Pancreas MY1 Repro/Endo Notes PDF

MY1 Repro/Endo - LEFF Pancreas Page 1 of 15 The Endocrine Pancreas Session Learning Objectives: 1. Describe the major hormones secreted from the endocrine pancreas and their cells of origin. 2....

MY1 Repro/Endo - LEFF Pancreas Page 1 of 15 The Endocrine Pancreas Session Learning Objectives: 1. Describe the major hormones secreted from the endocrine pancreas and their cells of origin. 2. Describe the hormonal, nutritional and neuronal stimuli for both insulin and glu- cagon secretion. 3. Describe in detail the cellular mechanism by which an increase in blood glucose stimulates insulin secretion from the pancreatic beta cell. 4. Describe the primary cellular effects of insulin action in muscle, liver and adipose tissue. 5. Describe the global (i.e. whole-body) effects of insulin action on circulating glu- cose levels and how insulin action in muscle, liver and adipose contribute to these effects. 6. Describe the primary cellular effects of glucagon action in liver including the re- ceptor and signaling pathways that are activated by the hormone. 7. Describe the global (i.e. whole-body) effects of glucagon action on circulating glucose levels and how muscle, liver and adipose contribute to these effects. Session Outline: 1. Glucose homeostasis – background 2. Insulin production from β-cells 3. Insulin action 4. Glucagon production from a-cells 5. Glucagon action 6. Diabetes MY1 Repro/Endo - LEFF Pancreas Page 2 of 15 Glucose homeostasis The primary role of the endocrine pancreas is to regulate nutrient (mainly glucose) distribution throughout the body. Its primary hormones, insulin and its counter- regulatory hormone glucagon, work together to maintain circulating glucose levels at around 100 mg/dL, even in the face of dramatic fluctuations in both nutrient intake and energy expenditure. This is accomplished by balancing the uptake and deposition of glucose into tissues after a meal with the mobilization of stored glucose from internal sources when dietary sources are unavailable. In general terms, insulin acts as the hormonal signal of nutrient excess (e.g. the circumstance immediately following a meal), and glucagon functions as the hormonal signal nutrient shortage (e.g. during an over- night fast). Insulin levels rise after a meal in response to elevated blood glucose. It di- rects tissues to absorb and store glucose. Glucagon is elevated during a fast and acts to maintain blood glucose levels by stimulating the liver to synthesis glucose and se- crete it into the circulation. Development of the pancreas Developmentally, the pancreas forms from the embryonic foregut and is therefore of endodermal origin. Insulin and glucagon can be detected in the human fetal circulation by the fourth or fifth month of fetal development. MY1 Repro/Endo - LEFF Pancreas Page 3 of 15 Insulin production from β-cells of the islets of Langerhans Insulin synthesis Insulin is produced in beta cells α Cells produce glucagon. δ Cells produce somatostatin. of the islets of Langerhans. It Insu- lin, a 51 amino acid polypeptide, β Cells produce insulin. consists of two chains, A and B, F cell held together by two disulfide bridges. Insulin is first synthesized as pre-proinsulin and then convert- ed to an 86 amino acid polypeptide, proinsulin. The proteolytic conver- sion of proinsulin to insulin clips the chain in two places generating insu- lin and C-peptide (connecting pep- tide). The secretory granules Blood flows from the packaged by the golgi system con- center to the periphery. sist of insulin and C-peptide in equal molar concentrations. Insulin is stored in these granules as hex- Islet of Langerhans americ units of insulin-zinc crystals. Pancreas Common bile duct Pancreatic duct Duodenum Figure 51-1 Islet of Langerhans. Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved. MY1 Repro/Endo - LEFF Pancreas Page 4 of 15 Regulation of insulin release Insulin release is stimulated by a variety of hormonal, neuronal and nutritional inputs into the pancreas. Although the primary regulator of insulin secretion is the level of blood glucose, the other regulators shown in the figure below play important roles in various aspects of beta-cell function. These include insulin secretion during the cephalic phase (preceding food intake) mediated by the parasympathetic nervous system, and the early postprandial phase which is mediated by incretin production from the gut (pre- sented in more detail below). The incretins (GLP1 and GIP) are peptide hormones produced by L-cells in the lin- ing of