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Pancreatic Hormones 19 • Introduction to the pancreas, its cell types, its hormones, its functional organization, its venous output to liver and its regulation • Overview of intermediary metabolism and enzyme sites of major actions of insulin and glucagon • Pancreatic hormones, insulin, glucagon, SS and PPY. Their structure, synthesis, related peptides, secretion, regulation, receptors and effects. Effect of exercise on insulin and on its counter-regulatory hormones • Regulation of pancreatic hormones, Diabetes Mellitus, hypoglycemia, fasting, NIDDM Introduction Pancreas and its “story lines” Insulin decreases glycemia while glucagon increases it. As glycemia increases blood levels of insulin decrease while those of glucagon decrease. Page 1 Glucose metabolism Introduction • Endocrine pancreas a bird’s eye view of metabolism • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Storage and utilization of biological fuels. Introduction • Endocrine pancreas a bird’s eye view of metabolism • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S Intraorgan flow of substrate and the competitive regulatory effects of glucose and fatty acids that comprise the glucose–fatty acid cycle. E Storage and utilization of biological fuels. Page 2 Introduction • Endocrine pancreas effects of metabolic hormones • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S Effects of metabolic hormones on adipose tissue. *Lipolytic effects of cortisol are permissive. E Storage and utilization of biological fuels. Introduction • Endocrine pancreas effects of metabolic hormones • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S Effects of metabolic hormones on skeletal muscle. *The stimulation of fatty acid oxidation by growth hormone and cortisol are indirect and result from increased fatty acid mobilization. E Storage and utilization of biological fuels. Page 3 Introduction • Endocrine pancreas effects of metabolic hormones • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Effects of metabolic hormones on the liver. S E Storage and utilization of biological fuels. Introduction • Endocrine pancreas changes induced by fasting • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S Quantitative turnover of substrates in the basal state after fasting for 24 hours. Follow the “ready available money” E Page 4 Introduction • Endocrine pancreas changes induced by fasting Glucose GH Insulin • Intermediary metabolism Glucagon • Pancreatic hormones Cortisol GH GH T3 • Diabetes mellitus Representative values for plasma glucose and metabolic hormones during fasting. Values for growth hormone are averaged over 24 hours. The small decline in cortisol may reflect a decrease in cortisol binding globulin. Effects of 1 day of fasting on GH secretion. A. Normal fed young man. B,L,D indicate meal times. GHRH (1μg/kg) was given intravenously at the time indicated by the arrow. B. GH concentrations in plasma in the same subject after a 24-hour fast Hormonal changes in the basal state after fasting for 24 h. S E Introduction • Endocrine pancreas changes induced by fasting • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Plasma concentrations of glucose in normal subjects and patients suffering from isolated deficiency of GH during control days of normal food intake and while fasting. Some GH-deficient patients were untreated and others were given 5 mg of hGH per day (treated). The fast began after the collection of blood on day 2. Hormonal changes in the basal state after fasting for 24 h. S E Page 5 Introduction changes induced by exercise • Endocrine pancreas O2 consuption Epi Insulin • Intermediary metabolism Nepi • Pancreatic hormones Glucagon • Diabetes mellitus exercise in minutes Changes in sources of fuels utilized during prolonged exercise at 30% of maximal oxygen consumption. exercise in minutes Cortisol GH exercise in minutes Changes in concentration of insulin and counterregulatory hormones during prolonged moderate exercise. Values shown are means obtained for 8 young men exercising on a bicycle ergometer at ~50% of maximum oxygen consumption. Hormonal changes in the basal state after fasting for 24 h. S E Introduction • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S • • • • • • • • pancreas, main regulator of sugar metabolism sugars from food digestion and from glycogen endocrine (islets) & exocrine pancreas (acinar) the islets