Endocrine System | Pancreas & CHO metabolism PDF

Physiology Endocrine System Chapter 24 | Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism Endocrine System | Pancreas & CHO metabolism Contents : Introduction 3 Structure, Biosynthesis, & Secretion Of Insulin 8 Fate Of Secreted Insulin 9 Glucose Transporters 19 Effects of...

Physiology Endocrine System Chapter 24 | Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism Endocrine System | Pancreas & CHO metabolism Contents : Introduction 3 Structure, Biosynthesis, & Secretion Of Insulin 8 Fate Of Secreted Insulin 9 Glucose Transporters 19 Effects of Hyperglycemia 27 Regulation of Insulin Secretion 36 Glucagon 44 Other Islet Cell Hormones 54 Diabetes Mellitus 60 Chapter Summary 76 Endocrine System | Pancreas & CHO metabolism Introduction: There are four polypeptides with regulatory activity are secreted by the islets of Langerhans in the pancreas. Two of these, insulin and glucagon, are hormones and have important functions in the regulation of the intermediary metabolism of carbohydrates, proteins, and fats. Endocrine System | Pancreas & CHO metabolism The third polypeptide, somatostatin, plays a role in the regulation of islet cell secretion, and the fourth, pancreatic polypeptide, is probably concerned primarily with the regulation of ion transport in the intestine. The islets of Langerhans are collections of cells. The cells in the islets can be divided into types on the basis of their staining properties and morphology Endocrine System | Pancreas & CHO metabolism Humans have at least four distinct cell types: A, B, D, and F cells. A, B, and D cells are also called α, β, and δ cells. β-Islets make up about 2% of the volume of the gland, whereas the exocrine portion of the pancreas makes up 80%, and ducts and blood vessels make up the remainder. Humans have 1 to 2 million islets. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism The A cells secrete glucagon, the B cells secrete insulin, the D cells secrete somatostatin, and the F cells secrete pancreatic polypeptide. The B cells, which are the most common and account for 60– 75% of the cells in the islets, are generally located in the center of each islet. They tend to be surrounded by the A cells, which make up 20% of the total, and the less common D and F cells. Endocrine System | Pancreas & CHO metabolism Structure, Biosynthesis, & Secretion Of Insulin : Insulin is a polypeptide containing two chains of amino acids linked by disulfide bridges. Insulin is synthesized in the rough endoplasmic reticulum of the B cells. It is then transported to the Golgi apparatus, where it is packaged into membrane bound granules. These granules move to the plasma membrane by a process involving microtubules, and their contents are expelled by exocytosis. Endocrine System | Pancreas & CHO metabolism Fate Of Secreted Insulin : Metabolism The half-life of insulin in the circulation in humans is about 5 min. Insulin binds to insulin receptors, and some is internalized. It is destroyed by proteases in the endosomes formed by the endocytotic process. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Effects Of Insulin: The physiologic effects of insulin are far-reaching and complex. They are conveniently divided into rapid, intermediate, and delayed actions. The insulin has many actions on adipose tissue; skeletal, cardiac, and smooth muscle; and the liver. Endocrine System | Pancreas & CHO metabolism Table: Principal actions of insulin Principal actions of insulin Rapid (seconds) Intermediate (minutes) Delayed (hours) Increased transport of glucose, amino acids, and K+ into insulin sensitive cells Stimulation of protein synthesis Inhibition of protein degradation Activation of glycolytic enzymes and glycogen synthase Inhibition of phosphorylase and gluconeogenic enzymes Increase in mRNAs for lipogenic and other enzymes Endocrine System | Pancreas & CHO metabolism In general insulin increase cell growth, but also has specific action on : Adipose tissue: it ↑ glucose entry, ↑ fatty acid synthesis, ↑ glycerol phosphate synthesis, ↑ triglyceride deposition, activation of lipoprotein lipase, inhibition of hormone sensitive lipase and ↑ K+ uptake. Endocrine System | Pancreas & CHO metabolism Muscle: ↑ glucose entry, ↑ glycogen synthesis, ↑ amino acid uptake, ↑ protein synthesis in ribosomes, ↑ ketone & K+ uptake and finally ↓ protein catabolism & release of gluconeogenic amino acids. Endocrine System | Pancreas & CHO metabolism Liver : ↑ protein & lipid synthesis, ↓ ketogenesis, ↓ glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis. Endocrine