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Phys chap 78 Insulin, Glucagon, and Diabetes Mellitus Acini – exocrine pancreas Islets of Langerhans organized around small capillaries into which cells secrete their hormones o Alpha, beta, and delta cells can be distinguished by staining characteristics and morphology o Majority are beta cells, followed by alpha cells, then delta cells (secrete somatostatin) o PP cell present in small numbers and secretes pancreatic polypeptide (don’t know what it does) Insulin inhibits glucagon secretion Amylin inhibits insulin secretion Somatostatin inhibits secretion of both insulin and glucagon Insulin and Its Metabolic Effects Abnormalities of fat metabolism (causing acidosis and arteriosclerosis) that are usual causes of death in diabetic patients, not hypoglycemia itself In patients with prolonged diabetes, diminished ability to synthesize proteins leads to wasting of tissues and cellular functional disorders Excess carbs in diet makes insulin secretion increase; insulin causes carbs to be stored as glycogen mainly in liver and muscles; all excess carbs that can’t be stored as glycogen converted to fats and stored in adipose tissue (under stimulus of insulin) Insulin has direct effect in promoting amino acid uptake by cells and conversion of amino acids into protein; inhibits breakdown of proteins already in cells Insulin composed of 2 amino acid chains connected by disulfide linkages; when amino acid chains split apart, functional activity of insulin molecule lost Synthesized with translation of insulin RNA by ribosomes attached to rER to form preproinsulin; cleaved in rER to form proinsulin (A, B, and C chains); most of proinsulin cleaved in Golgi apparatus to form insulin (A and B chains); insulin and C peptide packaged in secretory granules and secreted in equimolar amounts o 5-10% of secreted product still proinsulin (has virtually no insulin activity) o C-peptide binds to PM receptor and elicits activation of Na+/K+-ATPase and endothelial NO synthase o Measurement of C-peptide levels by radioimmunoassay determines how much insulin is patient’s own When insulin secreted into blood, it circulates almost entirely in unbound form; plasma half-life averages 6 minutes, so mainly cleared from circulation in 10-15 minutes o Except for portion that combines with receptors in target cells, remainder degraded by insulinase, mainly in liver and to lesser extent kidneys and muscles (can happen almost anywhere though) Insulin binds to receptor protein on target cell; receptor contains 2 alpha subunits (completely extracellular) and 2 beta subunits (have intracellular domains) linked by disulfide linkages o Binding of insulin to alpha subunits causes autophosphorylation of beta subunits (enzyme-linked receptor); autophosphorylation of beta subunits activates local tyrosine kinase, which causes phosphorylation of insulin-receptor substrates (IRS) o Different types of IRS expressed in different tissues End effects of insulin stimulation are o Cell PM increases glucose uptake (not most neurons in brain); glucose immediately phosphorylated to become substrate for carb metabolic functions Increased transport from translocation of intracellular vesicles to PM; vesicles carry glucose transport proteins, which bind with PM and facilitate glucose uptake When insulin no longer available, vesicles separate from PM within 3-5 minutes and move back to cell interior (recycled) o PM becomes more permeable to amino acids, K+, and HPO42-, causing increased transport into cell o Changes in activity levels of intracellular metabolic enzymes o Changed rates of translation of mRNAs at ribosomes to form new proteins; changed rates of transcription of DNA in cell nucleus During much of day, muscle tissue depends on fatty acids for energy; normal resting muscle membrane only slightly permeable to glucose, except when muscle fiber stimulated by insulin o o Between meals, amount of insulin secreted too small to promote significant amounts of glucose entry Muscles use large amounts of glucose during moderate to heavy exercise (exercising muscle fibers become more permeable to glucose even in absence of insulin because of contraction process itself) o Muscles use large amounts of glucose during few hours after meal; blood glucose concentration high and pancreas secretes large quantities of insulin, causing rapid transport of glucose into muscle cells If muscles not exercising after meal, most glucose transported into muscle cells in abundance stored as muscle glycogen (limited concentration); glycogen later used for energy by muscle (short spurts of anaerobic energy) Insulin inactivates liver phosphorylase (principal enzyme that causes liver glycogen to split into glucose) o Causes enhanced uptake of glucose from blood by hepatocytes by increasing activity of glucokinase; once phosphorylated, glucose temporarily trapped inside hepatocytes because phosphorylated glucose can’t cross PM o Increases activities of enzymes that promote