of Langerhans (triads: , ß, , cells) hormones: insulin, glucagon, SS, PPY pancreatic endocrine secretion to portal vein blood glucose decreased by insulin, SS, IGFs blood glucose increased by glucagon, CAs, glucocorticoids, GI hormones, GH, CRH, ACTH, T3 / T4, Ang II, food (arginine). The opposite direction of plasma insulin and glucagon define the metabolic state E Page 6 Introduction • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Cytoarchitecture of a typical human pancreatic islet as revealed in immunostained confocal scanning microscopic images. Endocrine cells are closely but randomly associated with vascular cells. Most insulin- (red), glucagon- (green), and somatostatin- (cyan) immunoreactive cells are in close proximity to vascular cells immunoreactive for smooth muscle cell actin (blue). Endocrine cells are aligned along the blood vessels in a random order. Introduction • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S Plasma levels of glucose and insulin in relation to meal intake. Glucose increases insulin secretion E Page 7 Introduction • Endocrine pancreas glucose • Intermediary metabolism • Pancreatic hormones gluconeogenesis glycogen • Diabetes mellitus S Time course of the origin of glucose under fasting conditions. Look at the intermediary metabolic paths. E Introduction • Endocrine pancreas • Intermediary metabolism FUEL METABOLISM IN ANABOLIC AND CATABOLIC PHASES State anabolism Hormones insulin Fuel Source diet glycogen synth. triglycerid synth. protein synth. storage depots glycogenolysis lipolysis proteolysis ketogenesis glucagon • Pancreatic hormones • Diabetes mellitus S catabolism insulin glucagon Process An opposite direction in the profile of plasma insulin and glucagon defines the individual’s metabolic state E Page 8 Metabolic pathways • Endocrine pancreas glycogen glycogen phosphorilase glycogen synthetase G-1-P G-6-Pase • Intermediary metabolism glucose hexokinase F-6-P PFK F-1,6-diPase • Pancreatic hormones • Diabetes mellitus S glucose G-6-P F - 1,6 -diP transaminases insulin glucagon epinephrine glucocorticoids triose amino acids pyruvate proteins Krebs cycle acetyl CoA fats JP’s colorful version indicating the main action site of various metabolic hormones E Metabolic pathways • Endocrine pancreas Glucose Glycogen Glycogenesis • Intermediary metabolism Glycolytic pathway Glucokinase • Pancreatic hormones Glycogen synthetase Glycogen phosphorilase • Diabetes mellitus S Glycogenolysis Hadley’s textbook version of the intermediary metabolic pathway E Page 9 Introduction • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus 1. 2. S LEFT: Effects of insulin on glucose metabolism in hepatocytes. Green arrows indicate reactions that are increased, and dashed red arrows indicate reactions that are decreased. RIGHT: Biochemical pathways of glucose metabolism in hepatocytes. Reactions that are accelerated in the presence of glucagon are shown in green. Broken red arrows indicate reactions that are inhibited by protein kinase A catalyzed phosphorylation. The hexosemono-phosphate shunt is indirectly inhibited. Roman numerals indicate substrate cycles. Goodman’s textbook version of the intermediary metabolic pathway E Metabolic pathways • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus some associations to remember for an endocrine regulatory viewpoint S E Page 10 Metabolic pathways • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus some associations to remember for an endocrine regulatory viewpoint S E Metabolic pathways • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Hormonal effects on FFA production. Epinephrine and norepinephrine stimulate hormonesensitive lipase through a cyclic AMP mediated process. Insulin antagonizes this effect by stimulating cyclic AMP degradation. T3, cortisol, and growth hormone increase the response of adipocytes to epinephrine and norepinephrine. Growth hormone also directly stimulates lipolysis. Insulin indirectly antagonizes the release of FFA by increasing reesterification. Growth hormone and cortisol increase FFA release by inhibiting reesterification. some associations to remember for an endocrine regulatory viewpoint S E Page 11 Insulin and its counterregulatory hormones • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Interaction of hormones to maintain the blood glucose concentration. Green arrows denote increase; red arrows denote decrease. Insulin decreases