the gut. They are secreted into the bloodstream shortly after food enters the gut lumen and act on the pancreas to enhance insulin secretion. The incretin effect can be seen by comparing insulin secretion levels when glucose is introduced orally (solid red A NORMAL SUBJECT RECEIVING ORAL VERSUS IV GLUCOSE line on right) to its introduction directly into the circulation (IV), which bypasses the gut (dashed 300 150 red line). Many current diabetes Insulin after oral glucose therapies are based on the GLP1 pathway and include hor- 200 100 mone mimetics, GLP1 receptor Glucose Insulin (mg/dL) (µU/mL) activators, and inhibitors of GLP1 degradation. Glucose 100 50 Glucose-stimulated insulin secretion. Insulin after As blood glucose rises, as af- IV glucose ter a meal, insulin secretion from 0 0 1 2 3 4 5 6 β-cells increases proportionally. Time (hr) Figure 51-3A Glucose tolerance test. A, When a person ingests a glucose me g), plasma [glucose], shown by the green curve, rises slowly, reflecting the inte uptake of the glucose. In response, the pancreatic β cells secrete insulin, and p [insulin], shown by the solid red curve, rises sharply. When the glucose is give MY1 Repro/Endo - LEFF Pancreas Page 5 of 15 This is accomplished by linking the rate of intracellular glucose metabolism to the rate of insulin granule fusion to the plasma membrane. Glucose enters the β-cell through GLUT2 transporters is metabolized by the glycolytic pathway. Increased glycolysis leads to an increase in the intracellular ATP steps 1 & 2. Increased intracellular ATP inhibits the activity of K+ channels located in the membrane. Normal membrane poten- tial is maintained by the activity of these K+ channels, and when they are inhibited, the membrane becomes depolarized (steps 3 & 4). Membrane depolarization’ stimulates the activity of L-type (voltage-gated) Ca++ channels in the plasma membrane, causing an influx of Ca++ into the cell and an in- crease in the intracellular free Ca++ concentration. Increased intracellular calcium pro- motes the fusion of insulin containing granules with the cell membrane and the release of insulin into circulation (steps 5, 6 and 7). Many amino Extracellular space Leucine Glucose acids (e.g. leu- GLUT2 transporter 1 cine) can stimu- β cell Glucose enters the cell cytosol via a GLUT2 transporter, late beta-cells to GLYCOLYSIS which mediates facilitated diffusion of secrete insulin glucose into the cell. by activating a Glucokinase 2 The increased glucose influx stimulates Glucose-6-phosphate pathway that glucose metabolism, leading to an increase in [ATP]i, [ATP]i / [ADP]i, and [NADH]i/[NAD+]i. strongly over- Pyruvate Mitochondrion laps with the 3 The increased [ATP]i, and/or [NADH]i / + [NAD ]i inhibits the KATP channel. glucose- Citric acid H2O + CCK K stimulated insu- acetylcholine CO2 cycle + 4 Closure of this K channel causes Vm to lin secretory Gq become more positive (depolarization). Kir 6.2 pathways. Sur Phospholipase C Depolarization 5 PLC Finally, the PIP 2 The depolarization activates a voltage-gated Ca channel in 2+ hormonal and IP 3 the plasma membrane. 2+ neurotransmitter DAG ER [Ca ] Ca 2+ signals men- Protein kinase C Voltage-gated Ca channel 2+ tioned above in- PKC Protein [Ca ] 2+ i 6 The activation of this Ca channel 2+ Secretory 2+ fluence insulin Other modulators of kinase A granules promotes Ca influx, and thus 2+ increases [Ca ] , which also evokes i 2+ 2+ PKA Ca -induced Ca release. secretion by in- secretion act via the adenylyl cyclase-cAMP- 7 Adenylyl 2+ teractive with protein kinase A pathway and the phospholipase cyclase The elevated [Ca ] leads to exocytosis and release into the i C- phosphoinositide blood of insulin contained specific recep- pathway. cAMP within the secretory granules. tors on the sur- G G αs AC αs G αi face of the beta- β-adrenergic Glucagon Somatostatin galanin Insulin agonists α-adrenergic cell and activat- agonists ing signaling Figure 51-4 Mechanism of insulin secretion by the pancreatic β cell. Increased levels of extracellular glucose trigger the β cell to secrete insulin in the seven steps outlined in this figure. Metabolizable sugars (e.g., galactose and pathways that either promote mannose) and certain oramino inhibit vesicle acids (e.g., fusion arginine and leucine) and can alsoinsulin fusion of vesicles!that contain secretion. stimulate the previously synthesized insulin. In addition to these fuel sources, certain hormones (e.g., glucagon, somatostatin, cholecystokinin [CCK]) can also modulate insulin secretion. DAG, diacylglycerol; ER, endoplasmic reticulum; IP3, inositol 1,4,5-triphosphate; PIP2, phosphatidylinositol 4,5-biphosphate. Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved. MY1 Repro/Endo - LEFF Pancreas Page 6 of 15 Insulin Action Insulin is a powerful hormone with broad influences that directly or indirectly effect the function of all physiological systems. Major actions of insulin: Stimulates anabolism: Insulin acts to increase the cellular uptake of glucose, fatty acids and amino acids, and stimulates their conversion into glycogen, triglyceride and protein. Antagonizes catabolism: Insulin decreases glycogenolysis, lipolysis and proteoly- sis. In addition, it suppresses hepatic gluconeogenesis. Alters electrolyte balance: Insulin acts to increase the cellular uptake of potassium and phosphate, and decrease the cellular uptake of sodium and calcium Although insulin acts on nearly all cells in the body, its primary target tissues regard- ing its metabolic effects are muscle, liver and adipose. Although the metabolic effects of insulin in these three tissues are distinct, the initial steps in insulin signaling share many molecular features including receptor activation and at least the initial steps of the intra- cellular insulin signaling cascade. The insulin receptor The cysteine-rich Insulin exerts its action by domain binds insulin. binding to the insulin receptor on the cell surface. This Glycosylation 340,000 kD membrane receptor site is a hetero-tetrameric glycopro- S S α tein Binding of insulin to the re- S S S S ceptor leads to a conformational change in the β-chains that acti- vate the receptor’s intrinsic tyro- sine kinase. The activated ki- nase carries out an auto- phosphorylation of tyrosine resi- dues in the receptor, as well as phosphorylation of additional β cellular proteins that ‘dock’ onto the now phosphorylated recep- tor. Tyrosine kinase Phosphorylation domain sites Figure 51-5 The insulin receptor. The insulin receptor is a heterotetramer that consists of two extracellular α chains and two membrane-spanning β chains. Insulin binding takes place on the cysteine-rich region of the α chains. Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserv MY1 Repro/Endo - LEFF Pancreas Page 7 of 15 Insulin signaling Receptor auto-phosphorylation triggers a protein phosphorylation cascade that af- fects many aspects of cellular physiology. Although details of the signaling cascade dif- fer in each tissue, the generic insulin signaling pathway includes many common steps and components. An early and common step is the phosphorylation of an IRS (or insu- lin receptor substrate) protein by the receptor’s tyrosine kinase. This phosphorylated IRS protein then serves as a docking site for additional intracellular signaling proteins (mainly protein kinases) that once activated, go on to initiate specific branches of the insulin signaling network. A branch of the insulin signaling network of importance to metabolic regulation is the MY1 Repro/Endo - LEFF Pancreas Page 8 of 15 IRS/PI3K/AKT pathway (upper left of the above diagram). This portion of the insulin signaling pathway is active in many insulin target tissues and is responsible for mediat- ing insulin’s effects on glucose uptake (by activating GLUT4) and glycogen synthesis (by inhibiting the kinase that inactivates glycogen synthase. Overview of the metabolic effects of insulin In general, the overall effect of postprandial insulin elevation is to convert circulating diet-derived glucose into glycogen and triglyceride stored in muscle, liver and adipose. This is accomplished by increasing glucose uptake into these tissues, stimulating glyco- gen synthesis is skeletal muscle and liver, and stimulating lipogenesis in liver and adi- pose. The brain, while not strictly considered an insulin responsive organ, plays an im- portant ‘silent’ role in whole-body glucose homeostasis. This is due mainly to its nearly completely dependence glucose for its metabolic fuel, its inability to store glucose in the form of glycogen, and its considerable appetite for glucose. The brain consumes about 120 g daily, which corresponds to an energy input of 420 kcal, or about half the utiliza- tion of glucose by the whole body in the resting state. Insulin’s effects in the liver MY1 Repro/Endo - LEFF Pancreas Page 9 of 15 The primary effects of insulin in the liver is to suppress hepatic glucose output and stimulate glycogen synthesis. This is accomplished by enhancing glucokinase (1) and suppressing the activity of G6Pase (4), which act together to ensure that all the glucose