Integration of Metabolism

Integration of Metabolism The human body functions as one community. Communication between tissues is mediated by the nervous system, by the availability of circulating substrates and by variation in the levels of plasma hormones. The integration of energy metabolism is controlled primarily by the action of hormones, including insulin, glucagon and catecholamines (epinephrine and nor epinephrine).The four major organs important in fuel metabolism are liver, adipose tissue muscle and brain. I-Insulin Insulin is a polypeptide hormone produced by the B-cells of the islets of Langerhans of the pancreas. Insulin is one of the most important hormones coordinating the utilization of fuels by tissues. Its metabolic effects are anabolic stimulating the synthesis of glycogen (glycogensis), triacylglycerols (lipogenesis) and protein. A-Structure of insulin: Insulin is composed of 51 amino acids arranged in two polypeptide chains A and B which are linked together by two disulfide bridges. The insulin molecule also contains an intramolecular disulfide bridge in A chain. Beef insulin differs from human insulin at three amino acid positions, whereas pork insulin varies at only one position. Figure 1- A-Structure of insulin B- Formation of insulin from preproinsulin B- Biosynthesis of Insulin: Insulin is first synthesized as preproinsulin which is changed to insulin as follows: Endoplasmic reticulum Golgi apparatus Preproinsulin Proinsulin Insulin + C-peptide Small peptide Figure 2: Biosynthesis of Insulin Preproinsulin and pro insulin are inactive. Insulin is stored in the cytosol in granules that are released by exocytosis. Insulin is degraded by the enzyme insulinase present in the liver and to a lesser extent in the kidneys. Insulin has a plasma half-life of about 6 minutes. This short duration of action permits rapid changes in circulating levels of the hormone. C- Regulation of Insulin Secretion 1-Stimulation of insulin secretion: The relative amounts of insulin and glucagon secreted by the pancreas are regulated so that the rate of hepatic glucose production is kept equal to the use of glucose by peripheral tissues. a)Glucose: ingestion of glucose or a carbohydrate rich meal leads to a rise in blood glucose which stimulates insulin secretion. Glucose is the most important stimulus for insulin secretion. b)Amino Acids: ingestion of protein leads to a rise in plasma amino acids which stimulate insulin secretion. Elevated plasma arginine is a particularly potent stimulus for insulin secretion c)Gastrointestinal hormones: The intestinal peptide secretin as well as other gastrointestinal hormones, stimulate insulin secretion after the ingestion of the food. They cause an anticipatory rise in insulin secretion. The same amount of glucose given orally stimulates more insulin secretion than if given intravenously. 2. Inhibition of insulin secretion: The synthesis and release of insulin are decreased during starvation and stress. These effects are mediated by epinephrine which is secreted by the adrenal medulla in response to stress, trauma or extreme exercise. Under these conditions the secretion of epinephrine is controlled by the nervous system. Epinephrine stimulates glycogenolysis, gluconeogenesis and lipolysis. Epinephrine inhibits insulin secretion by the pancreas. Thus, in emergency situations, the sympathetic nervous system largely replaces the plasma glucose concentration as the controlling influence over ? –cell secretion D- Metabolic effects of Insulin: 1-Effects on carbohydrate metabolism: The effects of insulin on glucose metabolism are most prominent in three tissues: liver, muscle and adipose tissue. In muscle and adipose tissue, insulin increase glucose uptake by increasing the number of glucose transporters in the cell membrane. In muscle and liver, insulin increases glycogensis. In the liver, insulin decreases the production of glucose by inhibiting both glycogenolysis and gluconeogenesis. Insulin is the only hypoglycemic hormone. Insulin increases glucose oxidation and utilization by tissues 2-Effects on Lipid Metabolism: Insulin decreases the release of fatty acids from adipose tissue by: a) Decrease in triglycerol degradation: Insulin inhibits the activity of hormone- sensitive lipase in adipose tissue. b) Increase triglycerol synthesis: Insulin increases the transport and metabolism of glucose into adipocytes, providing glycerol 3- phosphate for triglycerol synthesis. Insulin also increases lipoprotein lipase activity of adipose tissue by increasing the enzyme synthesis, providing fatty acids for esterification. 