SHS 203 Biochemistry & Genetics (III) Lecture Notes

COURSE CODE: 203 Pre-requisite: 109 Ms. ALMINA/Ms. RABIA SEMESTER: 3 BIOCHEMISTRY & GENETICS (III) REFERENCE TEXT BOOK: Lippincott’s illustrated review of biochemistry by pamela C. Champe and richard A. Harvey latest ed.  Review of previous lecture Steroid hormones Aldo...

COURSE CODE: 203 Pre-requisite: 109 Ms. ALMINA/Ms. RABIA SEMESTER: 3 BIOCHEMISTRY & GENETICS (III) REFERENCE TEXT BOOK: Lippincott’s illustrated review of biochemistry by pamela C. Champe and richard A. Harvey latest ed.  Review of previous lecture Steroid hormones Aldosterone Synthesis of Aldosterone Functions of aldosterone Regulation of aldosterone Renin-angiotensin system Escape mechanism Acidosis and alkalosis INSULIN & GLUCAGON  Outlines Insulin Synthesis Mechanism of action Functions Glucagon Mechanism of action Significance Somatostatin Diabetes Mellitis Insulin and its metabolic effects Insulin was first isolated from the pancreas in 1922 by Banting and Best Insulin is a small protein and it is synthesized in the beta cells  Insulin chemistry and synthesis Polypeptide containing two amino acid chains (21 and 30 A.A) connected by disulfide bridges. When split apart, the functional activity of the insulin molecule is lost.  Insulin circulates unbound to carrier proteins and have short half-lives of 6 minutes. (as well as glucagon) Approximately 50% of the insulin in blood is metabolized in the liver Most of the remaining hormone is metabolized by the kidneys  Insulin chemistry and synthesis Insulin synthesis starts with translation of the insulin RNA by ribosomes to form an insulin preprohormone. This initial preprohormone is then cleaved in the endoplasmic reticulum to form a proinsulin Most of this is further cleaved in the golgi apparatus to form insulin and peptide fragments before being packaged in the secretory granules.  One sixth of the final secreted product is still in the form of proinsulin. The proinsulin has virtually no insulin activity Insulin Biosynthesis  Activation of target cell receptors by insulin and the resulting cellular effects To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein.  The insulin receptor is a tetramer made up of two α-subunits that lie outside the cell membrane a Two β-subunits that penetrate the cell membrane and protrude into the cytoplasm  When insulin binds with the alpha subunits on the outside of the cell, Portions of the beta subunits protruding into the cell become autophosphorylated. Thus, the insulin receptor is an example of an enzyme-linked receptor. Activation of target cell receptors by insulin and the resulting cellular effects  Activation of target cell receptors by insulin and the resulting cellular effects  Autophosphorylation of the beta subunits of the receptor activates a local tyrosine kinase.  Phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS).  Activation of target cell receptors by insulin and the resulting cellular effects The net effect is to activate some of these enzymes while inactivating others. In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein  Role of the Pancreas 1. Digestion – secretes digestive enzymes 2. Metabolism Regulation Carbohydrates Lipids Proteins Produces primary messengers (hormones) Insulin Glucagon  Physiologic anatomy of the pancreas The islets cells contain three major types of cells: 1. The alpha cells: 25 % of the total, secrete glucagon. 2. The beta cells: 60 % of all the cells of the islets, lie mainly in the middle of each islet and secrete insulin and amylin. 3. The delta cells: about 10 %, secrete Insulin is a hormone associated with energy abundance 1. Insulin is secreted when there is great abundance of energy-giving foods in the diet (carbohydrates). 2. It plays an important role in storing the excess energy. 3. In the case of excess carbohydrates, it  It has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. In addition, it inhibits the breakdown of the proteins that are already in the cells.  Importance of Blood Glucose Regulation Glucose is the only nutrient that normally can be used by the brain, retina, and germinal epithelium of the gonads  Importance of Blood Glucose Regulation Long-term increases in blood glucose may cause damage to many tissues, especially to blood vessels. Vascular injury, associated with uncontrolled diabetes mellitus, leads to increased risk for heart attack, stroke, end-stage renal disease, and blindness Insulin and its metabolic effects Insulin Promotes Muscle Glucose Uptake and Metabolism  Two conditions During moderate or heavy exercise Exercising muscle fibers become more permeable to glucose even in the absence of insulin.  During few hours after a meal At this time the blood glucose concentration is high and the pancreas is secreting large quantities of insulin. The extra insulin causes rapid transport of glucose into the muscle cells. Mechanism of glucose uptake and storage in the liver 1. Insulin causes enhanced uptake of glucose from blood by liver by the enzyme glucokinase, causes the initial phosphorylation of glucose after it diffuses into liver 2. Insulin also increases the activities of the enzymes that promote glycogen synthesis, glycogen synthase  Insulin Promotes Conversion of Excess Glucose into Fatty Acids and Inhibits Gluconeogenesis in Liver When the quantity of glucose entering the liver cells is more than can be stored as glycogen, insulin promotes the conversion of all this excess glucose into fatty acids. These are packaged as triglycerides in VLDL and transported by blood to the adipose tissue and deposited as fat. Insulin also inhibits gluconeogenesis. (quantities and activity of the enzymes) Lack of Effect