MHS Endocrine Pancreas 2023 Students.pptx

Endocrine pancreas Marina Ioudina MD, PhD, MS Objectives • Identify two major hormones secreted from the endocrine pancreas: glucagon and insulin. Describe their cells of origin, chemical nature, synthesis and secretion. List factors that regulate the secretion of insulin and glucagon. • List the...

Endocrine pancreas Marina Ioudina MD, PhD, MS Objectives • Identify two major hormones secreted from the endocrine pancreas: glucagon and insulin. Describe their cells of origin, chemical nature, synthesis and secretion. List factors that regulate the secretion of insulin and glucagon. • List the major target organs for insulin and glucagon and discuss their actions. • Explain the effects of insulin and glucagon on glucose, fatty acids, and amino acid metabolism. • Explain the interrelationships between insulin and glucagon on maintaining plasma glucose levels. Explain the role of insulin/glucagon (I/G) ratio in the regulation of body metabolism • Discuss the integrated endocrine and neural responses to hypoglycemia and hyperglycemia • Identify disease states caused by: a) over-secretion, b) under-secretion of insulin, or c) decreased sensitivity to insulin. • Explain complications of hyperglycemia. • Explain the benefits of physical activity on blood glucose levels. Reading assignment • Physiology. 6th Ed, • Chapter 9: Endocrine pancreas https://www.clinicalkey.com/#!/brows e/book/3-s2.0-C20150056192 Reading assignment • Endocrine pancreas  Boron, WF and Boulpaep, LE (2017) Medical Physiology, 3rd ed. Elsevier. ISBN: 978-14557-14377-3 (Chapter 51) Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Pancreas is the endocrine and exocrine gland Endocrine (hormones) Exocrine (enzymes) Synthesis and release: insulin, glucagon, amylin, somatostatin, gastrin Amylase, lipase Release into: The portal vein (circulation) The intestine Major stimuli for secretion: Glucose Depends on the phase of digestion Hormones of endocrine pancreas are peptides/polypeptides • Cells of the islets of Langerhans secrete hormones: • Insulin, amylin: B( ) cells – 65 - 70%of the cells (insulin is released in response to high plasma [glucose], both hormones regulate food intake) • Glucagon: A (α) cells - ~20% of the cells (is released in response to low plasma [glucose], regulates food intake) • Somatostatin: D( ) cells – is inhibitory peptide (inhibits islets cell secretion) • Gastrin (G-cells) cells stimulates gastric HCl secretion Pancreatic hormones are secreted in response to a meal • Insulin, amylin and glucagon after a meal provide satiety (in the hypothalamus) signals leading to termination of the meal • Insulin is an anabolic hormone secreted in times of excess of nutrients. It allows the body to use carbohydrates as energy source and store nutrients. • Glucagon is a catabolic hormone. Levels rise during period of food deprivation, and stored nutrient reserves are mobilized. It mobilizes glycogen, fat, and protein to serve as energy sources. • Somatostatin inhibits secretion of pancreatic hormones. Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Insulin synthesis • Pre-pro-insulin • Pro-insulin (Insulin+PeptideC) • C peptide is detached before secretion • Active insulin and C peptide are secreted by exocytosis • Insulin is a polypeptide containing two chains of amino acids (A and B chain) B& B. 51-2 Insulin and C-peptide • 90 - 97% of insulin and C-peptide are released in equimolar amounts • Insulin has half-life of ~3-5 min, catabolized in the liver (50% of secreted catabolized in the liver on its first pass) • C-peptide has half life ~of 10-15 min, catabolized by the kidney • C-peptide can be measured in plasma and its level provides an index of the β cell function • C-Peptide functions are not fully understood: • in patients with diabetes reduces glomerular hyperfiltration and reduces urinary albumin excretion • repairs the muscular layer of arteries • improves nerves functions • protects functional β-cells from oxidative stress Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Glucose is a stimulus for insulin secretion. Increased plasma glucose concentration stimulates insulin secretion Steps of insulin secretion: 1. Glucose enters the β cells via GLUT2 transporter 2. Glucose → glucose-P → → ↑ATP production 3. ATP binds to the ATP-sensitive K+ channels (KATP) → ↓K+ efflux → β cell depolarization 4-7. Depolarization causes the voltage-gates Ca 