIU/mL  Insulin is a protein hormone with 2 polypeptide chains (glycine & phenylalanine chains) The α-chain has 21 amino acids and β-chain has 30 amino acids 2 chains are joined together by 2 interchain disulphide bonds An intrachain disulphide bond in α-chain between 6th and 11th amino acids  Biosynthesis of Insulin The insulin is synthesized as preproinsulin Preproinsulin is rapidly converted to proinsulin in the endoplasmic reticulum Pro-insulin is transported to Golgi apparatus where it is cleaved by a protease and insulin is formed  Secretion of Insulin Insulin secretion is in response to an elevation of glucose level The GLUT2 allows the entry of glucose into the β-cell Glucose is further metabolized producing ATP This closes potassium channels and activates the calcium channels The influx of Ca2+ causes release of insulin into the blood Factors Affecting Insulin Secretion Glucose Gastrointestinal hormones (e.g. secretin, cholecystokinin & gastrin) Incretin hormones (e.g glucagon-like peptide-1 & glucose dependent insulinotropic polypeptide) Both secreted by specialized cells in the gastrointestinal tract and have receptors located on the pancreatic islet cells Proteins & amino acids (e.g. leucine and arginine) Epinephrine During stressful conditions or exercise, adrenal medulla release adrenaline. This suppresses insulin release, and at the same time, mobilizes glucose from liver for energy purpose  Degradation of Insulin Insulin is rapidly degraded by the liver Plasma half-life is less than 5 minutes An insulin specific protease (insulinase) is involved in the degradation of insulin  Mechanism of Insulin Action Insulin receptors and signal transduction Insulin acts by binding to a plasma membrane receptor on the target cells Insulin binds to the α subunits of the receptor. Oligomerization of α units would trigger the tyrosine kinase activity of the β subunit The phosphorylated sites act as binding sites for insulin receptor substrates (IRS) This recruit GLUT4 from the intracellular vesicular pool to muscle & adipocyte cell surface  Gene transcription (new enzyme synthesis) Insulin acts at the transcriptional level to regulate synthesis Insulin induces the following enzymes: Glucokinase Pyruvate kinase Phosphofructokinase Acetyl CoA carboxylase Insulin represses the following enzymes: Glucose-6-phosphatase Phosphoenolpyruvate carboxykinase Fructose-1,6-bisphosphatase  Activation of enzymes Insulin activates the existing molecules of enzymes by covalent modification (phosphorylation or dephosphorylation) Insulin activates protein phosphatase I which dephosphorylates enzyme proteins DNA synthesis Through the IRS pathway, insulin increases DNA synthesis, cell growth and anabolism  Physiological Actions of Insulin (Metabolic Effect of Insulin) Insulin plays a role in regulation of the metabolism of carbohydrates, lipids & proteins Uptake of glucose by tissues Insulin facilitates the membrane transport of glucose. Facilitated diffusion of glucose in muscle is enhanced by insulin GluT4 is under the control of insulin. GluT4 is the major glucose transporter in skeletal muscle and adipose tissue  Utilization of glucose Glycolysis is stimulated by insulin Hypoglycemic effect Insulin lowers the blood glucose level by promoting utilization & storage. Insulin inhibits gluconeogenesis and glycogenolysis Lipogenesis Lipogenesis is favored by providing more acetyl CoA by pyruvate dehydrogenase reaction & also by increasing the availability of NADPH Anti-lipolytic effect Insulin inhibit lipolysis in adipose tissue due to inhibition of hormone sensitive lipase. The increased level of FFA in plasma in diabetes is due to the loss of this inhibitory effect of lipolysis  Glucagon Protein synthesized and secreted by the α-cells of the islets of Langerhans of the pancreas Having the opposite effect of insulin Normal glucagon level in blood: 50-100 pg/mL Is a polypeptide hormone with 29 amino acids Plasma half-life is about 5 minutes Is degraded in the liver & kidney  Biosynthesis of Glucagon Glucagon is synthesized initially as proglucagon (160 amino acids) Proglucagon undergoes cleavage and give rise to glucagon Factors Affecting Glucagon Secretion Decrease in blood glucose level Amino acids (e.g., arginine, alanine) derived from a protein- containing meal also will induce glucagon release Epinephrine and norepinephrine, in the adrenal medulla and sympathetic nervous system, stimulate glucagon secretion from pancreatic cells Free fatty acids and ketone bodies suppress secretion of glucagon Insulin Somatostatin inhibits the secretion of glucagon Mechanism of Glucagon Action Glucagon combines with a membrane bound receptor This activates the GDP-bound G-protein, by converting it into GTP The α subunits of the G protein dissociates from the β and γ subunits The α subunits binds to GTP. The GTP-G protein activate adenylate cyclase to convert ATP to cAMP cAMP combines with the regulatory subunit of the protein kinase The active protein kinase will phosphorylate enzyme proteins and alter their activity (e.g. activation of glycogen phosphorylate, inactivation of glycogen synthase)  Physiological Actions of Glucagon Glycogenolysis The active form of glycogen phosphorylase is formed under the influence of glucagon. Liver is the primary target for the glycogenolytic effect of glucagon Gluconeogensis Gluconeogenesis is favoured by glucagon by inducing enzymes like PEPCK, glucose-6- phosphatase and fructose-1,6- bisphosphatase Increases plasma FFA level In adipose tissue glucagon favours beta-oxidation, as it activates carnitine acyl transferase Inhibit glycogen synthesis GK: Glucokinase PFK: Phosphofructokinase PK: Pyruvate kinase PEPCK: Phosphoenolpyruvate carboxykinase G6 Pase: Glucose-6-phosphatase F-bisphosphatase: Fructose-1,6-bisphosphatase