glycogen synthesis, including glycogen synthase (responsible for polymerization of monosaccharide units to form glycogen molecules) When blood glucose levels begin to fall between meals, decreasing blood glucose causes pancreas to decrease insulin secretion; lack of insulin stops further synthesis of glycogen in liver and prevents further uptake of glucose by liver from blood o Lack of insulin and increase in glucagon activate phosphorylase, which causes splitting of glycogen into glucose phosphate o Glucose phosphatase (inhibited by insulin) becomes activated by insulin lack and causes phosphate radical to split away from glucose, allowing free glucose to diffuse back into blood When quantity of glucose entering liver cells more than can be stored as glycogen or used for hepatocyte metabolism, insulin promotes conversion of excess glucose into fatty acids, which are packaged as triglycerides in VLDL, transported to adipose tissue, and deposited as fat Insulin inhibits gluconeogenesis mainly by decreasing quantities and activities of enzymes required for it o Part of effect caused by action of insulin that decreases release of amino acids from muscle and other extra-hepatic tissues (no precursors for gluconeogenesis) Most of brain cells permeable to glucose and can use it without intermediation of insulin; normally only use glucose for energy (very difficult to use fats) Transport of glucose into adipose cells mainly provides substrate for glycerol portion of fat molecule; hence insulin promotes deposition of fat in these cells o Long-term insulin lack causes extreme atherosclerosis o Insulin increases utilization of glucose by most of body’s tissues, which automatically decreases utilization of fat, thus functioning as fat sparer o Insulin promotes fatty acid synthesis, using carbs as substrate; almost all fat synthesis occurs in liver cells, and fatty acids transported from liver by lipoproteins to adipose cells to be stored Factors that lead to increased fatty acid synthesis in liver o Insulin increases transport of glucose into liver cells; after liver glycogen reaches a certain concentration, it inhibits further glycogen synthesis; all additional glucose entering liver cells becomes available to form fat; glycolytic pathway makes pyruvate, which is converted to acetyl-CoA for fatty acid synthesis o Excess of citrate and isocitrate ions formed by TCA cycle when excess amounts of glucose being used for energy; ions have direct effect in activating acetyl-CoA carboxylase (required for first stage of fatty acid synthesis) o Most of fatty acids synthesized in liver and used to form triglycerides; released from hepatocytes to blood in lipoproteins; insulin activates LPL in capillary walls of adipose tissue, which split triglycerides into fatty acids for them to be absorbed into adipose cells, where they are converted to triglycerides and stored Insulin inhibits action of hormone-sensitive lipase (enzyme that causes hydrolysis of triglycerides already stored in fat cells; release of fatty acids from adipose tissue into circulating blood inhibited Insulin promotes glucose transport through PM into fat cells; some glucose used to synthesize minute amounts of fatty acids, and some forms large quantities of α-glycerol phosphate (supplies glycerol that combines with fatty acids to form triglycerides that are storage form of fat in adipose) All aspects of fat breakdown and use for providing energy greatly enhanced in absence of insulin o Hormone-sensitive lipase in fat cells becomes strongly activated; causes hydrolysis of stored triglycerides, releasing large quantities of fatty acids and glycerol into circulating blood o Free fatty acids become main energy substrate used by essentially all tissues of body Excess fatty acids in plasma associated with insulin deficiency promote liver conversion of some fatty acids into phospholipids and cholesterol, which are discharged into blood in lipoproteins (along with excess triglycerides) o High lipid concentration (especially high cholesterol) promotes development of atherosclerosis Insulin lack causes excessive amounts of acetoacetic acid to be formed in liver because in absence of insulin and presence of excess fatty acids in liver, carnitine transport mechanism for transporting fatty acids into mitochondria becomes increasingly activated o In mitochondria, beta oxidation of fatty acids proceeds rapidly, releasing excess acetyl-CoA o Large part of excess acetyl-CoA condensed to form acetoacetic acid, which is released into bloodstream o Acetoacetic acid converted back to acetyl-CoA by tissues and used for energy in usual manner o Absence of insulin depresses utilization of acetoacetic acid, so produces metabolic acidosis o Some of acetoacetic acid converted to ketone bodies Insulin stimulates transport of many amino acids into cells; increases translation of mRNA to form new proteins; increases rate of transcription of selected DNA genetic sequences (forming increased quantities of RNA and protein