2+ channels to open → ↑ Ca2+ influx → Ca2+ stimulates insulin release by exocytosis Stimulation of insulin secretion by the pancreatic  cells B&B Regulation of insulin secretion Stimulators of insulin secretion • Serum • ↑Glucose (> 100mg/dl) • ↑ Amino acids • ↑ Free fatty acids • ↑ Ketone bodies • Hormones: • Glucagon-like peptide1(GLP-1), Gastric inhibitory peptide (GIP), gastrin, cholecystokinin (CCK), secretin, vasoactive peptide (VIP), • Glucagon, epinephrine (β2AR) Inhibitors of insulin secretion • Serum • ↓Glucose • ↓ Amino acids • ↓ Free fatty acids • Hormones: • Somatostatin • Epi/Norepi ( 2-AR) • Sympathetic stimulation ( 2-AR) Insulin secretion is increased in response to a meal: nutrients → GI hormones → insulin and glucagon • Secretion of islet hormones insulin and glucagon is coordinated with the secretion of exocrine pancreatic enzymes • Insulin and glucagon secretion is regulated by the entry of nutrients into GI tract and by GI hormones: • GIP (gastric inhibitory polypeptide, or glucose-dependent insulinotropic peptide) – stimulates secretion of insulin and glucagon • GLP-1 (glucagon-like peptide-1) I stimulates secretion of insulin, inhibits secretion of glucagon Insulin secretion is greater in response to an oral glucose intake compared to intravenously administered glucose • The difference in insulin secretion (IV vs. oral intake) is refereed as the incretin effect Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Insulin and insulin receptors • Insulin receptors exist in many tissues • Insulin binds the insulin receptors which are the tyrosine-kinase (Tk) linked receptors • Binding activates insulin receptor • The activated insulin receptor phosphorylates insulin-receptor substrate and induces effects: • cellular metabolism • membrane transport • activity of transcription factors (the growth-promoting effects) Actions of insulin: metabolism, transport, and transcription factors Insulin “shifts” K+ into cells Bern &Levy Metabolic effects of insulin on the liver, skeletal muscle and adipose tissue Liver  protein synthesis  lipid synthesis  ketogenesis glucose output (due to  gluconeogenesis,  glycogen synthesis, and  glycolysis) Skeletal muscle Adipose tissue  glucose entry  glycogen synthesis  amino acid uptake  protein synthesis in ribosomes ¯ protein catabolism ¯ release of gluconeogenic amino acids ketone uptake  K+ uptake  glucose entry  fatty acid synthesis  glycerol phosphate synthesis  triglyceride deposition activity of lipoprotein lipase  activity of hormonesensitive lipase K+ uptake Insulin receptors exist in many tissues • In the brain (hypothalamus, cerebral cortex, olfactory bulb, cerebellum, brain stem) • Suggest role in CNS growth, development and metabolism (neurotrophic) • Modulates functions of some neurotransmitters • In the kidney (glomerular, mesangial cells, epithelial and endothelial cells) • Some role in glomerular and tubular functions, gluconeogenesis • Vasculature causes vasodilation via NO production • In bone (osteoblasts) • Controls osteoblasts development and metabolism. Diabetes I is linked to osteoporosis and bone fragility. Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Insulin-dependent glucose uptake via GLUT4 Review of Medical Physiology. Ganon. Fig. 19-5 1 (1) Activation of insulin receptors → (2) activation of phosphatidylinositol -3-kinase → (3) translocation of the GLUT4 containing endosomes into the cell 2 3 membrane. Cycling of GLUT 4 transporters facilitates the insulin-stimulated glucose uptake in the insulinsensitive tissues: skeletal, adipose tissue, and cardiac muscle The hexoses (GLUCOSE, galactose, fructose) transporters: insulin-dependent and insulin-independent glucose transport Transport er SGLUT 1 SGLUT 2 Major Sites of Expression Characteristics Intestinal mucosa, kidney tubules Sodium-dependent transport. Cotransports molecule of glucose or galactose. Does not transport fructose. GLUT-1 Brain, erythrocyte, endothelial cells, fetal tissues, cardiac myocytes Transports glucose (high affinity) and galactose, not fructose. Expressed in many cells. GLUT-2 Liver, pancreatic beta cell, small intestine, kidney Transports glucose, galactose and fructose. A low affinity, high capacity glucose transporter; serves as a "glucose sensor" in pancreatic beta cells. GLUT-3 Brain, placenta and testes Transports glucose (high affinity) and galactose, not fructose. The primary glucose transporter for neurons. GLUT-4 