Hormonal Control of Metabolism and Blood Glucose Regulation (PDF)

Glucagon: glycogenolysis Glucagon is a polypeptide hormone secreted by the α cells of the pancreatic islets of Langerhans. Glucagon, along with epinephrine, cortisol, and growth hormone (the “counterregulatory hormones”), opposes many of the actions of insulin . Most importantly, glucagon acts to...

Glucagon: glycogenolysis Glucagon is a polypeptide hormone secreted by the α cells of the pancreatic islets of Langerhans. Glucagon, along with epinephrine, cortisol, and growth hormone (the “counterregulatory hormones”), opposes many of the actions of insulin . Most importantly, glucagon acts to maintain blood glucose levels by activation of hepatic glycogenolysis and gluconeogenesis. glucosefromaminoacidpyruvate oxallacetate breakdown glycogen of togiveglucoseof 29 amino acids arranged in a single polypeptide chain. Glucagon is composed which hormone is consideredcounterregulatory 10/10/2023 33 Unlike insulin, the amino acid sequence of glucagon is the same in all mammalian species examined to date. Glucagon is synthesized as a large precursor molecule (preproglucagon) that is converted to glucagon through a series of selective proteolytic cleavages, similar to those described for insulin biosynthesis. I glucagonbecame 29 10/10/2023 34 Differential posttranslational processing of proglucagon in the pancreas and in the gut and brain. The numbers indicate amino acid positions in the 160-amino acid proglucagon sequence. The vertical lines indicate positions of basic amino acid residues, typical cleavage sites. GRPP, glicentin-related pancreatic polypeptide; IP-1, intervening peptide-1; IP-2, intervening peptide-2. Stimulation of glucagon secretion: The α cell is responsive to a variety of stimuli that signal actual or potential hypoglycemia. Glucagon secretion is increased by: 1. Low blood glucose: is the primary stimulus for glucagon release. 2. Amino acids: Amino acids derived from a meal containing protein stimulate the release of both glucagon and insulin. 3. Epinephrine and norepinephrine stimulate the release of glucagon. Consumingof glucose During periods of stress, trauma, or severe exercise, the elevated epinephrine levels can override the effect on the α cell of circulating substrates. Atsometimes after a heavy meal you so glucagon is 10/10/2023 secreted too can have hypoglycemia due to insulin 36 Inhibition of glucagon secretion: Glucagon secretion is significantly decreased by: 1. Elevated blood glucose 2. Insulin. Both substances are increased following ingestion of glucose or a carbohydrate-rich meal. 10/10/2023 37 Regulation of glucagon release from pancreatic α cells. [Note: Amino acids increase release of insulin and glucagon, whereas glucose increases release of insulin only.] 10/10/2023 38 Metabolic effects of glucagon: Effects on carbohydrate metabolism: The intravenous administration of glucagon leads to an immediate rise in blood glucose. This results from an increase in the breakdown of liver (not muscle) glycogen and an increase in gluconeogenesis. Asno receptors ofglucagonon muscle Effects on lipid metabolism: Glucagon activates lipolysis in adipose tissue. The free fatty acids released are taken up by liver and oxidized to acetyl coenzyme A, which is used in ketone body synthesis. Catecholamines also activate lipolysis. 10/10/2023 39 Effects on protein metabolism: Glucagon increases uptake of amino acids by the liver, resulting in increased availability of carbon skeletons for gluconeogenesis. As a consequence, plasma levels of amino acids are decreased. 10/10/2023 40 important Actions of glucagon on target tissues Opposing actions of insulin and glucagon plus epinephrine. 10/10/2023 42 Mechanism of action of glucagon: Glucagon binds to high-affinity G protein-coupled receptors on the cell membrane of hepatocytes. The receptors for glucagon are distinct from those that bind insulin or epinephrine. Glucagon receptors are not found on skeletal muscle. Glucagon binding results in activation of adenylyl cyclase in the plasma membrane. 