Give an account of the regulation of secretion and the functions of Insulin.

Outline:

·        Factors regulating secretion:

- nutrients

- GI hormones

- autonomic nervous system

- counter-regulatory hormones

·        Role in metabolism: carbohydrate, lipid, protein

Essay:

            Insulin is a polypeptide containing 2 chains of amino acids linked together by disulfide linkages. It is synthesized in the endoplasmic reticulum of the b cells of the pancreatic islet. Insulin is an anabolic hormone that directs the flow of nutrients toward utilization and storage and suppresses their mobilization.

            Insulin secretion is governed by a feedback relationship with exogenous nutrient supply. Glucose is the primary regulator of insulin secretion. Virtually no insulin is secreted below a blood glucose level of 50 mg/dL. Glucose enters b cells via the GLUT 2 transporter, which does not depend on insulin for activation. The glucose is metabolized, generating ATP. The ATP closes ATP-sensitive K⁺ channels, and the resultant decrease in K⁺ channels, and the resultant decrease in K⁺ efflux depolarizes the cell membrane. This opens voltage-sensitive Ca²⁺ channels, and Ca²⁺ enters the cells and activates Ca²⁺-dependent protein kinases, which in turn trigger the release of insulin by exocytosis. Insulin secretion is also stimulated by amino acids that result from digestion of protein in a meal. The basic amino acids, arginine, lysine and others like leucine are the most potent stimulants, as do ketoacids such as acetoacetate. Triglycerides and fatty acids exert only a small stimulatory effect on insulin release.

            When glucose is given orally, a greater insulin response is elicited than when plasma glucose is comparably elevated by intravenous administration. This augmented insulin response to oral glucose is accounted for by one or more gastrointestinal hormones that are released in response to meals and are capable of potentiating glucose-stimulated insulin secretion. Glucagon, secretin, CCK, gastrin and GIP all have such an action.

            Both potassium and calcium are essential for normal insulin responses to glucose. Branches of the right vagus nerve innervate the pancreatic islets, and stimulation of the right vagus causes increased insulin secretion via M₄ receptors. Sympathetic nerves and epinephrine stimulate insulin secretion via b-adrenergic receptors but inhibit insulin secrretion via a-adrenergic receptors.

            A variety of hormones, collectively known as counter-regulatory hormones antagonizes the actions of insulin and helps to prevent hypoglycaemia under conditions when blood glucose is low, as during exercise or fasting. These hormones are glucagon, cortisol, growth hormone and epinephrine. Insulin has a negative feedback effect on its own secretion, and this effect is independent of any effect on plasma glucose. Leptin can also inhibit insulin release. The net result of these many influences of insulin secretion is to maintain an average basal peripheral plasma insulin level of 10 mU/ml.

            Binding of insulin to its receptor triggers the tyrosine kinase activity of the b subunits, producing autophosphorylation of the b subunits on tyrosine residues. The fully active tyrosine kinase phosphorylates tyrosines on one or two specific insulin receptor substrates, which act as a docking site for other protein kinases.

            Insulin is the hormone of abundance. When the influx of nutrients exceeds energy needs and rates of anabolism, insulin induces efficient storage of the excess nutrients while suppressing mobilization of endogenous substrates. The stored nutrients can then be made available during subsequent fasting periods to maintain glucose delivery to the central nervous system and free fatty acid delivery to the muscle mass and viscera.

The net effects of insulin on metabolism of nutrients are as follows:

Carbohydrate: stimulates glucose oxidation and storage while inhibiting glucose production.

Fat: enhances storage of fatty acids and blocks their mobilization and oxidation.

Protein: enhances protein and amino acid sequestration in all target tissues.

The major targets for insulin action are the liver, adipose tissue, and the muscle mass.

            In the liver, insulin enhances inward movement of glucose by inducing hepatic glucokinase which catalyzes phosphorylation of the incoming glucose to glucose-6-phosphate. Insulin then promotes storage of glucose as glycogen by activating the glycogen synthase-enzyme complex. At the same time, insulin stimulate glycolysis, which converts glucose to pyruvate and lactate, by increasing the activities of phosphofructokinase and pyruvate kinase. Insulin also rapidly inhibits hepatic glycogenolysis and therefore hepatic glucose output by decreasing glycogen phosphorylase activity. In addition, insulin inhibits gluconeogenesis by decreasing the hepatic uptake of precursor amino acids and their availability from muscle. Free fatty acids entering from the circulation are shunted away from b oxidation and ketogenesis. Insulin activates acetyl CoA carboxylase and fatty acid synthase, key enzymes in fatty acid synthesis. The antiketogenic action of insulin in the liver is mediated by stimulation of malonyl CoA formation because malonyl CoA inhibits carnitine acyltransferase, the enzyme responsible for transferring fatty acids from the cytoplasm into the mitochondria for oxidation and conversion to ketoacids. Insulin also favors hepatic synthesis of cholesterol from acetyl CoA by activating the rate-limiting enzyme HMG-CoA reductase.

            In the muscle, insulin stimulates the transport of glucose into muscle cells. Depending on the insulin concentration, 20% to 50% of the glucose that enters undergoes oxidation. The remainder is specifically directed to storage as glycogen by insulin activation of glycogen synthase. Within muscle, insulin suppresses lipoprotein lipase, inhibiting fatty acid uptake and oxidation. Insulin stimulates the sodium-dependent transport of amino acids across the muscle cell membrane. It inhibits proteolysis by suppressing the release of branched-chain and aromatic amino acids from muscle and inhibition of their oxidation.

In adipose tissue, insulin stimulates the transport of glucose into the cells. Much of this glucose is then converted to glycerophosphate, which is used in the esterification of fatty acids and permits their storage as triglycerides. Adipose tissue can also metabolize glucose by means of the pentose phosphate pathway, producing NADPH, essential for fat synthesis. Insulin suppresses lipolysis and release of stored fatty acids by inhibiting hormone-sensitive lipase activity. It also actively promotes deposition of circulating fat into adipose tissue by activating lipoprotein lipase.