Integration of Metabolism Metabolic effects of Insulin and Glucagon Metabolism in the Well fed state Metabolism in the Starvation and Diabetes Mellitus

Metabolic Map

Integration of metabolism Individual tissues don’t function in isolation but form part of community. Communication between tissues is mediated by - Nervous system. - Circulating substrates. - Plasma hormones. * The integration of energy metabolism is controlled mainly by action of hormones. (Insulin, glucagon, epinephrine, norepinephrine). * Changes in hormone levels allow the body to store energy when food is available .

Insulin : polypeptide hormone - β-cells of islets of langerhans of pancreas. - Important in coordinating the utilization of fuel by tissues. Its metabolic effects are anabolic  favoring, for example, the synthesis of glycogen, tricylglycerols, and protein. 1- Semisynthesis of insulin from porcine insulin. 2- Synthesis of human insulin by recombinant DNA technology # 51 amino acid

Insulin Biosynthesis

Formation of Insulin from preproinsulin

* Regulation of insulin secretion Insulin secretion of β- cells is coordinated with the release of glucagon of α- cells. So  Insulin/ Glucagon ratio is regulated the rate of hepatic glucose production and glucose utilization are balanced Insulin secretion is affected by: a)    Glucose β- cells are most important glucose-sensing cells in body. Ingestion of CHO meal  increase level of glucose which is a signal for increasing insulin secretion and decrease glucagon. Glucose is the most important stimulus for insulin secretion. b)   Amino acids Ingestion of protein increase secretion of insulin. Mainly amino acid Arginine which is a potent insulin stimulus.

c) Gastrointestinal Hormones The intestinal hormone secretion with other GIT hormones stimulate insulin secretion. These hormones are released after the ingestion of food. They cause anticipatory rise in insulin level in the portal vein before actual rise in blood glucose. * Inhibition of insulin secretion The synthesis and release of insulin are decreased when there is decrease in CHO or food (dietary fuels) and also during period of trauma, stress, extreme exercises. Where Epinephrine plays direct effect on energy metabolism. Causing rapid mobilization of energy-yielding fuels like glucose from liver, fatty acids from TG - In emergency situations The sympathetic nervous system  increases the release of the epinephrine.

*Metabolic effect of insulin Effect on CHO metabolism the effect of insulin on glucose metabolism is important in three tissues: ( liver, muscle, adipose tissue ) A) In liver Insulin inhibits gluconeogenesis, and break down glycogen Decrease production of glucose. also it increase glycogen synthesis. B) In muscle and adipose tissue Increase Glucose uptake increase synthesis of TG. Effect on TG metabolism: Insulin  decrease TG degradation  decrease fatty acid level in the circulation. Insulin inhibits hormone sensitive lipase enzyme inhibits TG degradation - Insulin increase the transport and metabolism of glucose into adipocyte providing glycerol 3-P for TG synthesis  activate the TG synthesis in the adipocytes - Also increase lipoprotein lipase activity  increase degradation of chylomicrones to release fatty acid that will enter to the adipocytes and will be esterfied with glycerol phosphate  increase TG synthesis. Effect of insulin on protein metabolism: - Insulin stimulates the energy of amino acid into the cells and increase protein synthesis.

Anabolic effect of Insulin

Mechanism of insulin action Insulin binding site α-subunit Insulin receptor substrate β-subunit Mechanism of insulin action Insulin receptors: tetramer protein linked by disulfide bonds The systolic domain of β-subunit is a tyrosine kinase activated by insulin

Time course of insulin action - The most immediat response is an increase in glucose transport into cells which occurs within seconds - Insulin induce enzyme activity over minutes to hours phosphorylation starts. - Insulin affects gene transcription that affect the enzyme synthesis Insulin action over hours or days.

* Insulin sensitive and insulin insensitive glucose transport.

Glucagon - Polypeptide hormone secreted by α-cells of the pancreatic cells - (29a.a of 1 chain) - Glucagon, epinephrine, cortisol, growth hormone have opposite action of insulin. - α-cells respond to many stimuli that signal of hypoglycemia * Glucagon secretion increased by: 1) Low glucose level is the primary stimulus for glucagon release. 2) a.a stimulate both insulin and glucagon Glucagon prevents hypoglycemia that occurs after a protein meal. 3) Epinephrin: released from adrenal medulla increases the release of glucagon regardless the concentration of glucose in the blood.

Glucagon Mechanism of action The action of glucagon is mediated by the activation of adenylate cyclase  cAMP activates cascade of enzyme reactions.

Inhibition of glucagon secretion: Glucagon secretion is decreased by elevated blood sugar and by insulin ingestion of CHO rich meal *Metabolic effects of glucagon: A) Effect on CHO metabolism Increases breakdown of liver (not muscle) glycogen and increases gluconeogenesis. B) Effect on Lipids metabolism Glucagon favors hepatic oxidation of fatty acids and also formation of keton bodies. C) Effect on protein metabolism Glucagon increases uptake of a.a by liver resulting in increased availability of carbon skeleton for gluconeogenesis plasma level of a.a will decrease.

Hypoglycemia The CNS has an absolute requirement for a continuous supply of blood-glucose to serve as fuel for energy. - Transient hypoglycemia  causes cerebral dysfunction. - Prolonged hypoglycemia  causes brain death. * The body has multiple overlapping mechanisms to prevent or correct hypoglycemia. - Hormonal changes in reversing hypoglycemia are increase glucagon and epinephrine with decrease release of insulin. *Symptoms of hypoglycemia: Appear when glucose level of 45mg/dl or less The symptoms are divided into: Adrenergic symptoms: anxiety, palpitation, tremor, sweating are mediated by epinephrine release which is regulated by hypothalamas. (sudden decline of glucose  increases epinephrine) Neuroglycopenic symptoms: neuroglycopenia (decrease delivery of glucose to brain) results of impairment of brain function  causing headache, confusion, seizures, coma, death. Resulted from slow decline of glucose.

Glucoregulatory systems - humans have two overlapping glucose-regulating systems that activated by hypoglycemia. A) The islets of langerhans that release glucagon. B) receptors in hypothalamus that respond to low glucose level. hypothalamic glucoreceptors  activate the release of ACTH and GH. Glucagon, epinephrine, cortisol and GH have opposite action of insulin. *Glucagon and epinephrine: hypoglycemia is combated by decrease release of insulin and increase secretion of glucagon, epinephrine, cortisol and GH. - glucagon and epinephrine are important in short term regulation of blood-glucose level Glucagon: Increases the hepatic glycogenolysis and increases gluconeogensis. Epinephrine: Increases glycogenolysis, increases lipolysis, decreases Insulin secretion decreases the uptake of glucose by peripheral cells. *Cortisol and growth hormone - play a role in long term management of glucose metabolism.

Types of hypoglycemia A) Reactive hypoglycemia (postprandial hypoglycemia) “excessive insulin release after meal” transient hypoglycemia B) Fasting hypoglycemia: neuroglycopenia symptoms  hepato cellular damage, adrenal insufficiency, - Fasting hypoglycemia may due to increase utilization of glucose by peripheral tissues. - High insulin level due to tumor of β-cells. C) Fasting individuals who have consumed large amount of ethanol

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