synthesis), promoting enzymes for storage of carbs, fats, and proteins; inhibits catabolism of proteins, decreasing rate of amino acid release from cells (results from ability of insulin to diminish normal degradation of proteins by cellular lysosomes); depresses rate of gluconeogenesis in liver by decreasing activity of enzymes that promote gluconeogenesis, conserving amino acids in protein stores in body Virtually all protein storage comes to a halt when insulin not available; catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids dumped into plasma o Most excess amino acids used directly for energy or as substrates for gluconeogenesis o Degradation of amino acids leads to enhanced urea excretion in urine Insulin required for growth (because of requirement for protein synthesis); functions synergistically with GH Glucose transport stimulation of insulin secretion from pancreatic beta cells o Glucokinase is rate-limiting step for glucose metabolism in beta cell; major mechanism for glucose sensing and adjustment of amount of secreted insulin to blood glucose levels o ATP inhibits ATP-sensitive K+ channels of cell; closure of K+ channels depolarizes PM, opening voltage-gated Ca2+ channels o Influx of Ca2+ stimulates fusion of docked insulin-containing vesicles with PM and secretion of insulin via exocytosis o Other nutrients (certain amino acids) can be metabolized by beta cells to increase intracellular ATP and stimulate insulin secretion o Glucagon, GIP, and ACh increase intracellular Ca2+ through other signaling pathway and enhance effect of glucose (don’t have major effects on insulin secretion in absence of glucose) o Somatostatin and norepi (by activating α-adrenergic receptors) inhibit exocytosis of insulin o Sulfonylurea drugs stimulate insulin secretion by binding to ATP-sensitive K+ channels and blocking their activity; depolarizes cell, triggering insulin secretion Effects of steadily increased glucose level on insulin secretion (plasma glucose held at elevated level) o First spike results from immediate dumping of preformed insulin from beta cells; initial high rate of secretion not maintained o After a while, secretion rises again from additional release of preformed insulin and from activation of enzyme system that synthesizes and releases new insulin from cells Arginine and lysine stimulate insulin secretion; amino acid rise in absence of rise in blood glucose causes only small increase in insulin secretion; when administered at same time as blood glucose concentration elevated, glucose-induced secretion of insulin may be doubled in presence of excess amino acids (amino acids potentiate glucose stimulus for insulin secretion) o Important because insulin important for proper utilization of excess amino acids Gastrin, secretin, CCK, and GIP cause moderate increase in insulin secretion; cause anticipatory increase in blood insulin in preparation for glucose and amino acids to be absorbed from meal o Increase sensitivity of insulin response to increased blood glucose Glucagon, GH, cortisol, and to lesser extent progesterone and estrogen all increase insulin secretion o Prolonged secretion of any one of them in large quantities can lead to exhaustion of beta cells and increase risk for developing DM Under some conditions, stimulation of PNS nerves to pancreas can increase insulin secretion; SNS stimulation decreases insulin secretion GH and cortisol secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while promoting fat utilization; effects develop slowly (requiring many hours for max expression) Epi increases plasma fatty acid concentration at same time as increasing plasma glucose o Epi has potent effect of causing glycogenolysis in liver, releasing large quantities of glucose into blood o Epi has direct lipolytic effect on adipose cells, activating adipose tissue hormone-sensitive lipase, greatly enhancing blood concentration of fatty acids as well o Enhancement of fatty acids far greater than enhancement of blood glucose Glucagon and Its Functions Secreted by alpha cells of islets of Langerhans when blood glucose concentration falls; increases blood glucose concentration Major effects of glucagon on glucose metabolism are breakdown of liver glycogen (glycogenolysis) and increased gluconeogenesis in liver Glucagon activates adenylyl cyclase in hepatic PM, which causes formation of cAMP, which activates protein kinase regulator protein, which activates protein kinase, which activates phosphorylase b kinase, which converts phosphorylase b into phosphorylase a, which promotes degradation of glycogen into glucose-1-phosphate, which is dephosphorylated and glucose released from hepatocytes o Cascade in which each succeeding product produced in greater quantity than preceding product Even after all glycogen in liver has been exhausted under influence of glucagon, continued infusion of glucagon still causes continued hyperglycemia because of increase rate of amino acid uptake by hepatocytes and conversion to glucose by