blood glucose while all counter-regulatory hormones increases it S E Insulin and its counterregulatory hormones • Endocrine pancreas Insulin infusion Epi • Intermediary metabolism • Pancreatic hormones Nepi Glucagon Glycemia after the injection of ….. cortisol + glucagon + epinephrine glucagon + epinephrine Cortisol epinephrine glucagon • Diabetes mellitus GH control Insulin decreases blood glucose while all counter-regulatory hormones increases it S E Page 12 Insulin and its counterregulatory hormones hormone effects on fat metabolism in adipocytes • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Insulin Epi + Nepi GH Cortisol T3 hormone effects on glucose metabolism in muscle Insulin Epi + Nepi GH Cortisol T3 Insulin decreases blood glucose while all counter-regulatory hormones increases it S E Insulin and its counterregulatory hormones hormonal regulation of metabolism in liver • Endocrine pancreas • Intermediary metabolism Insulin glucagon Epi + Nepi GH Cortisol T3 hormonal effects on insulin secretion and on target cells’ sensitivity to insulin • Pancreatic hormones • Diabetes mellitus Insulin glucagon Epi + Nepi GH Cortisol T3 Insulin decreases blood glucose while all counter-regulatory hormones increases it S E Page 13 Insulin and its counterregulatory hormones control • Endocrine pancreas fasting plasma glucose GH-deficient treated with GH • Intermediary metabolism normal • Pancreatic hormones glucose • Diabetes mellitus glycogen GH-deficient gluconeogenesis days Insulin decreases blood glucose while all counter-regulatory hormones increases it Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus • it has 51 aa, 2 chains, 3 S-S bonds, C-peptide • stimulates anabolism and favors energy storage • increases glycogen storage and inhibits both glycogen breakdown and gluconeogenesis • increases fatty acid synthesis and decreases lipolysis and ketogenesis • stimulates transport of glucose and of some amino acids into striated muscle and adipose tissue • increases protein synthesis in liver, muscle, adipose • Like growth factors it has a growth promoting effect An overview of the main effects of pancreatic insulin S E Page 14 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Insulin secreted from the pancreatic ß cells decreases blood glucose levels S E Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus An overview of the factors affecting insulin signalling S E Page 15 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Metabolic, hormonal, and neural influences on insulin secretion. An overview of the factors affecting insulin signalling S E Insulin • Endocrine pancreas insulin • Intermediary metabolism glucose • Pancreatic hormones • Diabetes mellitus An overview of blood glucose stimulation of insulin secretion and intracellular effects S E Page 16 Insulin A.- “Resting” beta-cell B.- Glucose activated beta-cell • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Triggering of insulin secretion by glucose. A. “Resting” beta cell (blood glucose < 100 mg/dl). ADP/ATP ratio is high enough so that ATP-sensitive potassium channels (KATP) are open, and the membrane potential is about -70 mv. Voltage-sensitive calcium channels (VSCC) and calcium-sensitive potassium channels (CSKC) are closed. B. B. Beta cell response to increased blood glucose. Increased entry and metabolism of glucose decreases the ratio of ADP/ATP, and KATP channels close. Voltage-sensitive calcium channels (VSCC) are activated; calcium enters and stimulates insulin secretion. Mitochondrial metabolites formed in response to glucose and calcium amplify secretion. Influx of calcium inhibits voltagesensitive calcium channels and activates calcium-sensitive and voltage-sensitive potassium channels, thereby allowing the cell membrane to repolarize and calcium channels to close. Calcium is extruded by membrane calcium ATPase. Persistence of high glucose results in repeated spiking of electrical discharges and oscillation of intracellular calcium concentrations. C. Effect of incretins (GLP-1 and GIP) on insulin release by beta cells (see next slide). Insulin B.- Glucose activated beta-cell C.