Skeletal muscle, adipocytes, cardiac myocytes The INSULIN-DEPENDENT glucose transporter. High affinity for glucose. Transports fructose, but not glucose or GLUT-5 Small intestine, sperm galactose. Present also in brain, kidney, http://www.vivo.colostate.edu/hbooks/molecules/hexose_xport.html Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Glucagon • Is a single-chain polypeptide • Hypoglycemia is the major signal for release • Binds glucagon receptors (Gs): cAMP is the second messenger • Increases the plasma levels of glucose • Increases the plasma levels of free fatty acids, and keto acids • Decreases amino acid levels • Increases urea production • Major target organs: the liver and adipose tissue • In the pancreas stimulates Regulation of glucagon secretion Stimulation Inhibition • ↓Serum glucose • ↑Serum amino acids* (arginine, alanine) • Sympathetic stimulation (via β2-AR) • Glucocorticoids • Prolonged fasting • Exercise • • • • ↑ Serum glucose Somatostatin Insulin GLP1 Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratio • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Plasma glucose, glucagon and insulin levels vary during a 24hour period • Fasting plasma glucose level ~90 mg/dl (70-110mg/dl) • After a meal plasma glucose rises and stimulates insulin secretion • During an overnight fasting, plasma glucose concentration decreases, insulin secretion decreases, glucagon secretion remains steady The insulin-to-glucagon ratio regulates metabolism • Plasma [glucose] is a major regulator for insulin and glucagon secretion • Insulin and glucagon act in antagonistic fashion to keep plasma glucose concentration • Insulin dominates in the fed state • Glucagon prevents hypoglycemia in the fasted state • Insulin inhibits glucagon secretion • Glucagon stimulates insulin Intracellular sensors and regulators that balance anabolic and catabolic pathways Glucag on Effects of nutritional state (insulin/glucagon ratio) Parameter Plasma [glucose], mg/dL After a 24-Hr Fast 60-80 2 Hr After a Mixed Meal 100-140 Plasma [insulin], μU/mL 3-8 50-150 Plasma [glucagon], pg/mL 40-80 80-200 Liver ↑Glycogenolysis ↑ Gluconeogenesis Adipose tissue ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis Lipids mobilized for fuel Lipids synthesized Muscle Lipids metabolized Protein degraded and amino acids exported • I/G: large carb meal – 10 or higher • Small meal – 7 • Glucose IV – 25 • • • Glucose oxidized or stored as glycogen Protein preserved I/G: Overnight fast – 2.3 Low carb diet – 1.8 Starvation - 0.5 or less Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Plasma glucose levels • Fasting plasma glucose concentration: • Normal: 70 - 99 mg/dl • Impaired glucose control: 100-126 mg/dl • Diabetes: > 126 mg/dl • Non-fasting (after a meal): • Normal: 200 mg/dl • Diabetes: >200mg/dl after 2 hours after a meal Plasma glucose levels increases in response to a meal • Plasma glucose levels rises after a meal in healthy and patients with diabetes • Postprandial hyperglycemia is a major contributing factor for diabetes complications • Hyperglycemia causes glycosylation of various plasma and cellular proteins leading to abnormal cellular/organ functions • A marker for hyperglycemia is plasma levels of Hb1Ac • Postprandial hyperglycemia can be reduced in diabetes by limiting carbohydrates in diet Parameters Healthy Diabetes Plasma glucose before a meal 70 -100 mg/dL 80 – 130 mg/dL Low insulin synthesis or insulin resistance: Diabetes mellitus (DM) • DM is a diseases in which insulin levels and/or responsiveness to insulin is inefficient to maintain normal levels of plasma glucose. • DM results in an increase in hepatic glucose output and decreased glucose uptake by insulin-dependent transport (GLUT4) and hyperglycemia • Type I - Insulin deficiency (low synthesis) • Type II - Insulin resistance (defective insulin/receptors interaction/signaling) Metabolic consequences and complications of DM • Metabolic results of DM: • Chronic hyperglycemia (most common) • Dyslipidemia • Skeletal muscle wasting • Hyperglycemia causes cellular damage and is the major reason for complications of DM by activation of pathophysiological mechanisms, such as: • Mitochondrial dysfunction • Oxidative stress • Inflammation • Complications of hyperglycemia: • Macrovascular: atherosclerosis, hypertension • Microvascular (angiopathy): neuropathy (nerve damage), nephropathy (renal failure), retinopathy (micro