of Insulin on Glucose Uptake and Usage by the Brain It is essential that the blood glucose level always be maintained above a critical level. When the blood glucose falls too low (20-50 mg/100ml), symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting, seizures and coma. Effect of Insulin on Fat Metabolism Insulin’s effects on fat metabolism are, in the long run, as equally important as to the effects on the carbohydrates. The long-term effect of insulin lack in causing extreme atherosclerosis, often leading to heart attacks, cerebral strokes, and other vascular accidents. Role of Insulin in Storage of Fat in the Adipose Cells Insulin has two other essential effects : 1. Insulin inhibits the action of hormone-sensitive lipase; this is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells. 2. Insulin promotes glucose transport through the cell membrane into the fat cells.. Insulin deficiency causes lipolysis of storage fat and release of free fatty acids. The most important effect is that the enzyme hormone- sensitive lipase in the fat cells becomes strongly activated. Consequently, the plasma concentration of free fatty acids begins to rise within minutes.  Effect of Insulin on Protein Metabolism and on Growth Insulin Promotes Protein Synthesis and Storage During the few hours after a meal proteins are also stored in the tissues by insulin. 1. Insulin stimulates transport of many of amino acids into the cells, most common: valine, leucine, isoleucine, tyrosine, and phenylalanine.  Effect of Insulin on Protein Metabolism and on Growth Insulin Lack Causes Protein Depletion and Increased Plasma Amino Acids The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus. It can lead to extreme weakness as well as many deranged functions of the organs.  Insulin Most Cells  amino  Protein synthesis acids Control Muscle  Glucose uptake  Glycogen synthesis Gastrointestinal hormones Adipose  triglycerides ­ Glucose uptake ­ Glycerol production ¯ Triglyceride breakdown Amino  Triglyceride synthesis acids Pancreas Insulin Beta cells Liver Blood  Glucose uptake  glucose glucose ­ Glycogen synthesis ­ Fatty acid synthesis ¯ Glucose synthesis Brain No effect Feedback Anabolic effect of Insulin GLUCAGON  Conti…. It is secreted by the alpha cells of the islets of Langerhans when the blood glucose concentration falls. Its functions are opposed to those of insulin; most important of these functions is to increase the blood glucose concentration. Like insulin, glucagon is a large polypeptide. It is composed of a chain of 29 amino acids.  Glucagon and its Functions “Hyperglycemic hormone” Its actions achieved by activation of Adenylyl Cyclase in hepatic cell membrane The binding of glucagon to hepatic receptors results in activation of adenylyl cyclase  Generation of the second messenger cyclic AMP, which in turn activates protein kinase, Leading to phosphorylation that results in the activation or deactivation of a number of enzymes. MECHANISM 1) β – adrenergic stimulation 2) glucagon  Glucagon Control Adipose ­ Triglyceride breakdown  Fatty acids ¯ Triglyceride storage Exercise Amino acids Pancreas Alpha cells Liver  Glycogen breakdown ­ Glucose synthesis  Blood glucose Epinephrine  Glucose release (stress) Brain No effect Feedback  Glucagon and its Functions Effects on Glucose Metabolism 1. Breakdown of liver glycogen (glycogenolysis) 2. Increased gluconeogenesis in the liver. Both of these effects greatly enhance the availability of glucose to the other organs of the body.  Other Effects of Glucagon Glucagon in very high concentrations also : (1) Enhances the strength of the heart (2) Increases blood flow in some tissues, especially the kidneys (3) Enhances bile secretion; and (4) Inhibits gastric acid secretion. All these effects are probably of minimal importance in the normal function of the body.  Regulation of Glucagon Secretion Increased Blood Glucose Inhibits Glucagon Secretion. (most potent factor) A decrease in the blood glucose concentration from its normal fasting level of about 90 mg/100 ml of blood down to hypoglycemic levels can increase the plasma concentration of glucagon several fold.  Regulation of Glucagon Secretion Increased Blood Amino Acids Stimulate Glucagon Secretion High concentrations of amino acids, after a protein meal (especially alanine and arginine), 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 opposites.  Somatostatin Inhibits Glucagon and Insulin Secretion Somatostatin is secreted by the delta cells of the islets of Langerhans. It’s a polypeptide containing only 14 amino acids that has an extremely short half-life of only 3 minutes in the circulating blood.  Stimulus of somatostatin 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 intake.  Somatostatin Inhibits Glucagon and Insulin Secretion Somatostatin has multiple inhibitory actions: 1. Somatostatin acts locally and depresses the secretion of both insulin and glucagon. 2. Somatostatin decreases the motility of the stomach, duodenum, and gallbladder. 3. Somatostatin decreases both secretion and absorption in the gastrointestinal tract. Type I Diabetes Mellitus Form of diabetes mellitus in which not enough insulin is produced Lack of insulin results in high blood sugar levels  Symptoms Frequent urination Increased thirst Increased hunger Weight loss  Additional symptoms Blurry vision Feeling tired Poor healing.  DIABETES MELLITUS TYPE 2 Long term metabolic disorder that is characterized by high blood sugar, insulin resistance and relative lack of insulin.  Symptoms Increased thirst Frequent urination Weight loss Increased hunger Feeling tired Sores that do not heal  Prevention Normal weight Exercise Eating properly THANK YOU