entering the cell is phosphorylated, which prevents its re-release back into circulation. Insulin stimulates glycogen synthase (2) and inhibits glycogen phosphorylase (3) to drive the conversion of glucose to glycogen. Insulin inhibits gluconeogenesis by reduc- ing the amount of PEPCK (9), FBPase (10), and G6Pase (4). Additionally, insulin pro- motes the synthesis and storage of fats (11-13), and can stimulate the release of excess lipid into circulation as VLDL. Finally, by mechanisms that are not well understood, in- sulin promotes protein synthesis (14) and inhibits protein breakdown (15). Blood Extracellular space Hepatocyte cytosol (of Disse) Liver 3 GLYCOGEN 2 Glycogen GLYCOGENOLYSIS Noninsulin SYNTHESIS Blood sensitive Glucose-1-phosphate sinusoid transporter (GLUT2) 1 Glucose Glucose-6-phosphate Glucose Inhibit 4 Activate Hepatocyte Fructose-6-phosphate 7 5 10 Fructose-1,6-bisphosphate Insulin receptor Insulin Bile Phosphoenolpyruvate 9 canaliculus 6 GLYCOLYSIS Pyruvate GLUCONEOGENESIS 8 Mitochondrion LIPOGENESIS Acetyl CoA Malonyl CoA 11 12 Fatty acids CoA Citric acid 13 cycle VLDL Triacylglycerols Carnitine carrier Ketone bodies Lipid droplets protein PROTEIN METABOLISM Cellular amino acids 15 14 Protein Figure 51-8 Effect of insulin on hepatocytes. Insulin has four major effects on liver cells. First, insulin promotes glycogen synthesis from glucose by enhancing the transcription of glucokinase (1) and by activating glycogen synthase (2). Additionally, insulin together with glucose inhibits glycogen breakdown to glucose by diminishing the activity of G6Pase (4). Glucose also inhibits glycogen phosphorylase (3). Second, insulin promotes glycolysis and carbohydrate oxidation by increasing the activity of glucokinase (1), phosphofructokinase (5), and pyruvate kinase (6). Insulin also promotes glucose metabolism through the hexose monophosphate shunt (7). Finally, insulin promotes the oxidation of pyruvate by stimulating pyruvate dehydrogenase (8). Insulin also inhibits gluconeogenesis by inhibiting the activity of PEPCK (9), FBPase (10), and G6Pase (4). Third, insulin promotes the synthesis and storage of fats by increasing the activity of acetyl CoA carboxylase (11) and fatty acid synthase (12) as well as the synthesis of several apoproteins packaged with VLDL. Insulin also indirectly inhibits fat oxidation because the increased levels of malonyl CoA inhibit CAT I (13). The inhibition of fat oxidation helps shunt fatty acids to esterification as triglycerides and storage as VLDL or lipid droplets. Fourth, by mechanisms that are not well understood, insulin promotes protein synthesis (14) and inhibits protein breakdown (15). MY1 Repro/Endo - LEFF Pancreas Page 10 of 15 Insulin’s effects in muscle and fat Most of the glucose absorbed from the gut after a meal is rapid- ly taken up by skeletal muscle and adipose tissue. This is an insulin mediated process in both tissues. In both muscle and adi- pose, insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma mem- brane. However, the fate of glu- cose is different in the two tis- sues. In muscle insulin promotes glycogen synthesis by the same pathways seen in the liver. In adipose glucose metabo- lites generated in glycolysis are used primarily to synthesize fatty acids. Insulin also promotes the esterification of α-glycerol phos- phate with fatty acids to form tri- glycerides, which the adipocyte stores in fat droplets. This pro- cess is enhanced by insulin’s ef- fects on two different lipases. In- sulin inhibits hormone-sensitive triglyceride lipase (3), which would otherwise break the triglyc- erides down into glycerol and fat- ty acids. In contrast, insulin pro- motes the synthesis of LPL (lipo- protein lipase) in the adipocyte. The adipocyte then exports this enzyme to the endothelial cell, where it breaks down the triglyc- erides contained in chylomicrons and VLDL, thus yielding fatty ac- ids. These fatty acids then enter the adipocyte where they are converted to triglyceride. MY1 Repro/Endo - LEFF Pancreas Page 11 of 15 Glucagon production from a-cells of the islets of Langerhans Glucagon is produced by a-cells, which are located mostly on the outer mantle of the islets and constitute 5-20% of the islet cells. Glucagon is initially produced as a pre- proglucagon, which is processed in the pancreas to produces the active 29 aa peptide. Interestingly, intestinal L-cells in the gut process the same preproglucagon into the in- cretin hormones GLP1 and GLP2 (glucagon-like peptides 1 and 2). GLP-1 GLP-2 Proglucagon N— G —C GRPP IP-1 IP-2 