10/10/2023 43 This causes a rise in cAMP (the “second messenger”), which, in turn, activates cAMP-dependent protein kinase and increases the phosphorylation of specific enzymes or other proteins. This cascade of increasing enzymic activities results in the phosphorylation mediated activation or inhibition of key regulatory enzymes involved in carbohydrate and lipid metabolism. Glucagon also affects gene transcription. 10/10/2023 44 Mechanism of action of glucagon. [Note: For clarity, G-protein activation of adenylyl cyclase has been omitted.] R = regulatory subunit; C = catalytic subunit. 10/10/2023 45 Why is it important to control blood glucose? 10/10/2023 46 Maintaining Glucose Homeostasis • Goal is to maintain blood glucose levels between ~ 70 and 110 mg/dL • Two main hormones play a role in maintaining glucose homeostasis: • Insulin • Glucagon • Both are pancreatic hormones 47 Shortperiod glycogenolysis Longperiod gluconeogenesis Sources of blood glucose during a normal day. •Between meals, blood glucose is derived primarily from hepatic glycogen. •Depending on the frequency of snacking, glycogenolysis and gluconeogenesis may be more or less active during the day. •Late in the night or in early morning, following depletion of a major fraction of hepatic glycogen, gluconeogenesis becomes the primary source of blood glucose. 48 Hypoglycemia: Hypoglycemia is characterized by: 1) central nervous system symptoms, including confusion, unusual behavior, or coma. 2) a simultaneous blood glucose level ≤ 40 mg/dl 3) symptoms being resolved within minutes following the administration of glucose. 10/10/2023 49 Types of hypoglycemia: Hypoglycemia may be divided into: 1. Insulin-induced Type I DM Hypoglycemia glucagonis not affected by it 2. Postprandial Hypoglycemia exaggerated insulin release following a meal 3. Fasting hypoglycemia. Rare, pancreatic tumors 4. Hypoglycemia due to Alcohol intoxication in fasting individuals. NAD+/NADH ratio is decreased 10/10/2023 50 doesnotgo tocytosol alcoholconsumers consume NAD A. Normal gluconeogenesis in the absence of ethanol consumption. B. Inhibition of gluconeogenesis resulting from hepatic metabolism of ethanol. 10/10/2023 51 Reversal of insulin-induced hypoglycemia by administration of subcutaneous glucagon. 10/10/2023 52 Glucose-regulatory systems: Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia: 1) the islets of Langerhans, which release glucagon; and 2) The hypothalamic glucoreceptors, which respond to abnormally low concentrations of blood glucose. They can trigger both the secretion of epinephrine and release of adrenocorticotropic hormone (ACTH) and growth hormone by the anterior pituitary. ACTH increases cortisol synthesis and secretion in the adrenal cortex. 10/10/2023 53 every hormoneAt effects on which process A. Actions of some of the glucoregulatory hormones in response to low blood glucose. B. Glycemic thresholds for the various responses to hypoglycemia. + = weak stimulation; ++ = moderate stimulation; +++ = strong stimulation; 0 = no effect. [Note: Normal fasted blood glucose is 70–99 mg/100 ml.] 10/10/2023 54 Liver glycogen: Liver glycogen is an essential postprandial source of glucose. It can meet the needs for only 8-10 hrs in the absence of dietary intake of CHO. Glycogen is stored in two tissues in the body for different reasons: in liver for short-term maintenance of blood glucose homeostasis, and in muscle as a source of energy. Glycogen metabolism in these tissues responds rapidly to both allosteric and hormonal control. Gluconeogenesis: It is a pathway for glucose synthesis. Some tissues require a continuous supply of glucose as an energy source: • Brain • Red blood cells • Kidney medulla • Lens • Cornea • Testes • Exercising muscles. Gluconeogenesis is required to maintain blood glucose during fasting and starvation 10/10/2023 57 10/10/2023 58 • Somatostatin Release of insulin • IGF-I glucose uptake • Resistin Release of TSH ? Affecting glucose uptake • Leptin Gluconeogenesis, • C-Peptide insulin-dependent glucose uptake Appetite Summary of metabolic effects of some hormones [email protected] GR-35 10/10/2023 60