- Incretins activated beta-cell • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Triggering of insulin secretion by glucose and by incretins. B. Glucose (G). Increased entry and metabolism of G decreases the ratio of ADP/ATP, and KATP channels close. Voltage-sensitive Ca channels (VSCC) are activated; Ca enters and stimulates insulin secretion. Mitochondrial metabolites formed in response to G and Ca amplify secretion. Influx of Ca inhibits voltage-sensitive Ca channels and activates Ca-sensitive and voltage-sensitive K channels, thereby allowing the cell membrane to repolarize and Ca channels to close. Ca is extruded by membrane CaATPase. Persistence of high G results in repeated spiking of electrical discharges and oscillation of intracellular Ca concentrations. C. Major acute cellular actions of incretins. GLP-1 and GIP acting through GPCR activate AC to increase intracellular cAMP). Cyclic AMP increases the activity of PKA or binds to a GTP exchange factor to increase cytosolic Ca and enhance the effects of Ca on insulin secretion. KATP = ATP-sensitive potassium channels; KV = voltage sensitive potassium channels: VSCC = voltage sensitive calcium channels; RP = reserve pool of secretory granules; ER = endoplasmic reticulum. Page 17 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Insulin release from pancreatic beta-cells acts on its targets by binding to its receptor S E Insulin • Endocrine pancreas Cys residues kinase NH2 hydrophobic aa Cys rich • Intermediary metabolism • ECF membrane • Pancreatic hormones ICF EGF • Diabetes mellitus JAK2 insulin PDGF COOH • GH Prl cytokines ANP The insulin receptor contains an intrinsic protein kinase that specifically catalyzes the phosphorylation of tyrosine residues on proteins Cystein and its thiol (SH) group linking the aa to another Cystein aa may form part of a binding cleft for ligands The insulin receptor is a one transmembrane domain tyrosine kinase receptor S E Page 18 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Binding of insulin and its receptor in the ECF domain causes phosphorylation of the receptor intra-cellular domain and elicits a conformational change in its tyrosine kinase portion, thus activating its enzyme activity. Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Binding of insulin and its receptor in the ECF domain causes phosphorylation of the receptor intra-cellular domain and elicits a conformational change in its tyrosine kinase portion, thus activating its enzyme activity. Page 19 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Binding of insulin and its receptor in the ECF domain causes phosphorylation of the receptor intra-cellular domain and elicits a conformational change in its tyrosine kinase portion, thus activating its enzyme activity. Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E The main effect of insulin is on the Glut - 4 transporter. This is how insulin decreases glycemia and increases glucose absorption Page 20 Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Confocal fluorescent microscope images of cultured mouse adipocytes that were transfected with GLUT4 linked to green fluorescent protein and then incubated in the absence (A) or presence (B) of insulin for 30 min. Insulin stimulation results in the translocation of GLUT4 from intracellular storage sites to the plasma membrane. The main effect of insulin is on the Glut - 4 transporter. This is how insulin decreases glycemia and increases glucose absorption Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Effect of insulin on 6–phosphofructokinase enzyme, or how insulin increses glycolysis Effect of insulin on glycogen synthetase enzyme, or how insulin increases glycogenesis S E Other effects of insulin are mediated by its action on metabolic enzymes. This is how insulin increases glycolysis & glycogenesis. Page 21 Insulin Main actions of insulin on metabolic pathways. Notice the 3 main targets. • Endocrine pancreas Organ liver • Intermediary metabolism ketogenesis glycogen synthesis fatty acid synthesis • Pancreatic hormones • Diabetes mellitus S E Net effect glycogenolysis gluconeogenesis Chief mechanism phosphorylase (glucose-dependent de-P) PEPCK (transcriptional regulation) FDPase-2 (enzyme dephosphorylation) substrate (alanine) delivery from muscle substrate (FFA) delivery from fat glycogen synthase (enzyme de-P) acetyl CoA carboxylase (transcription) fatty acid synthase muscle proteolysis protein synthesis glucose uptake glycogen synthesis multiple mechanisms activity at multiple steps recruit glucose transporter to cell surface glucose uptake glycogen synthase (enzyme de-P) fat hormone sensitive lipase (enzyme de-P) delivery of tryglyceride from liver lipoprotein lipase lipolysis