Pancreatic Intestinal islet Primary L cells α cells processing + + + + + GRPP Glucagon Major proglucagon Glicentin GLP-1 IP-2 GLP-2 fragment Figure 51-11 The synthesis of the glucagon molecule. The proglucagon molecule includes amino acid sequences that, depending on how the peptide chain is cleaved, can yield glucagon-related polypeptide (GRPP), glucagon, IP-1, GLP-1, IP-2, and GLP-2. Proteases in the pancreatic Regulation α cells cleave of glucagon proglucagon at points that yield GRPP, glucagon, and a secretion C-terminal fragment. Proteases in neuroendocrine cells in the intestine cleave proglucagon to The primary regulators of glucagon secretion are changes in the serum levels of glu- yield glicentin, GLP-1, IP-2, and GLP-2. cose, amino acids, and fatty acids, making its Copyright © 2009 by rate of secretion Saunders, an imprint of Elsevier Inc. All rights reserved. directly linked to the metabolism of carbo- hydrates, proteins, and fats. In general, the secretion of glucagon bears an inverse relationship to the concentration of glucose. In addition to these nutritional signals, glucagon secretion can be affected by sensory stimulation (e.g. loud noise, pain), and by activation of α-adrenergic signaling. Signifi- cant control may be mediated through autonomic fibers that termi- nate near the surface of the α-cells. The secretion of glucagon is also stimulated by a reduction in the level of fatty acids in the serum. Since glucagon increases the concentration of glucose and of fatty acids in the serum and decreases that of amino acids, it induces a feedback regulation of its own secretion. MY1 Repro/Endo - LEFF Pancreas Page 12 of 15 Global Metabolic Effects of Glucagon Action Hepatic actions of glucagon Glucagon is released into the portal vein and is carried to the liver, its primary target organ, where it binds to a specific GPCR on the hepatocyte membrane. The gluca- gon receptor signals through a clas- sic adenylate cyclase, cAMP, PKA pathway. In liver this pathway stimu- lates the production and release of glucose from the liver by stimulating both gluconeogenesis and gly- cogenolysis. Glucagon stimulates gluconeo- genesis by stimulating the produc- tion of phosphoenolpyruvate car- boxykinase (PEPCK), and fructose 1,6 bisphosphatase and glucose-6- phosphatase (steps 9, 10 & 4). Gly- cogenolysis is stimulated by activat- ing glycogen phosphorylase (3) and suppressing glycogen synthase (2). Note that glucagon’s effects on gly- MY1 Repro/Endo - LEFF Pancreas Page 13 of 15 cogen metabolism are exactly the opposite of insulin’s. Glucagon also inhibits glycoly- sis and lipogenesis which has a glucose sparing effect. Glucagon stimulates fatty acid oxidation, which produces ATP to meet the energy demands of the cells. Finally, gluca- gon stimulates the uptake of amino acids by the liver, which are used as substrates for gluconeogenesis. Thus, glucagon converts the liver from an organ of glucose storage to an organ of glucose production. At the same time, the nitrogen lost by the amino acids is converted to urea and excreted, tending to cause negative nitrogen balance, while the stimulation of lipolysis in the adipose tissue increases the flux of fatty acids to the liver, providing substrate for an increased production of ketone bodies. Hyperglycemia, negative nitro- gen balance and ketosis are hallmarks of diabetes mellitus. Indeed, an excessive se- cretion of glucagon has been demonstrated in diabetes, compounding the difficulties created by insulin insufficiency. Curiously, the secretion of glucagon is stimulated by certain amino acids. This seems paradoxical given that amino acids also stimulate insulin secretion. This con- current stimulation of both glucagon and insulin secre- tion occurs after a pure pro- tein meal is consumed. Ex- cess amino acids, which cannot be stored, are con- verted in the liver to glucose via gluconeogenesis - a pro- cess stimulated by glucagon. This action prevents hypo- glycemia that could result from a pure protein diet but will also eventually lead to elevated plasma glucose. The insulin, which is present (because amino acids also stimulate insulin secretion) promotes the absorption and storage of this glucose by muscle and fat tissue, thus preventing hyperglycemia. MY1 Repro/Endo - LEFF Pancreas Page 14 of 15 Pathologies associated with the endocrine pancreas Type I diabetes Type 2 diabetes MY1 Repro/Endo - LEFF Pancreas Page 15 of 15 The relationship between type 2 diabetes and obesity Adipose tissue dysfunction leads to lipotoxicity and insulin resistance