3-Effects on protein synthesis: Insulin stimulates the entry of amino acids into cells and increases protein synthesis in most tissues. E- Mechanism of Insulin Action: Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle and adipose. This is the first step in a cascade of reactions leading to many biological actions. 1-Insulin receptor: It is a tetramer linked by disulfide bonds. The extracellular -subunit contains the insulin binding site. The sytosolic domain of the -subunit is a tyrosine kinase, which is activated by insulin. 2-Signal transduction: At least four IRSs have been identified that show similar structures but different tissue distributions. The actions of insulin are terminated by dephosphorylation of the receptors. 3-Membrane effects of Insulin: Glucose transport in many tissues, such as skeletal muscle and adipocytes, increases in the presence of insulin. Insulin stimulates the recruitment of glucose transporters (GLUT-4) from a pool present in intracellular vesicles. Some tissues have insulin independent systems for glucose transport e.g. hepatocytes, erythrocytes, cells of the nervous system, intestinal mucosa, renal tubules and cornea. 4- Receptor regulation: Elevated levels of insulin increase the degradation of receptors, thus decreasing the number of surface receptors. This is one type of down regulation. 5-Time course of insulin actions: After insulin binding to the receptors the responses will be: a) Increase glucose transport (seconds). b) Change in enzyme activity (change in phosphorylation states) minutes to hours c) Increase in the amount of enzymes e, g glucokinase, phosphofructokinase, and pyruvate kinase (hours to days) this means increase protein synthesis IIGlucagon Glucagon is a polypeptide hormone secreted by the ?-cells of the pancreatic islets of Langerhans. Glucagon is composed of 29 amino acids arranged in a single polypeptide chain. The amino acid sequence of glucagon is the same in all mammalian species. Epinephrine, glucagon, cortisol, and growth hormone are anti-insulin (counter regulatory) hormones. A-Regulation of Glucagon Secretion: 1-Stimulation of glucagon secretion: a-Low blood glucose: hypoglycemia is the primary stimulus for glucagon secretion. b-Amino acids: stimulate the secretion of both glucagon and insulin. c-Epinephrine and norepinephrine: stimulate glucagon secretion (during stress, trauma or severe exercise) B-Inhibition of glucagon secretion : Glucagon secretion is markedly decreased by elevated blood sugar and by insulin (carbohydrate-rich meal). C-Metabolic Effects of Glucagon: 1-Effects on carbohydrate metabolism: The most important action of glucagon is to maintain blood glucose levels by stimulation of hepatic glycogenolysis and gluconeogenesis 2 -Effects on lipid metabolism: Glucagon stimulates hepatic oxidation of fatty acids and formation of ketone bodies. The lipolytic effect of glucagon in adipose tissue is minimal in humans 3- Effects on protein metabolism: Glucagon increases the uptake of amino acids by the liver for gluconeogenesis D-Mechanism of action of glucagon : Glucagon binds to high-affinity receptors on the cell membrane of the hepatocyte ? activation of adenylate cyclase in the plasma membrane? increase cAMP (second messenger). cAMP activates protein kinase and increases the phosphorylation of specific enzymes or other proteins. The phosphorylation activates or inhibits the key regulatory enzymes of carbohydrate and lipid metabolism. III Hypoglycemia Hypoglycemia is characterized by: 1) central nervous system symptoms, including confusion, aberrant behavior, or coma; 2) a simultaneous blood glucose level equal to or less than 40 mg/dl; and 3) symptoms being corrected within minutes following the administration of glucose. Hypoglycemia is a medical emergency The central nervous system has an absolute need for a continuous supply of blood glucose as a fuel for energy metabolism. Transient hypoglycemia can causes cerebral dysfunction, but severe, prolonged hypoglycemia causes brain death. The most important hormonal changes to correct hypoglycemia are elevated glucagon and epinephrine combined with decrease insulin secretion. Symptoms of hypoglycemia: The symptoms of hypoglycemia can be divided to two groups, 1) Adrenergic symptoms: Anxiety, palpitation, tremor, and sweat. These symptoms are due to increased epinephrine secretion regulated by the hypothalamus due to hypoglycemia. These symptoms occur when the blood glucose levels fall rapidly. 