endo pancreas dupe .pptx

Endocrine pancreas Marina Ioudina MD, PhD, MS 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 stimul...

Endocrine pancreas Marina Ioudina MD, PhD, MS 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. 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 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 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 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) 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 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 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 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) 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