gluconeogenesis Glucagon activates adipose cell lipase, making increased quantities of fatty acids available for energy Glucagon inhibits storage of triglycerides in liver, which prevents liver from removing fatty acids from blood and makes additional amounts of fatty acids available for tissues to use for energy Glucagon in high concentrations enhances strength of heart, increases blood flow in some tissues (especially kidneys), enhances bile secretion, and inhibits gastric acid secretion Decrease in blood glucose is most important stimulus for secretion of glucagon High concentrations of amino acids (especially alanine and arginine) stimulate secretion of glucagon; glucagon promotes rapid conversion of amino acids to glucose, making even more glucose available to tissues Glucagon level increases in exhaustive exercise, preventing decrease in blood glucose Somatostatin Delta cells secrete somatostatin (1-14); secretion stimulated by increased blood glucose, increased amino acids, increased fatty acids, and increased concentrations of GI hormones released from upper GI tract in response to food intake Somatostatin depresses secretion of both insulin and glucagon; decreases motility of stomach, duodenum, and gallbladder; decreases secretion and absorption in GI tract Sam chemical substance as growth hormone inhibitory hormone secreted in hypothalamus; suppresses anterior pituitary secretion of GH Summary of Blood Glucose Regulation Liver functions as important blood glucose buffer system, taking up glucose after meal and storing it as glycogen, then releasing it later as blood glucose starts to fall; dampens fluctuation in blood glucose In severe hypoglycemia, direct effect of low blood glucose on hypothalamus stimulates SNS; epi increases release of glucose from liver, protecting against severe hypoglycemia GH and cortisol decrease rate of glucose utilization by most cells of body, converting to fat utilization Glucose is only nutrient that normally can be used by brain, retina, and germinal epithelium of gonads in sufficient quantities to supply them optimally with required energy o Most of glucose formed by gluconeogenesis during interdigestive period used for metabolism in brain Important that blood glucose concentration not rise too high because o Glucose can exert large amount of osmotic pressure in extracellular fluid, causing cellular dehydration o Excessively high blood glucose causes loss of glucose in urine o Loss of glucose in urine causes osmotic diuresis by kidneys, which can deplete body of fluids and electrolytes o Long-term increases in blood glucose may cause damage to many tissues, especially blood vessels (increased risk for MI, stroke, renal disease, and blindness) Diabetes Mellitus DM – syndrome of impaired carb, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of tissues to insulin Type I diabetes – can be caused by viral infections or autoimmune disorders involved in destruction of beta cells o Usual onset of type I diabetes around 14 years of age, but can occur at any age o Onset characterized by increased blood glucose, increased utilization of fats for energy and for formation of cholesterol by liver, and depletion of body’s proteins High blood glucose causes more glucose to filter into renal tubules than can be reabsorbed, and excess glucose spills into urine Very high levels of blood glucose can cause severe cell dehydration throughout body; glucose doesn’t diffuse easily through pores of PM, and increased osmotic pressure in extracellular fluids causes osmotic transfer of water out of cells Loss of glucose in urine causes osmotic diuresis; osmotic effect of glucose in renal tubules greatly decreases tubular reabsorption of fluid, so massive loss of fluid in urine, causing dehydration of extracellular fluid, which causes compensatory dehydration in intracellular fluid Peripheral neuropathy and autonomic nervous system dysfunction – frequent complications of chronic, uncontrolled DM o Can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in extremities, and other symptoms of peripheral nerve damage Hypertension secondary to renal injury and atherosclerosis secondary to abnormal lipid metabolism amplify tissue damaged caused by elevated glucose Shift from carb to fat metabolism increases release of ketoacids more rapidly than they can be taken up and oxidized by tissue cells, resulting in severe metabolic acidosis from excess ketoacids in association with dehydration due to excessive urine formation o Symptoms include deep rapid breathing, which causes increased expiration of CO2 to buffer acidosis, but also depletes extracellular fluid of bicarb stores, so kidneys compensate by decreasing bicarb excretion and generating new bicarb, which is added back to extracellular fluid Excess fat utilization in liver over long time causes large amounts of cholesterol in circulating blood and increased deposition of cholesterol in arterial walls, leading to severe arteriosclerosis and other vascular lesions Failure to