System | Pancreas & CHO metabolism Table: Effects of insulin on various tissues. Adipose tissue Increased glucose entry Increased fatty acid synthesis Increased glycerol phosphate synthesis Increased triglyceride deposition Activation of lipoprotein lipase Inhibition of hormone-sensitive lipase Increased K+ uptake Endocrine System | Pancreas & CHO metabolism Table: Effects of insulin on various tissues. Muscle Increased glucose entry Increased glycogen synthesis Increased amino acid uptake Increased protein synthesis in ribosomes Decreased protein catabolism Decreased release of gluconeogenic amino acids Increased ketone uptake Increased K+ uptake Endocrine System | Pancreas & CHO metabolism Table: Effects of insulin on various tissues. Liver Decreased ketogenesis Increased protein synthesis Increased lipid synthesis Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis General Increased cell growth Glucose Transporters Endocrine System | Pancreas & CHO metabolism Glucose Transporters : Glucose enters cells by facilitated diffusion or, in the intestine and kidneys, by secondary active transport with Na+. In muscle, adipose, and some other tissues, insulin stimulates glucose entry into cells by increasing the number of glucose transporters (GLUTs) in the cell membranes. The GLUTs that are responsible for facilitated diffusion of glucose across cell membranes are a family of closely related proteins that span the cell membrane 12 times and have their amino and carboxyl terminals inside the cell. Endocrine System | Pancreas & CHO metabolism Insulin also increases the entry of glucose into liver cells, but it does not exert this effect by increasing the number of GLUT-4 transporters in the cell membranes. Instead, it induces glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Mechanism of Action: Insulin Receptors Insulin receptors are found on many different cells in the body. The insulin receptor, is a tetramer made up of two α and two β glycoprotein subunits. The α subunits bind insulin and are extracellular, whereas the β subunits span the membrane. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Consequences of Insulin Deficiency: In humans, insulin deficiency is a common pathologic condition. In animals, it can be produced by pancreatectomy; by administration many of toxins that in appropriate doses cause selective destruction of the B cells of the pancreatic islets; by administration of drugs that inhibit insulin secretion; and by administration of antiinsulin antibodies.. Endocrine System | Pancreas & CHO metabolism Effects of Hyperglycemia Endocrine System | Pancreas & CHO metabolism Effects of Hyperglycemia: Hyperglycemia by itself can cause symptoms resulting from the hyperosmolality of the blood. In addition, there is glycosuria because the renal capacity for glucose reabsorption is exceeded. Excretion of the osmotically active glucose molecules entails the loss of large amounts of water (osmotic diuresis). Endocrine System | Pancreas & CHO metabolism The resultant dehydration activates the mechanisms regulating water intake, leading to polydipsia. When plasma glucose is episodically elevated over time, small amounts of hemoglobin A are non-enzymatically glycated to form HbAIc. Careful control of the diabetes with insulin reduces the amount formed and consequently HbA>Ic concentration is measured clinically as an integrated index of diabetic control for the 4 to 6-weeks period before the measurement. Endocrine System | Pancreas & CHO metabolism Effect of hyperglycemia on protein metabolism: In diabetes, the rate at which amino acids are catabolized to CO2 and H2O is increased. In addition, more amino acids are converted to glucose in the liver. The increased gluconeogenesis has many causes. Endocrine System | Pancreas & CHO metabolism Adrenal glucocorticoids also contribute to increased gluconeogenesis when they are elevated in severely ill diabetics. The supply of amino acids is increased for gluconeogenesis because, in the absence of insulin, less protein synthesis occurs in muscle and hence blood amino acid levels rise. Endocrine System | Pancreas & CHO metabolism Fat Metabolism in Diabetes: The principal abnormalities of fat metabolism in diabetes are accelerated lipid catabolism, with increased formation of ketone bodies, and decreased synthesis of fatty acids and triglycerides. In diabetes, conversion of glucose to fatty acids in the depots is decreased because of the intracellular glucose deficiency. Insulin inhibits the hormone-sensitive lipase in adipose