Physiology of Endocrine Blood Glucose Regulation By Dr

Physiology of Endocrine Blood Glucose Regulation By Dr. Abdel Aziz M. Hussein Lecturer of Physiology Member of American Society of Physiology

Blood Glucose • The normal blood glucose level ranges ( ) 80 -120 mg %. • The total amount of glucose in circulating blood is about 3. 3 to 7 gm • 5 grams of glucose is about equivalent to a commercial sugar packet (as provided in many restaurants with coffee or tea). • Failure to maintain blood glucose in the normal range leads to conditions of persistently high (hyperglycemia) or low (hypoglycemia) blood sugar.

Regulation of Blood Glucose • Normal Blood glucose is regulated by 2 mechanisms: A. Hormones Pancreatic hormones e. g. insulin, glucagon, and somatostatin Other hormones e. g. adrenaline, thyroxin, glucocorticoids, and Growth hormone B. Tissues Liver acts as glucostat

Pancreatic Hormones

Pancreatic Hormones • Endocrine cells of the pancreas are present in groups called ‘islets of Langerhan’s’ • Are more numerous in the tail than in the body • Islets are 1 -2% of its pancreatic weight

Pancreatic Hormones Alpha cells 25 % Secretes Glucagon Beta cells 60% Secretes Insulin Delta cells 10% Secretes somatostatin F cells 5% Secretes pancreatic polypeptide

Insulin Chemistry : • Insulin is one of the most important peptide hormones. • Plays a central role in the rapid modulation of all energy reactions in the body. • Was first isolated from pancreas in 1922 by Banting and Best • It consists of 2 straight chains linked by 2 disulfide bridges. 1. A chain → contains 21 amino acids and an intra-chain disulfide ring. 2. B chain → contains 30 amino acids.

Insulin Synthesis and Release: • m. RNA → by Ribosomes → preproinsulin → split of 23 amino acids from preproinsulin → proinsulin (insulin + C or connecting peptide) → by trypsin-like and carboxypeptidase-like enzymes during transport from endoplasmic reticulum and package by Golgi apparatus → split into insulin and C peptide • Both insulin and C peptides are secreted by exocytosis in equimolar amounts • C peptide has 10% of insulin activity

Insulin Mechanism of action: • Insulin acts on insulin receptor (2 subunits, alpha and beta subunits). • It is a tyrosine kinase i. e. functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. • Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. • The activated receptor then phosphorylates a number of intracellular proteins called insulin-receptor substrates (IRS 1 -4). • These substrates are coupled to several additional protein kinase signal systems

Insulin Functions of insulin: 1. 2. 3. 4. CHO metabolism: it is hypoglycemic hormone Fat metabolism: stimulate lipogenesis Protein synthesis: anabolic hormone Electrolyte metabolism: K, Ca, Mg and PO 4

Insulin and CHO metabolism Insulin tends to lower blood glucose level by: 1. Stimulate glycogenesis in Liver and SK. Ms by activating the glycogen synthetase enzyme. 2. Inhibition of glycogenolysis by decreasing glycogen phosphorylase activity. 3. Increase glucose uptake by the tissues (liver, ms, and fat tissues) by activating glucokinase enzyme and insertion of GLUT 4 into cell membrane 4. Inhibition of gluconeogenesis by decreasing the hepatic uptake of amino acids. 5. Stimulate lipogenesis in adipose tissue, by activating lipoprotein lipase enzyme.

Insulin Action in Muscle and Fat Cells Mobilization of GLUT 4 to the Cell Surface Plasma membrane Insulin receptor Intracellular signaling cascades Intracellular GLUT 4 vesicles Insulin GLUT 4 vesicle mobilization to plasma membrane GLUT 4 vesicle integration into plasma membrane GLUT 4=glucose transporter 4 Glucose entry into cell via GLUT 4 vesicle

Insulin and Protein Metabolism Insulin is powerful anabolic hormone and stimulate tissue growth by : 1. Stimulates the uptake of certain amino acids by Sk. Ms 2. Stimulates the rate of protein synthesis (enhance activity of ribosomes) 3. Anticatabolic effects i. e. inhibits proteolysis. 4. Certain peptides called insulin-like growth factors, have similar amino acid sequences, and cross react modestly with insulin receptors.

Insulin and Electrolyte Metabolism 1. Insulin increases cellular uptake of potassium, phosphate and magnesium. 2. It increases the reabsorption of potassium, phosphate and sodium by renal tubules. N. B. • Insulin stimulate glucose entry in all tissues except brain cells, RBCs, intestinal cells and renal tubule cells

Regulation of Insulin Secretion

Stimuli of Insulin Secretion 1. Blood glucose: • Virtually, no insulin is secreted below a plasma glucose level of 50 mg%. • A half maximum insulin secretory response occurs at a plasma glucose level of about 150 mg% • A maximum response at 300 to 500 mg%.