use glucose for energy leads to increased utilization and decreased storage of proteins and fat; patient suffers rapid weight loss and asthenia despite eating large amounts of food Type II diabetes – often occurs between ages 50-60; develops gradually; obesity is most important risk factor o Associated with hyperinsulinemia as compensatory response for diminished sensitivity of target tissues to metabolic effects of insulin o Impairs carb utilization and storage, raising blood glucose and stimulating compensatory increase in insulin secretion o Most of insulin resistance caused by abnormalities of signaling pathways that link receptor activation with multiple cellular effects; impaired insulin signaling related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver secondary to excess weight gain o Can also occur as result of acquired or genetic conditions that impair insulin signaling Metabolic syndrome – obesity (especially abdominal fat), insulin resistance, fasting hyperglycemia, lipid abnormalities (increased blood triglycerides and decreased blood HDL), and hypertension; closely related to accumulation of excess adipose tissue in abdominal cavity around visceral organs o Major adverse effect is cardiovascular disease (atherosclerosis) o Increased risk for insulin resistance, which predisposes to development of type II DM Polycystic ovary syndrome (PCOS) associated with marked increases in ovarian androgen production and insulin resistance; insulin-resistance and hyperinsulinemia found in 80% of patients Excess formation of glucocorticoids (Cushing’s syndrome) or GH (acromegaly) decreases sensitivity of various tissues to metabolic effects of insulin and can lead to development of DM With prolonged and severe insulin resistance, even increased levels of insulin not sufficient, and moderate hyperglycemia occurs after ingestion of carbs in early stages of disease o In later stages of type II DM, pancreatic beta cells become exhausted or damaged and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after carb-rich meal o Genetic factors play role in whether type II diabetes ever turns to low insulin secretion o Effectively treated in early stages with exercise, caloric restriction, and weight reduction o Drugs that increase insulin sensitivity (TZDs), drugs that suppress liver glucose production (metformin), or drugs that cause additional release of insulin by pancreas (sulfonylureas) may be used o In later stages of type II DM, insulin administration usually required to control plasma glucose Can frequently make diagnosis of type I DM by smelling acetone on breath of patient; ketoacids can be detected by chemical means in urine o In early stages of type II DM, ketoacids not produced in excess amounts; when insulin resistance becomes severe and there is greatly increased utilization of fats for energy, ketoacids can be formed Patients given long-lasting insulin as once-daily to maintain basal level and additional quantities of regular insulin during mealtimes o Human insulin produced by recombinant DNA widely used because some patients develop immunity and sensitization against animal insulin, limiting its effectiveness Diabetics, mainly because of high levels of circulating cholesterol and other lipids, develop atherosclerosis, arteriosclerosis, severe coronary heart disease, and multiple microcirculatory lesions far more easily than normal people o Limiting carbs in diet keeps blood glucose from increasing too high and attenuates loss of glucose in urine, but doesn’t prevent abnormalities of fat metabolism o Modern day treatment has patient eat normal diet and just use insulin to compensate for what they eat o Because complications of diabetes (atherosclerosis, susceptibility to infection, diabetic retinopathy, cataracts, hypertension, and chronic renal disease) closely associated with levels of blood lipids and blood glucose, most physicians use lipid-lowering drugs to help prevent disturbances Insulinoma – Hyperinsulinism Excessive insulin production from adenoma of islet of Langerhans; 10-15% malignant and metastases spread throughout body, causing tremendous production of insulin by primary and metastatic cancers CNS normally derives essentially all energy from glucose metabolism, and insulin not necessary for CNS When blood glucose levels fall around 50-70 mg/dL, CNS usually becomes excitable because degree of hypoglycemia sensitizes neuronal activity o Sometimes hallucinations, but more often patient experiences nervousness, trembling, sweating o As blood glucose falls to 20-50 mg/dL, clonic seizures and loss of consciousness likely o As blood glucose levels fall farther still, seizures cease and only state of coma remains IV administration of large quantities of glucose usually brings patient out of shock in minutes Administration of glucagon (less effectively, epi) causes glycogenolysis in liver and increase blood glucose level If treatment not administered immediately, permanent damage to neuronal cells of CNS often occurs