aneurisms, retinal hemorrhage) • Hyperglycemia causes plasma hyperosmolality, and osmotic diuresis. May cause hyperosmolar coma (severe loss of intracellular fluid in the brain). Journal of Diabetes Research Volume 2016, Article ID 3425617, http://dx.doi.org/10.1155/2016/3425617 Causes of hypoglycemia and hyperglycemia • Causes of hypoglycemia: • Overproduction of insulin in response to a meal (may indicate a high risk for development of diabetes, or early stage of type II DM) • Some medications • Alcohol intake • Liver, kidney, or heart disorders • Eating disorders • Pregnancy • Causes of hyperglycemia: • Insulin deficiency or insulin resistance • Medications (steroids) • Illness or infection (stress induced hyperglycemia) • Being inactive Clinical manifestations of hypo- and hyper-glycemia Hypoglycemia Early manifestations • Weakness Hyperglycemia Early manifestations • Weakness • Shakiness • Polyuria, polydipsia, dehydration • Palpitation, tachycardia • Altered vision • Hunger • Weight loss • Nausea • Diaphoresis Prolonged or severe • Anxiety, hyperventilation Prolonged or severe • Hallucinations • Seizures • Hypothermia • Neurologic symptoms • Coma • Diabetic (keto)acidosis • Kussmaul hyperventilation (deep and rapid breathing) • Hypotension, arrhythmias • Stupor • Coma Hormonal responses to hypoglycemia • A supply of glucose is absolutely required to sustain brain function, • Hypoglycemia may slow mental processes, confusion, and coma • Ganon. Figure 19-11  1! Integrated endocrine and neural response to hypoglycemia GH ↑Glycogenolysis ↑ Gluconeogenesi s ↑ ketoacids • Modified from (Bern &Levy)Fig. Regulation of glucose: glucocorticoids • Glucocorticoids (cortisol) increase the plasma glucose • Decrease insulin-dependent glucose uptake (by reducing sensitivity to insulin, diabetogenic) • Stimulate gluconeogenesis • calorigenic effect and glycogenolysis (permissive effect on glucagon) Regulation of glucose: catecholamines • Catecholamines increase the plasma glucose level: • Stimulate glycogenolysis in the liver and in the muscle • Increase muscle glucose supply and glycolysis (via α 1 AR in the liver) • Inhibiting insulin secretion ( 2) Lecture outline • Hormones of the endocrine pancreas • Insulin • Structure and synthesis • Mechanism of secretion and regulation of secretion • Mechanism of action and effects • Insulin-dependent and insulin-independent glucose uptake • Glucagon • Structure, synthesis, effects • Regulation of secretion • Insulin-glucagon ratios • Hypoglycemia and hyperglycemia • Hormonal responses to hypoglycemia • Complications of hyperglycemia • Effect of exercise on carbohydrate metabolism Exercise increases skeletal muscle glucose uptake through GLUT4 by insulin-independent mechanism Physiology 20: 260-270, 2005; doi:10.1152/physiol.00012.2005 1548-9213/05 $8.00 Physiology, Vol. 20, No. 4, 260-270, August 2005 Some practice questions What is the most immediate hormonal response to low blood glucose levels? A. B. C. D. E. Activation of sympathetic nervous system Increased plasma epinephrine levels Increased glucagon secretion Decreased insulin secretion Increased cortisol secretion Which of the following plasma values would best explain the homeostatic regulation of plasma glucose levels? A. B. C. D. E. F. Glucose Insulin Epinephrine Glucagon Insulin/glucagon ratio HbA1C What is the mechanism of hyperglycemia in patients with low insulin effect (diabetes)? A. B. C. D. E. F. low glucose uptake by skeletal muscle and fat cells low glucose uptake by the liver low urinary glucose excretion low hepatic glucose output high hepatic glucose uptake low glucose uptake by skeletal muscle and fat cells and high hepatic glucose uptake G. low glucose uptake by skeletal muscle and fat cells and high hepatic glucose output Which of the following is true regarding regulation of insulin secretion? A. Insulin level B. Insulin C. Insulin D. Insulin levels secretion is inhibited by high plasma glucose secretion is stimulated by glucagon secretion is directly stimulated by somatostatin secretion is stimulated by low plasma amino acid Insulin receptors exist only in the skeletal and cardiac muscle and fat cells. A. True B. False Insulin mediates glucose transport through: A. GLUT1 B. GLUT4 C. GLUT1 and GLUT4 D. GLUT2 (in the liver) and GLUT4 E. SGLUT2 GLUT4-mediated insulin-dependent glucose uptake occurs in: A. All tissues B. Liver C. Small intestine D. Cardiac muscle E. Kidney