Transcript of "Glucagon and its metabolic effects"
GLUCAGON and ITS METABOLIC EFFECTS BY: Khuram Aziz M.Phill Biochemistry Scientist by IBC Life Sciences Member of Pakistan Young Scientist Association
OUTLINE• Glucose homeostasis• Sources of glucose• Glucagon• Metabolic effects• Stimulation of Glucagon• Physiological actions• Regulation• Mechanism of glucagon
Glucose Equilibrium – A Wonder !! • Normal Blood Glucose – Fasting state : 60 to 100 mg% – Postprandial : 100 to 140 mg %Let us grasp some blood glucose in such a • What keeps the of the fascinating answers !! narrow range? • Why are we not becoming hypoglycemic when we fast? • Why is our blood sugar not shooting up to very high levels after a rich meal ? • What are the regulatory and counter regulatory hormones ?3
Hormonal Regulation of Metabolism• Balance between anabolism and catabolism depends on levels of insulin, glucagon, GH, thyroxine, and others 19-35
Insulin and Glucagon Secretion• Normal fasting glucose level is 60– 100 mg/dl – Insulin and glucagon normally prevent levels from rising above 170mg/dl after meals or falling below 50mg/dl between meals 19-40
Glucose Homeostasis Lower Blood Glucose Between meals -cells release -cells release Glucagon insulin stimulate glycogen stimulate glucose breakdown and uptake by gluconeogenesis peripheral tissues Higher Blood Glucose Food6
Homeostasis of Glucose Counter Regulation Mechanisms • A steady maintenance of blood glucose with in a narrow range • Fasting state and fed states – their effects on BG • Rate of glucose appearance Ra • Rate of disappearance Rd must be in balance • Blood Glucose (BG) = Ra - Rd • Control systems – Glucose Receptors, GLUT 1-14 – Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc., – Insulin Signaling sequences, Glucagon signaling – Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue – Feedback loops • Negative feedback • Positive feedback7
Sources of Glucose in to blood • Glucose is derived from 3 sources • Intestinal absorption of dietary carbohydrates • Glycogen breakdown in liver and in the kidney. • Only liver and kidney have glucose-6-phosphatase. • Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply. • Gluconeogenesis, the formation of glucose from precursors • These include lactate and pyruvate, amino acids (alanine and glutamine), and to a lesser degree, from glycerol8
Fasting State • Short fast – Utilizes free glucose (15-20%) – Break down of glycogen (75%) • Overnight fast – Glycogen breakdown (75%) – Gluconeogenesis (25%) • Prolonged fast – Only 10 grams or less of liver glycogen remains. – Gluconeogenesis becomes sole source of glucose – Muscle protein is degraded for amino acids. – Lipolysis generates ketones for additional fuel.9
Counter Regulatory Hormones• Glucagon We will discuss in detail• GLP-1 (Glucagon Like Peptide -1) – The most potent known insulin Secretagogue – It is made in the intestine by alternative processing of the same precursor• Intracellular actions10
Responses to decreasing Glucose levelsResponse Glycemic Physiological Role in counter theshhold effects regulation↓ Insulin 80 - 85 mg% ↑ Ra (↓ Rd) Primary First Defense↑ Glucagon 65 - 70 mg% ↑ Ra Primary Second Defense↑ Epinephrine 65 - 70 mg% ↑ Ra ↓ Rd Critical Third Defense↑ Cortisol, GH 65 - 70 mg% ↑ R a ↓ Rd Not Critical↑ Food ingestion 50 - 55 mg% ↑ Exogenous < 50mg% no Glucose cognitive change 11
Glucagon• It is a peptide hormone.• Consists of a single chain of 29 amino acids.• Secreted by alpha cells of pancreatic islets of langerhans.• Its main action is on the liver.• It tends to increase the blood glucose level.• Known as hyperglycemic hormone.