2-Neuroglypenic Symptoms: The decrease glucose supply to the brain leads to brain dysfunction causing headache, confusion, slurred speech, seizures, coma and death. These symptoms result from a gradual decrease in blood glucose. Glucoregulatory Systems: Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia: 1) The islets of Langerhans, which secrete glucagon 2)The glucoreceptors in the hypothalamus stimulate the secretion of both epinephrine (through the autonomic nervous system) and ACTH and growth hormone (GH) by the anterior pituitary gland. Glucagon, epinephrine, cortisol and GH are called the counterregulatory hormones because they antagonize the action of insulin on glucose utilization. A- Glucagon and Epinephrine: Hypoglycemia is corrected by decreased secretion of insulin and increased secretion of glucagon, epinephrine, cortisol, and growth hormone. Glucagon and epinephrine are most important in the acute, short- term regulation of blood glucose levels. Glucagon stimulates hepatic glycogenolysis and gluconeogenesis. Epinephrine stimulates glycogenolysis and lipolysis, inhibits insulin secretion, and inhibits insulin dependent uptake of glucose by tissues. B- Cortisol and Growth hormone: These hormones are less important in the short term regulation of blood glucose levels, but they are important in the long term regulation of glucose metabolism. They stimulate gluconeogenesis. Types of hypoglycemia: Hypoglycemia may be divided into three groups 1-Insulin induced hypoglycemia Hypoglycemia occurs frequently in patients with diabetes receiving insulin treatment. Mild hypoglycemia in fully conscious patients is treated by oral administration of carbohydrate. More commonly, patients with hypoglycemia are unconscious or have lost the ability to coordinate swallowing. In these cases, glucagon, administered subcutaneously or intramuscularly, is the treatment of choice 2-Postprandial hypoglycemia: This is the second most common of the form of hypoglycemia It is caused by an exaggerated insulin release following a meal, causing a transient hypoglycemia with mild adrenergic symptoms. The blood glucose level returns to normal even if the patient is not fed. The only treatment usually needed is that the patient eat frequent small meals instead of the usual three large meals. Fasting hypoglycemia: It is rare and produces neuroglycopenic symptoms. It may be due to: a) reduction in the rate of glucose production by the liver as in patients with hepatocellular damage or adrenal insufficiency or in fasting persons who have consumed large quantities of ethanol which inhibits gluconeogenesis. Alcohol consumption can also increase the risk for hypoglycemia in patients using insulin b) An increased rate of glucose utilization by the peripheral tissues, most commonly due to elevated insulin resulting from a pancreatic B-cell tumor. If untreated, a patient with fasting hypoglycemia may lose consciousness and develop convulsions and coma. IV-Metabolism in the well –Fed state The absorptive state is the 2 to 4 hours period after ingestion of a normal meal. During this period transient increase in plasma glucose, amino acid, and triacylglycerols occur. Islet tissue of the pancreas responds to the elevation level of glucose and amino acids with an increased of insulin and a drop in the secretion of glucagons. It is an anabolic period (increased synthesis of glycogen, triacylglycerols and protein). During this absorptive period all tissues use glucose as fuel. 1-Enzymic changes in the fed state: The flow of intermediates through metabolic pathways is controlled by four mechanisms: (1) the availability of substrates (2) allosteric activation and inhibition of enzymes (3) covalent modification of enzymes and (4) induction repression of enzyme synthesis. A-_Allosteric effects: The allosteric changes usually affect the rate limiting reactions e.g. glycolysis in the liver is stimulated following a meal by increase in fructose 2, 6 – biphosphate, an allosteric activator of phosphofructokinase. I. Gluconeogenesis is inhibited by fructose 2, 6-biphosphate, an inhibitor of fructose 1, 6-biphosphate. Allosteric effects work within minutes. B- Regulation of enzymes by covalent modification Many enzymes are regulated by covalent