Unit Fourteen: Endocrinology and Reproduction Chapter 78: Insulin, Glucagon, and Diabetes Mellitus Guyton and Hall, Textbook of Medical Physiology, 12 edition

Physiologic Anatomy of the Pancreas Fig. 78.1 Physiolgic anatomy of an islet of Langerhans in the pancreas

Physiologic Anatomy of the Pancreas Composed of two major types of tissues, the acini, which secrete digestive juices, and the islets of Langerhans, which secrete insulin and glucagon directly into the blood Alpha cells of the islets-secrete glucagon Beta cells-secrete insulin Delta cells-secrete somatostatin

Insulin and Its Metabolic Effects Insulin is a Hormone Associated with Energy Abundance Composed of two amino acid chains, MW 5808 Preproinsulin to a proinsulin to insulin In the blood, it circulates as an unbound form Half-life in circulation is about 6 minutes

Insulin and Its Metabolic Effects Fig. 78.2

Insulin and Its Metabolic Effects Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects Fig. 78.3

Insulin and Its Metabolic Effects Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects Within seconds after insulin binds to its receptors, 80% of the cells increase their uptake of glucose (true of muscle and adipose cells but not the neurons of the brain) Cell membrane becomes more permeable to many amino acids, potassium ions, and phosphate ions, causing increased transport of these substances into the cell

Insulin and Its Metabolic Effects Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects c. Slower effects occur during the next 10-15 minutes to change the activity levels of many more intracellular metabolic enzymes d. Much slower effects continue for hours and even several days; enzymatic functions and protein synthesis

Insulin and Its Metabolic Effects Effect of Insulin on Cbh Metabolism Promotes muscle glucose uptake and metabolism; if the muscle is not exercising, the glucose is stored as muscle glycogen Promotes liver uptake, storage, an use of glucose Insulin inactivates liver phosphorylase and prevents the splitting of glycogen into glucose Insulin causes the enhanced uptake of glucose from the blood by liver cells; increases the activity of glucokinase

Insulin and Its Metabolic Effects Effect of Insulin on Cbh Metabolism Increases the activity of the enzymes that promote glycogen synthesis Glucose is released from the liver between meals 1) Decreasing blood glucose causes the pancreas to decrease insulin secretion 2) Lack of insulin reverses the effects of glycogen storage 3) Lack of insulin activates the splitting of glycogen into glucose; glucose phosphatase is activated

Insulin and Its Metabolic Effects Effect of Insulin on Cbh Metabolism Insulin promotes the conversion of excess glucose into fatty acids and inhibits gluconeogenesis in the liver In the brain most of the cells are permeable to glucose and can use glucose without the intermediation of insulin

Insulin and Its Metabolic Effects Effect of Insulin on Fat Metabolism Promotes fat synthesis and storage Increases the transport of glucose into liver cells; after the liver glycogen concentration reaches 5-6%, the glucose becomes available to form fat (split to acetyl CoA from pyruvate to make fatty acids) Excesses of citrate and isocitrate are formed when excess amounts of glucose are being used for energy—activate enzymes for the first steps of fatty acid synthesis

Insulin and Its Metabolic Effects Effect of Insulin on Fat Metabolism Promotes fat synthesis and storage Most of the fatty acids are then synthesized within the liver and used to form triglycerides Role of insulin in the storage of fat in the adipose cells Insulin inhibits the action of hormone sensitive lipase Promotes glucose transport through the membrane into the fat cells

Insulin and Its Metabolic Effects Effect of Insulin on Fat Metabolism Insulin deficiency causes lipolysis of storage fat and the release of fatty acids Insulin deficiency increases plasma cholesterol and phospholipid concentrations Excess usage of fats during insulin lack causes ketosis and acidosis

Insulin and Its Metabolic Effects Effect of Insulin on Protein Metabolism Insulin promotes protein synthesis and storage of amino acids Stimulates the transport of many of the aa into cells Increases the translation of mRNA Increases the rate of transcription of selected DNA genetic sequences Inhibits the catabolism of proteins In the liver, insulin depresses the rate of gluconeogenesis

Insulin and Its Metabolic Effects Effect of Insulin on Protein Metabolism Insulin deficiency causes protein depletion and increased plasma amino acids Insulin and growth hormone interact synergistically to promote growth

Insulin and Its Metabolic Effects Effect of Insulin on Protein Metabolism Fig. 78.6 Effect of GH, insulin, and GH plus insulin on growth in a depancreatized and hypophysectomized rat

Insulin and Its Metabolic Effects Mechanisms of Insulin Secretion Fig. 78.7 Basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas

Insulin and Its Metabolic Effects Control of Insulin Secretion Increased blood glucose stimulates insulin secretion Fig. 78.8 Increase in plasma insulin concentration after a sudden increase in blood glucose to 2-3x the normal range

Insulin and Its Metabolic Effects Control of Insulin Secretion Feedback relation between blood glucose concentration and insulin secretion rate- a rise in blood glucose increases the secretion of insulin which in turn increases the transport of glucose into liver, muscle, and other cells Other factors that stimulate insulin secretion-amino acids, GI hormones, other hormones, ANS

Insulin and Its Metabolic Effects Control of Insulin Secretion Fig. 78.9 Approximate insulin secretion at different plasma glucose levels

Glucagon and Its Functions Effects on Glucose Metabolism Causes glycogenolysis and increased blood glucose concentration Glucagon activates adenyl cyclase in the hepatic cell membrane Which causes the formation of cAMP Which activates protein kinase regulator protein Which activates protein kinase Which activates phosphorylase b kinase Which converts phosphorylase b to a Which promotes the degradation of glycogen into glucose-1-phosphate Which is dephosphorylated and glucose is released

Glucagon and Its Functions Effects on Glucose Metabolism Glucagon increases gluconeogenesis Glucagon activates adipose cell lipase-makes increased quantities of free fatty acids available Inhibits the storage of triglycerides In high concentrations-enhances the strength of the heart, increases blood flow in some tissues (kidney), enhances bile secretion, and inhibits gastric acid secretion

Glucagon and Its Functions Regulation of Glucagon Secretion Increased blood glucose inhibits glucagon Increased blood amino acids stimulates glucagon secretion c. Exercise stimulates glucagon secretion

Glucagon and Its Functions Regulation of Glucagon Secretion Fig. 78.10 Approximate plasma glucagon concentration at different blood glucose levels

Glucagon and Its Functions Somatostatin Inhibits Glucagon and Insulin Secretion Almost all factors related to the ingestion of food stimulate somatostatin secretion (increased amino acids, fatty acids, GI hormones, blood glucose) Acts locally within the islets to decrease secretion of insulin and glucagon Decreases the motility of the stomach, duoenum, and gall bladder Decreases secretion and absorption in the GI tract

Diabetes Mellitus Diabetes Mellitus Syndrome of impaired carbohydrate, protein, and fat metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin Type I-insulin dependent diabetes mellitus; lack of insulin secretion Type II-non insulin dependent diabetes mellitus; initially caused by the decreased sensitivity of tissues to insulin (insulin resistance)