triglyceride synthesis Insulin suppress glucose production by inhibiting the flux of gluconeogenic precursors (alanine, pyruvate, lactate, glycerol), energy substrates (free fatty acids) and glucagon secretion. All these suppress glucose release by the liver. Insulin • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Simplified model of insulin signaling pathways. The insulin receptor proteins (IRS 1,2,3,4), Cbl, Shc, and the subunits of the insulin receptor are phosphorylated on tyrosine residues by the insulin receptor kinase and serve as anchoring sites for cytosolic proteins that form signaling cascades. Proteins shown in blue boxes are serine/threonine kinases. Specific isoforms and/or subunits are not shown nor are the relevant phosphatases. Shc = Src homology containing protein; Cbl = Cacitas B lineage lymphoma protein; PI3K = phosphoinositol-3-kinase; PDK = phosphoinositide dependent kinase; PKC = isoform of protein kinase C; PKB = protein kinase B; PDE = phosphodiesterase; RAS = Ras oncogene, a small G-protein; mTOR = mammalian target of rapamycin; GSK = glycogen synthase kinase; ERK = extracellular receptor kinase. Page 22 Glucagon • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus • main counterregulator to insulin together with catecholamines (Epi) & cortisol • 29 aa, member of a related family peptides that includes VIP, GIP, and secretin • determines glycemia in postabsorptive state by glycogenolysis and gluconeogenesis • glucose, insulin and SS inhibit its release • aa, exercise and CAs stimulate its release • gene expression is restricted to cells in islet and is negatively regulated by insulin • glycentin, GI specific proteolytic processing Glucagon release is the main counterregulatory hormone to insulin secretion S E Glucagon • Endocrine pancreas (-) (+) Glucagon secretion Glucagon • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Glucagon Glucose Blood glucose Stimulatory and inhibitory signals for glucagon secretion. Glucagon secreted by the pancreatic alphacells increase blood glucose levels (glycemia) S E Page 23 Glucagon • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones R cell membrane Gs AC phosphodiesterase ATP ----------> cAMP -----------> 5’AMP inactive PKA ----------> active PKA inactive PKb <----------> active PKb glycogen phosphorilase b <-----> glycogen phosphorilase b glycogen + Pi --> glucose - 1 - P • Diabetes mellitus cell membrane T Glucose blood glucoserelease to blood Glucagon release is the main counterregulatory hormone to insulin secretion S E Glucagon • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus S E Glucagon’s main mechanism of action is through AC, cAMP and PKA. Amplification is an important event in the mechanism of action of glucagon (cascade). Page 24 Glucagon • Endocrine pancreas Organ liver • Intermediary metabolism Net effect glycogenolysis glycogen phosphorylase (cAMP-dep- P) glycogenesis glycogen synthase (phosphorylation) F - 1,6 - diPase (phosphorylation) pyruvate kinase (phosphorylation) substrate delivery, r eleasing inhibition of carnitine palmytoil transferase, allowing mitochondrial transfe r and FA oxidation gluconeogenesis • Pancreatic hormones Chief mechanism glycolysis ketogenesis • Diabetes mellitus Main actions of glucagon on metabolic pathways. Notice the single main target S E Glucagon • Endocrine pancreas insulin glycemia • Intermediary metabolism glucagon Liver glycogen • Pancreatic hormones Glucagon / Insulin Liver glucose • Diabetes mellitus Changes in insulin and glucagon in plasma and carbohydrate metabolism in normal subjects following ingestion of a liquid meal rich in carbohydrate. Although secretion of both insulin and glucagon was stimulated, insulin increased about twenty-fivefold while glucagon increased only threefold so that the ratio of glucagon to insulin fell dramatically. Plasma glucose increased transiently, but release of glucose from the liver fell precipitously, and liver glycogen increased. Effect of large carbohydrate meal on blood glucose, glucagon, insulin and liver glucose-related data S E Page 25 Glucagon • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Effect of large carbohydrate meal (left) and arginine infusion (right), on glycemia, glucagon and insulin S E Glucagon • Endocrine pancreas glycemia • Intermediary metabolism glucagon • Pancreatic hormones insulin • Diabetes mellitus Changes in the concentrations of plasma