Stimuli of Insulin Secretion 2. GIT hormones: a. Gastric inhibitory polypeptide (GIP): • The most important of insulinogogue i. e. stimulate insulin secretion • Released from specific intestinal cells in response to oral glucose and drop in p. H • So, oral glucose stimulate insulin secretion than IV insulin b. High concentrations gastrin, secretin, cholecystokinin, pancreatic glucagons and enteroglucagon stimulate insulin secretion • This mechanism inhibit the rise of blood glucose after ingestion and absorption of CHO meals 3. ↑ Blood free fatty acids, ketoacids and triglycerides have little effect 4. ↑ blood amino acids e. g. arginine, leucine, lysine and alanine

Stimuli of Insulin Secretion 5. Other hormones e. g. Glucagon, GH, cortisol • Glucagon stimulate insulin secretion by direct paracrine action on beta cells and indirect action through increase of blood glucose level 6. Minerals e. g. K and Ca ions (are essential for the response of insulin secretion to glucose) 6. Parasympathetic (Ach) and Beta adrenergic stimulation. 7. Obesity 8. Sulfonylurea drugs

Inhibitors of Insulin Secretion 1. 2. 3. 4. 5. 6. Fasting Exercise Somatostatin -Adrenergic stimuli Prostaglandins Drugs e. g. Diazoxide and Phenytoin

Glucagon Chemistry : • Polypeptide hormone (29 amino acid) synthesized from a precursor called proglucagon. • Secreted by cells of the pancreatic islets • Glucagon-like peptides, including glicentin, are synthesized and secreted by the small intestinal cells in humans and other species.

Glucagon Functions : 1. On CHO metabolism: • It increases blood glucose i. e. hyperglycemic factor by: a) Glucagon promotes and sustains hepatic glucose output. • It stimulate glycogenolysis by activation of glycogen phosphorylase. • Released G-6 -P is prevented from forming glycogen by inhibition of glycogen synthetase.

Glucagon Functions : 1. On CHO metabolism: b) It stimulates gluconeogenesis by: • Increasing hepatic uptake of amino acids, especially alanine. • Activating the necessary enzymes. N. B. : Glucagon has little or no influence on glucose utilization by peripheral tissues.

Glucagon Functions : 2. Glucagon activates adipose tissue lipase→ lipolysis→ delivery of free fatty acids from adipose tissue to the liver and ketogenesis. 3. It decreases hepatic cholesterol synthesis. 4. Natriuresis, by inhibition of renal tubular Na reabsorption. 5. Activation of myocardial adenyl cyclase, causing a moderate increase of cardiac output. 6. May act as a local CNS hormone for the regulation of appetite.

Glucagon Mechanism of action :

Stimuli of Glucagon 1. Hypoglycaemia causes 2 -4 fold increase in glucagon level. 2. Protein meal and, most powerfully, by amino acids such as arginine and alanine. However, the -cell response to protein is greatly reduced if glucose is administered concurrently. 3. Reduction in plasma free fatty acids. 4. Exercise of sufficient intensity and duration. 5. Vagal stimulation or administration of acetylcholine. 6. Stress, including infection, toxaemia, burns and major surgery. 7. Growth hormone.

Inhibitors of Glucagon 1. Hyperglycaemia. It lowers glucagon level by about 50%. 2. Increase in plasma free fatty acids. 3. The neurohormone somatostatin inhibits glucagons release.

Other hormones regulating Blood Glucose

Other hormones regulating blood glucose 1. Adrenaline: glycogenolytic acting on both liver and muscles. 2. Glucocorticoids: Stimulate gluconeogenesis and depress glucose uptake by the tissues. 3. Growth hormone: Stimulates the release of glucagon hormone and also inhibits glucose uptake by tissues. 4. Thyroxin: It increases glucose absorption from the intestine, glycogenolysis and glucose uptake by cells. The net result is a rise in blood glucose level.

Regulating of Blood Glucose

Regulating of Blood Glucose

Diabetes Mellitus Def. , • This is one of the oldest known endocrine disorders, the sweetness of urine, having been described in Egypt in 1500 B. C. Manifestations: • It results from deficiency of insulin which leads to: 1. Hyperglycaemia, due to absence of the above mentioned effects of insulin. 2. Glucosuria i. e. loss of glucose in urine. • This occurs when the blood glucose level becomes higher than the renal threshold (180 mg%).

Diabetes Mellitus Manifestations: • 3. Polyuria due to: • a) Excretion of glucose in urine→ osmotic diuresis. • b) ↑ed osmotic pressure of the blood drags water out of the cells towards the blood→ dehydration of the tissue cells. • 4. Polydepsia: intense thirst due to dehydration. • 5. Acidosis: due to inhibition of CHO metabolism. • The body depends on the fat metabolism which supplies most of the energy needed→ accumulation of the intermediary products of fat metabolism as acetoacetic acid and beta hydroxybuteric acid.

Diabetes Mellitus Manifestations: • 6. Loss of weight and asthenia: • Due to mobilization of fat and proteins for the supply of energy. • 7. Increased cholesterol and triglycerides level in the blood which leads to early development of arteriosclerosis.

Somatostatin • Secreted form; 1. Hypothalamus: • Somatostatin reaches the anterior pituitary via its portal circulation • Inhibits the secretion of GH and TSH 2. Delta cells of the pancreas: • Inhibits the release of all other islet hormones: insulin, glucagon and pancreatic polypeptide.

Somatostatin Secreted form; 3. Gastrointestinal tract a) Inhibits secretion of gut hormones: Gastrin, secretin, cholecystokinin and VIP. b) Reduces the secretion of gastric acid and pepsin. c) Decreases blood flow, motility and carbohydrate absorption. d) Increases water and electrolyte absorption.

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