modification, (phosphorylation and de phosphorylation). In the fed state most of the enzymes regulated by covalent modification are in dephosphorylated state and active e.g. Pyruvate kinase, Pyruvate dehydrogenase complex, glycogen synthase HMG – CoA reductase and acetyl –CoA carboxylase Three exceptions (active phosphorylated forms) are glycogen phosphorylase, fructose bisphosphate phosphatase and hormone-sensitive lipase of adipose tissue. Covalent modification takes minutes to hours Induction and repression of enzyme synthesis The key enzymes are usually regulated by hormones that affect their synthesis e.g. insulin stimulates (induction) the synthesis of glucokinase, phosphofructokinase I, pyruvate kinase, the key enzyme of glycolysis, regulation of enzyme synthesis takes hours to days LIVER: NUTRIENT DISTRIBUTION CENTER Thus, after a meal, the liver receives portal blood containing absorbed nutrients and high levels of insulin secreted by the pancreas A-Carbohydrate metabolism Hepatic metabolism of glucose is increased by the following mechanism 1. Increased phosphorylation of glucose: High levels of intra cellular glucose in the hepatocyte stimulates glucokinase to phosphorylate glucose to glucose 6-phosphate glucokinase has low affinity (high Km for glucose. 2- Increased gIycolysis: The conversion of glucose to pyruvate to acetyl CoA is stimulated by the elevated insulin to glucagon ratio that activates the key enzymes of glycolysis Acetyl CoA is used as either provides energy by oxidation by the TCA cycle or as a building block for fatty acid synthesis 3-Increased activity of the hexose monophosphate pathway (HMP): The increased availability of glucose 6-phosphate in the well-Fed state, combined with the active utilization of NADPH in hepatic lipogenesis, stimulate the HMP 4- Increased Glycogensis Increased glucose -6 phosphate and insulin to glucagon activate glycogen synthase the key enzyme of glycogensis 4-Decreased gluconeogenesis: The high insulin to glucagon ratio inhibits enzymes of gluconeogenesis, such as fructose 1,6-bisphosphatase B. Fat metabolism 1. Increased fatty acid synthesis: Liver is the primary tissue for de novo synthesis of fatty acids: Due to increase acetyl CoA and NADPH the substrates for de novo synthesis of fatty acids (derived from the metabolism of glucose) and the activation of acetyl carboxylase , that is rate-limiting a reaction in fatty acid synthesis). 2. Increased triacyl glycerol synthesis: The increased availability of fatty acids coming from : (a) Increased de novo synthesis of FA from acetyl CoA and (b) Increased from hydrolysis of the triacylglycerol component of chylomicron remnants and increased availability of glycerol 3-phosphate (Glucose Dihydroxyacetone phosphate glycerol 3-phosphate) TG formed by the liver lipoprotein (VLDL) extrahepatic especially adipose and muscle tissue C. Amino acid metabolism 1- Increased protein synthesis (stimulated by insulin) 2-Increased amino acid degradation In the absorptive period, more amino acids are present than the liver can use in the synthesis of proteins and other nitrogen compound. The excess amino acids are either released into the blood for all tissues to use in protein synthesis or are deaminated; to produce energy. The body cannot store proteins. The liver has limited capacity to degrade the branched-chain amino acids (leucine, isoleucine, and valine) which are metabolized in the muscle Adipose Tissue: Energy Storage Depot: Adipose tissue is second only to the liver in its ability to distribute fuel molecules. In a 70 kg man adipose tissue weighs about 14 kg or about half as much as the total muscle mass. In obese individuals adipose tissue can constitute up to 70% of body weight. A. Carbohydrate Metabolism 1. Increased glucose transport: stimulated by insulin (glucose transport) 2. Increased gIycolysis: to provide glycerol phosphate for triacylglycerol synthesis 3. Increased activity in the HMP: To supply NADPH (essential for fat synthesis). B. Fat Metabolism 1. Increased synthesis of fatty acids: De novo synthesis of fatty acids from acetyl CoA in adipose tissue is nearly undetectable in humans, except when refeeding a previously fasted individual. Most of the fatty acids added to the lipid stores of adipocytes is provided by dietary fat (in the form of chylomicrons), and a lesser amount is supplied by VLDL from the liver 2. Increased triacylglycerol synthesis: Fatty acid + glycerol 3-ph triacylglycerol (TG) Adipocytes lack glycerol kinase, so that glycerol 3-phosphate used in triacylglycerol synthesis must come from the metabolism of glucose Thus, in the well-fed state, elevated levels of glucose and insulin favor storage of TG 3. Decreased triacylglycerol degradation: Insulin inhibits the hormone-sensitive lipase (dephosphorylated form) and thus inhibits triacylglycerol degradation is in the well-fed state. Resting Skeletal Muscle: At rest, muscle accounts for about 30% of the oxygen consumption of the body; during vigorous exercise it is responsible for up to 90% of the total oxygen consumption. Skeletal muscle despite its potential for transient periods of anaerobic glycolysis is an oxidative tissue. Heart muscle differs from skeletal muscle in three important ways: 1- The heart is continuously active, wherease skeletal muscle contracts intermittent on demand 2- the heart has a completely aerobic metabolism 3- The heart contains negligible energy stores such as glycogen or lipid .Thus , any interruption of the vascular supply, for example, as occurs during a myocardial infraction, results in rapid death of myocardial cells .Heart muscle uses glucose , free fatty acid and ketone bodies as fuels. A. Carbohydrate Metabolism: 1. Increased glucose transport: due to increase insulin (glucose transporter 4). Glucose is phosphorylated to glucose 6-phosphate and metabolized to produce the energy needs of the muscle. This contrasts with the postabsorptive state in which ketone bodies and fatty acids are the major fuels of resting muscle. 2. Increased glycogen synthesis: The increased insulin to glucagon ratio and the availability of glucose 6-phosphate stimulate glycogenesis, especially if glycogen stores have been depleted as a result of exercise. . B. Fat Metabolism Fatty acids are of secondary importance as a fuel for muscle in the well- fed state in which glucose is the primary source of energy. C. Amino Acid Metabolism: 1. Increased protein synthesis: An increase in amino acid uptake and protein synthesis occurs in the absorptive period after ingestion of a meal containing protein ( stimulated by insulin). 2. Increased uptake of branched-chain amino acids: Muscle is the principal site for degradation of branched-chain amino acids. Leucine, isoleucine, and valine are taken up by muscle, where they are used for protein synthesis and as sources of energy Brain Although forming only 2% of the adult weight, the brain accounts for 20% of the basal oxygen consumption of the body at rest. The brain uses energy at a constant rate. Normally, glucose its primary fuel to the brain, because in the fed state the concentration of ketone bodies is too low to be an energy source. If the blood glucose levels fall below approximately 30 mg /dl (normal blood glucose is 70-90 mg/dl) cerebral function is impaired. A. Carbohydrate Metabolism: In the well-fed state, the brain uses glucose exclusively as a fuel, completely oxidizing about 140 g / day glucose to carbon dioxide and water. The brain contains no stores of glycogen, and is therefore completely dependent on the availability of blood glucose. B. Fat Metabolism: The brain has no significant stores of triacylglycerols. Blood fatty acids do not efficiently cross the blood-brain barrier (The endothelial cells that line the blood vessels in the brain).Thus, the oxidation of fatty acids is of little importance to the brain Metabolism in Fasting Fasting may result from an inability to obtain food, from the desire to lose weight rapidly, or in clinical situations in which an individual cannot eat because of trauma, surgery, neoplasmas and burns. In the absence of food, plasma levels of glucose, amino acids, and triaclyglycerols fall, stimulating the secretion of glucagon and inhibiting insulin secretion. Fasting is a catabolic period characterized by degradation of glycogen, triaclyglycerols, and protein for (1) Maintain sufficient plasma levels of glucose for energy metabolism of the brain and other glucose – requiring tissues (2) Mobilize fatty acids from adipose tissue and ketone bodies from liver to supply energy to all other tissues . 1-Fuel Stores: The metabolic fuels available in a normal 70-Kg man at the beginning of a fast are: (1) 15 Kg fat, (2) 0.2 Kg glycogen, and 6 Kg protein. Only about 1/3 of the body protein can be used for energy production without affecting the vital functions. The metabolic changes in fasting are opposite to those in the well fed -state. 