Glucagon Secretion Stimulation of Glucagon secretion – Blood glucose < 70 mg/dL – High levels of circulating amino acids – Especially arginine and alanine – Sympathetic and parasympathetic stimulation – Catecholamines – Cholecystokinin, Gastrin – Glucocorticoids13
Role of Glucagon • Metabolic Effects of Glucagon – Increases hepatic glycogenolysis – Increases gluconeogenesis – Increases amino acid transport – Increases fatty acid metabolism (ketogenesis)14
Role of Glucagon • Metabolic Effects of GlucagonClinical Pearl – Increases hepatic glycogenolysis 1. Glucagon is the treatment for hypoglycemia – Increases gluconeogenesis 2. Glucagon Kit – 1 mg s/c or IM or IV injection – – Increases amino acid transport 3. In 2 to 3 minutes recovery – Increases fatty acid metabolism (ketogenesis)16
Physiological actions Glucagon On glucose On fats On insulin Increases Stimulates DecreasesBlood glucose Insulin lipogenesis level secretion
Physiological actions Glucagon Increase Decreases Increases Hepaticlipogenesis lipolysis utilization of fats stimulates Ketogenesis Inhibits Hormone IncreaseAcetyl CoA Sensitive Formation ofcarboxylase Lipase in ketones liver Increase Free fatty acid
Physiological actions High levels Of glucagon Increases Inhibits Increases blood flow in Increases bileStrength of some tissues Gastric acid secretion The heart secretion e.g the kidneys
CellATP sensitiveK+ channel Voltage dependent Ca+ channel ATP Metabolism Glucokinase GLUCOSE INSULIN
Somatostatin inhibits glucagon and insulin secretion• somatostatin secretion is increased by the following;. 1-increased blood glucose 2-increased amino acids 3-increased fatty acids 4- increased concentrations of several of the gastrointestinal hormones released from the upper gastrointestinal tract in response to food uptake• In turn somatostatin has multiple inhibitory effects as follow: 1-acts locally within the islets of langerhans themselves to depress the secretion of both insulin and glucagon 2-decreases both secretion and absorption in the gastrointestinal tract 3-decrease the motility of the stomach ,duodenum, and gallbladder
Somatostatin Somatostatin -From delta cells -Inhibitory hormone Increase blood Increased amino glucose acids Increased fatty Upper acids GI-hormones Inhibts Decreases the Decreases both secretion Motility of stomach Secretion &Of insulin & Duodenum absorption in glucaon Gall bladder GIT
Regulation of glucagon secretion- Increased blood glucose inhibits glucagon secretion :- increase blood amino acids stimulate glucagon secretion : High concentrations of amino acids as occur in the blood after protein meals stimulate the secretion of glucagon .this is the same effect that amino acids have in stimulating insulin secretion. Thus in this instance the glucagon and insulin responses are not opposite. - exercise stimulates glucagon secretion.
-exercise stimulates glucagon secretion :In exhaustive exercise, the blood concentration of glucagon often increases fourfold to fivefold. A beneficial effect of the glucagon is that to prevents a decrease in blood glucoseOne of the factors that might increase glucagon secretion in exercise is increased circulating amino acids .other factors such as beta –adrenergic stimulation of the islets of langerhans ,may also play a role .
Regulation of blood glucose Regulation of Blood glucose Severe Prolonged Hyperglycemia Hypoglycemia hypoglycemia hypoglycemia Release Release of Release of Catecholamine of GH insulin glucagon release & cortisolGlycogenesis Release of Glycogenolysis Glucose glucose Gluconeogenesis storage By the From fat Gluconeogenesis In liver liver Decreased Increased blood bloodGlucose level Glucose level
GlucagonMechanism of action Binds to receptors On hepatocytes Stimulation Of adenyl cyclaseATP cAMP Activates protein kinases Desired action
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cAMP and activation of PKAGlucagon orepinephrine Liver cell ATP inactive active cAMP adenylyl cyclase p inactive active cAMP inactive active glycogen inactive active phosphorylase p phosphorylase protein kinase kinase A glycogen glucose-1-phosphate amplification cascade