tissue, and, in the absence of this hormone, the plasma level of free fatty acids is more than doubled. Endocrine System | Pancreas & CHO metabolism Thus, the FFA level parallels the plasma glucose level in diabetes and in some ways is a better indicator of the severity of the diabetic state. In uncontrolled diabetes, the plasma concentration of triglycerides and chylomicrons as well as FFA is increased, and the plasma is often lipemic. Endocrine System | Pancreas & CHO metabolism The rise in these constituents is mainly due to decreased removal of triglycerides into the fat depots. The decreased activity of lipoprotein lipase contributes to this decreased removal. In diabetes, the plasma cholesterol level is usually elevated and this plays a role in the accelerated development of the atherosclerotic vascular disease that is a major long-term complication of diabetes in humans. Endocrine System | Pancreas & CHO metabolism The rise in plasma cholesterol level is due to an increase in the plasma concentration of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). These in turn may be due to increased hepatic production of VLDL or decreased removal of VLDL and LDL from the circulation. Regulation of Insulin Secretion Endocrine System | Pancreas & CHO metabolism Regulation of Insulin Secretion: The glucose acts directly on pancreatic B cells to increase insulin secretion. The response to glucose is biphasic; there is a rapid but short-lived increase in secretion followed by a more slowly developing prolonged increase. Endocrine System | Pancreas & CHO metabolism Glucose enters the B cells via GLUT-2 transporters and is phosphorylated by glucokinase then metabolized to pyruvate in the cytoplasm. The pyruvate enters the mitochondria and is metabolized to CO2 and H2O via the citric acid cycle with the formation of ATP by oxidative phosphorylation. Endocrine System | Pancreas & CHO metabolism The ATP enters the cytoplasm, where it inhibits ATP-sensitive K+ channels, reducing K+ efflux. This depolarizes the B cell, and Ca2+ enters the cell via voltagegated Ca2+ channels. The Ca2+ influx causes exocytosis of a readily releasable pool of insulin-containing secretory granules, producing the initial spike of insulin secretion. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Metabolism of pyruvate via the citric acid cycle also causes an increase in intracellular glutamate. The glutamate appears to act on a second pool of secretory granules, committing them to the releasable form. Endocrine System | Pancreas & CHO metabolism The release of these granules then produces the prolonged second phase of the insulin response to glucose. The feedback control of plasma glucose on insulin secretion normally operates with great precision so that plasma glucose and insulin levels parallel each other with remarkable consistency. Endocrine System | Pancreas & CHO metabolism Glucagon Endocrine System | Pancreas & CHO metabolism Glucagon: Glucagon is produced by the A cells of the pancreatic islets and the upper gastrointestinal tract. Glucagon is glycogenolytic, gluconeogenic, lipolytic, and ketogenic. In the liver, it acts via Gs to activate adenylyl cyclase and increase intracellular cAMP. Endocrine System | Pancreas & CHO metabolism This leads via protein kinase A to activation of phosphorylase and therefore to increased breakdown of glycogen and an increase in plasma glucose. However, glucagon acts on different glucagon receptors located on the same hepatic cells to activate phospholipase C, and the resulting increase in cytoplasmic Ca2+ also stimulates glycogenolysis. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism It increases gluconeogenesis from available amino acids in the liver and elevates the metabolic rate. It increases ketone body formation by decreasing malonyl-CoA levels in the liver. Its lipolytic activity, which leads in turn to increased ketogenesis. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Regulation of Secretion: The Secretion of glucagon is increased by hypoglycemia and decreased by a rise in plasma glucose. Also, secretion is also increased by stimulation of the sympathetic nerves to the pancreas, and this sympathetic effect is mediated via β-adrenergic receptors and cAMP. Endocrine System | Pancreas & CHO metabolism A protein meal and infusion of various amino acids increase glucagon secretion. Cholecystokinin and gastrin increase glucagon secretion, whereas secretin inhibits it. Because CCK and gastrin secretion are both increased by a protein meal, either hormone could be the gastrointestinal mediator of the glucagon response. Endocrine System | Pancreas & CHO metabolism Table: Factors affecting insulin secretion Stimulators Inhibitors Glucose Mannose Somatostatin 2-Deoxyglucose Amino acids (leucine, arginine, others) Intestinal hormones (GIP, GLP-1 [7–36], gastrin, secretin, CCK; others?) β-Keto acids Acetylcholine Mannoheptulose α-Adrenergic stimulators (norepinephrine, epinephrine) β-Adrenergic blockers (propranolol) Endocrine System | Pancreas & CHO metabolism Table: Factors affecting insulin secretion Stimulators Inhibitors Glucagon Cyclic AMP and various cAMP generating substances Galanin Diazoxide Thiazide diuretics β-Adrenergic stimulators Theophylline K+ depletion Phenytoin Sulfonylureas Alloxan Microtubule inhibitors Insulin Other Islet Cell Hormones Endocrine System | Pancreas & CHO metabolism Other Islet Cell Hormones : Somatostatin Somatostatin 14 (SS 14) and its amino terminal-extended form somatostatin 28 (SS 28) are found in the D cells of pancreatic islets. Both forms inhibit the secretion of insulin, glucagon, and pancreatic polypeptide and act locally within the pancreatic islets in a paracrine fashion. Endocrine System | Pancreas & CHO metabolism SS 28 is more active than SS 14 in inhibiting insulin secretion. The secretion of pancreatic somatostatin is increased by several of the same stimuli that increase insulin secretion, that is, glucose and amino acids. It is also increased by CCK. Endocrine System | Pancreas & CHO metabolism Pancreatic Polypeptide It is produced by F cells in the islets. It is closely related to two other amino acid polypeptides, polypeptide YY, a gastrointestinal peptide and neuropeptide Y, which is found in the brain and the autonomic nervous system. Its secretion is increased by a meal containing protein and by fasting, exercise, and acute hypoglycemia. Secretion is decreased by somatostatin and intravenous glucose. Pancreatic polypeptide slows the absorption of food in humans. Endocrine System | Pancreas & CHO metabolism Hypoglycemia & Diabetes Mellitus In Humans: Hypoglycemia “Insulin reactions” are common in type 1 diabetics and occasional hypoglycemic episodes are the price of good diabetic control in most diabetics. Chronic mild hypoglycemia can cause incoordination and slurred speech, and the condition can be mistaken for drunkenness. Endocrine System | Pancreas & CHO metabolism In functional hypoglycemia, the plasma glucose rise is normal after a test dose of glucose, but the subsequent fall overshoots to hypoglycemic levels, producing symptoms 3–4 h after meals. This pattern is sometimes seen in individuals in whom diabetes develops later. Diabetes Mellitus Endocrine System | Pancreas & CHO metabolism Diabetes Mellitus : The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus. Diabetes is characterized by polyuria (passage of large volumes of urine), polydipsia (excessive drinking), weight loss in spite of polyphagia (increased appetite), hyperglycemia, glycosuria, ketosis, acidosis, and coma. Endocrine System | Pancreas & CHO metabolism The fundamental defects to which most of the abnormalities can be traced are 1. Reduced entry of glucose into various “peripheral” tissues. 2. Increased liberation of glucose into the circulation from the liver. Therefore, there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.”. Endocrine System | Pancreas & CHO metabolism Diabetes is sometimes complicated by acidosis and coma, and in long-standing diabetes, additional complications occur. These include microvascular, macrovascular, and neuropathic disease. The micro vascular abnormalities are proliferative scarring of the retina (diabetic retinopathy) leading to blindness and renal disease (diabetic nephropathy) leading to chronic kidney disease Endocrine System | Pancreas & CHO metabolism The macrovascular abnormalities are due to accelerated atherosclerosis, which is secondary to increased plasma LDL. The result is an increased incidence of stroke and myocardial infarction. The neuropathic abnormalities (diabetic neuropathy) involve the autonomic nervous system and peripheral nerves. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Clinical Box Diabetes Mellitus : The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus. Greek and Roman physicians used the term “diabetes” to refer to conditions in which the cardinal finding was a large urine volume, and two types were distinguished: “diabetes mellitus,” in which the urine tasted sweet; and “diabetes insipidus,” in which the urine had little taste. Endocrine System | Pancreas & CHO metabolism Today, the term “diabetes insipidus” is reserved for conditions in which there is a deficiency of the production or action of vasopressin, and the unmodified word “diabetes” is generally used as a synonym for diabetes mellitus. The cause of clinical diabetes is always a deficiency of the effects of insulin at the tissue level. Endocrine System | Pancreas & CHO metabolism Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is due to insulin deficiency caused by autoimmune destruction of the B cells in the pancreatic islets, and it accounts for 3–5% of cases and usually presents in children. Endocrine System | Pancreas & CHO metabolism Type 2 diabetes, or non–insulin dependent diabetes mellitus (NIDDM), is characterized by the dysregulation of insulin release from the B cells, along with insulin resistance in peripheral tissues such as skeletal muscle, brain, and liver. Type 2 diabetes historically presented in overweight or obese adults, although it is increasingly being diagnosed in children as childhood obesity increases. Endocrine System | Pancreas & CHO metabolism Endocrine System | Pancreas & CHO metabolism Diabetes is characterized by polyuria (passage of large volumes of urine), polydipsia (excessive drinking), weight loss in spite of polyphagia (increased appetite), hyperglycemia, glycosuria, ketosis, acidosis, and coma. Widespread biochemical abnormalities are present, but the fundamental defects to which most of the abnormalities can be traced are (1) reduced entry of glucose into various “peripheral” tissues and (2) increased liberation of glucose into the circulation from the liver. Endocrine System | Pancreas & CHO metabolism Therefore, there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.” Also, the entry of amino acids into muscle is decreased and lipolysis is increased. Endocrine System | Pancreas & CHO metabolism Therapeutic Highlights In type 1 diabetes, the mainstay of therapy is provision of exogenous insulin, carefully titrated to dietary intake of glucose. In type 2 diabetes, lifestyle changes such as alterations in the diet or increased exercise can often delay symptoms in early disease, but these are difficult to secure. Insulin-sensitizing drugs represent second-line agents. Endocrine System | Pancreas & CHO metabolism Obesity, the Metabolic Syndrome, & Type 2 Diabetes : Obesity is increasing in incidence, and relates to the regulation of food intake and energy balance and overall nutrition. As body weight increases, insulin resistance increases, that is, there is a decreased ability of insulin to move glucose into fat and muscle and to shut off glucose release from the liver. Weight reduction decreases insulin resistance. Endocrine System | Pancreas & CHO metabolism Associated with obesity there is hyperinsulinemia, dyslipidemia (characterized by high circulating triglycerides and low high-density lipoprotein [HDL]), and accelerated development of atherosclerosis. This combination of findings is commonly called the metabolic syndrome. Chapter Summary Endocrine System | Pancreas & CHO metabolism Chapter Summary : Four polypeptides with hormonal activity are secreted by the pancreas: insulin, glucagon, somatostatin, and pancreatic polypeptide. Insulin increases the entry of glucose into cells. In skeletal muscle cell it increases the number of GLUT-4 transporters in the cell membranes. In liver it induces glucokinase, which increases the phosphorylation of glucose, facilitating the entry of glucose into the cell. Endocrine System | Pancreas & CHO metabolism Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Insulin increases the activity of Na, K ATPase in cell membranes, so that more K+ is pumped into cells. Hypokalemia often develops when patients with diabetic acidosis are treated with insulin. Endocrine System | Pancreas & CHO metabolism Insulin receptors are found on many different cells in the body and have two subunits, α and β. Binding of insulin to its receptor triggers a signaling pathway that involves autophosphorylation of the β subunits on tyrosine residues. This triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of others, mostly on serine and threonine residues. Endocrine System | Pancreas & CHO metabolism The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus. Type 1 diabetes is due to insulin deficiency caused by autoimmune destruction of the B cells in the pancreatic islets. Type 2 diabetes is characterized by the dysregulation of insulin release from the B cells, along with insulin resistance in peripheral tissues such as skeletal muscle, brain, and liver.