glucose, immunoreactive glucagon (IRG), and immunoreactive insulin (IRI) throughout the day. Values are the mean ± SEM (n = 4). (From Tasaka, Y., Sekine, M., Wakatsuki, M., Ohgawara, H., and Shizume, K. (1975) Levels of pancreatic glucagon, insulin and glucose during twenty-four hours of the day in normal subjects. Horm. Metab. Res. 7: 205–206.) S E Effect of daily meals on glycemia, glucagon & insulin Page 26 SS and PPY • Endocrine pancreas • Intermediary metabolism • Pancreatic hormones • SS has 14 aa and 1 disulfide bond. It was discovered and named for its GH inhibiting activity. SS inhibits a wide variety of endocrine and exocrine secretory activities in the pituitary and in the GI tract. In the pancreas, SS inhibits insulin, glucagon, PPY and exocrine secretion • PPY release is largely neurally mediated. Sensing of food in the CNS causes its vagal-mediated secretion. Food in proximal GI tract also stimulates its release. PPY affects GI motility, secretory activity of stomach, intestine and pancreas • Diabetes mellitus Somatostatin & Pancreatic Polypeptide Y are two of the many GI peptides S E Effect of exercise glucose • Endocrine pancreas • Intermediary metabolism glucose insulin glycogen Epi Nepi lactate glucagon • Pancreatic hormones • Diabetes mellitus working muscle cortisol GH glycogen glucose lactate nonworking muscle fuels consumed by leg muscles of man during mild prolonged exercise Contribution to O2 uptake in % Exercise (min) 40 80 120 240 Plasma glucose Plasma FFA Muscle glycogen 27 41 36 25 37 37 50 67 36 22 14 8 Exercise decreases insulin and increases all its counter-regulatory hormones S E Page 27 Diabetes • Endocrine pancreas • • • • Intermediary metabolism • Pancreatic hormones • • • Diabetes mellitus • hallmark of insulin hyposecretion and insulin resistance is hyperglycemia in the fasting state hyperglycemia, polyuria (diabetes = siphon), urine sweetens (mellitus = honey), polydipsia precise mechanism for the deleterious effect of high glucose is not known. Whether from non-enzymatic glycation of proteins or from regulatory effects of excess glucose, blood vessels are damaged, resulting in turn in damage to the retina and kidney, and circulation compromise to the heart, brain and extremities. Main morbidity causes are blindness, renal failure, heart attack, stroke, amputations glucose tolerance test, diabetes mellitus, insulin deficit / resistance insulin resistance: prereceptor resistance (autoantibodies, mutant insulin), receptor resitance (decreased number and affinity, point mutation, impaired kinase expression), & post-receptor resistance (down regulation of Glut4 or autoantibodies of Glut2 transporters, mutation of glucokinase gene, ßcell exhaustion as in GH abuse) diabetic ketoacidosis, dehydration due to hyperglycemic diuresis, negative nitrogen balance, tissue wasting, poor resistance to infections, metabolic acidosis, fruity smell of ketosis in breath, cardiovascular involvement, hyperglycemic vs hypoglycemic coma Diabetes mellitus has been linked to every step in the mechanism of action of insulin S E Page 28 Diabetes • Endocrine pancreas Diabetes Mellitus can be Type 1 or Type 2 • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Idealized glucose tolerance tests in normal and diabetic subjects. Subjects are given a standardized solution of glucose to drink and blood samples are taken at the indicated times thereafter. An impairment of glucose disposition results in a greater than normal and prolonged increase in blood glucose concentration. Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Diabetes • Endocrine pancreas Diabetes Type 1 – beta cells do not make insulin • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Page 29 Diabetes • Endocrine pancreas Diabetes Type 2 – insulin is not “seen” by target cells • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Diabetes • Endocrine pancreas Diabetics have a “sluggish” response to glucose • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Page 30 Diabetes • Endocrine pancreas Diabetes has been linked to every step in the mechanism of action of insulin • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Diabetes • Endocrine pancreas Diabetes has been linked to every step in the mechanism of action of insulin • Intermediary metabolism • Pancreatic hormones • Diabetes mellitus Diabetes is a good example of “pushing the regulatory feedback envelope” in endocrinology S E Page 31