2-Liver in Fasting A-Carbohydrate Metabolism. The liver first uses glycogen degradation, then gluconeogenesis to maintain blood glucose levels. 1-Increased glyconeolysis: several hours after a meal, blood glucose levels decrease stimulating the secretion of glucagon and inhibiting insulin secretion. . The increased glucagon to insulin ratio stimulates glyconeolysis. Liver glycogen is nearly depleted after 10 – 18 hours of fasting. Thus hepatic glyconeolysis is a transient response to early fasting. Adult's liver contains 100 g of glycogen in the well -fed state. 2-Increaased Gluconeogensis: gluconeogensis begins 4 –6 hours after the last meal and becomes fully active as liver glycogen stores are depleted. Gluconeogenesis plays an essential role in maintaining blood glucose during both overnight and prolonged fasting. The main sources for gluconeogenesis are amino acids, glycerol and lactate. B-Fat Metabolism: 1-Increased fatty acid oxidation: The oxidation of fatty acids derived from adipose tissue is the major source of energy in hepatic tissue in the post absorptive state. 2-Increased Synthesis of Ketone bodies: The availability of circulating ketone bodies is important in fasting because they can be used as fuel by most tissues including brain, once their level in blood is sufficiently high. This reduces the need for gluconeogenesis from amino acids, thus slowing the loss of essential protein. Ketone body synthesize is favored when the concentration of acetyl CoA, produced from fatty acid oxidation exceeds the oxidative capacity of the tricarboxylic acid (TCA) cycle. Unlike fatty acids Ketone bodies are water –soluble, and appear in the blood and urine by the second day of a fast. 3-Adipose Tissue in Fasting: A-Carbohydrate Metabolism: Glucose transport into the adipocyte and its metabolism are depressed due to low levels of blood insulin .This leads to a decrease in fatty acid and triacyl- glycerol synthesis. B-Fat Metabolism. 1-Increased degradation of triaclyglycerols: The activation of hormone – sensitive lipase and subsequent hydrolysis of stored triacylglycerol are stimulated by high levels of catecoholamines (epinephrine and particularly norepinephrine). 2-Increased release of fatty acids: Fatty acids resulting from the hydrolysis of stored triacylglycerol are released into the blood. Bound to albumin, they are transported to other tissues for use as fuel. Part of the fatty acids is oxidized in the adipose tissue to produce energy. The glycerol produced from triacylglycerol degradation is used by the liver for gluconeogenesis. 3-Decreased uptake of fatty acid: In fasting, lipoprotein lipase activity of adipose tissue is low. Thus, circulating triacylglycerol of lipoproteins is not available for triacylglycerol synthesis in adipose tissue . 4-Resting Skeletal Muscle in Fasting: Resting muscle uses fatty acids as its major fuel source. By contrast, exercising muscle initially uses its glycogen stores as a source of energy. During intense exercise, glucose -6-phosphate derived from glycogen is converted to lactate by anaerobic glycolysis. As these glycogen reserves are depleted, free fatty acids provided by the mobilization of triacylglycerol from adipose tissue become the major sources. A. Carbohydrate Metabolism: Glucose transport and subsequent glucose metabolism are depressed because of low blood insulin. B.Fat Metabolism: During the first 2 weeks of fasting, muscle uses fatty acids from adipose tissue and ketone bodies from the liver as fuels. After about 3 weeks of fasting, muscle decreases its utilization of ketone bodies and oxidize only fatty acids. This leads to a further increase in the already elevated levesl of blood ketone bodies. C.Protein Metabolism: During the first few days of starvation there is rapid breakdown of muscle protein, giving amino acids that are used by the liver for gluconeogenesis. Alanine and glutamine are quantitatively the most important glucogenic amino acids released from muscle. After several weeks of fasting, the rate of muscle proteolysis decreases due to a decline in the need for glucose as a fuel for brain 5-Brain in Fasting During the first days of fasting, the brain continues to use only glucose as a fuel. In prolonged fasting ( greater than 2-3 weeks ) , plasma ketone bodies reach markedly high levels and are used in addition to glucose as a fuel by the brain. This decreases the need for protein catabolism for gluconeogenesis. 1