Endocrinology Summers |
Hormones Endocrine Glands Receptors Homeostasis 2nd Messengers |
Nuclear Receptors Genetic Regulation Hormone Synthesis Receptor Regulation Hypothalamo-Hypophysial Communication |
Tropic Hormones Neurohypophysial Nonapeptides Thyroid Axis Steroids Adrenal Axis |
Adrenal Medulla Osmo-Pressure Balance Reproductive Endocrinology Prolactin Somatic Axis |
Growth Factors Immune System Ca++, PO4 Homeostasis Pancreatic Hormones GI Hormones |
Guts 'n Brains Brain Hormones Neurosteroids Neuropeptides Evolution |
Figures for Endocrionology text:Vertebrate Endocrinology4th Edition - David O. Norris: Read pages 453-461, 475-484 for this lecture acronyms end |
XXVI. Pancreatic Hormones and Glucose Balance A. Endocrine pancreas primarily secretes 2 hormones: insulin and glucagon 1. exocrine pancreas secretes digestive enzymes into the lumen of the intestine 2. insulin and glucagon are secreted from the islets of Langerhans (1% of the organ) a. insulin from b or B cells i. 2 polypeptide chains 21aa (A) & 30aa (B) connected by disulfide bridges, MW = 6000 (1) can aggregate as dimer ® hexamer (zinc) (2) from proinsulin (MW = 9000) = continuous chain from N-terminal at B chain to C-terminus with A ii. even found in invertebrates, but there are major variations in sequences between species of vertebrates b. glucagon from a2 cells (= A cells) i. 29 aa, very conservative (homologies with secretin, VIP, GIP) c. F or PP cells secrete pancreatic polypeptide i. 36 aa d. D or a1 or d secrete somatostatin i. inhibits both insulin and glucagon e. islets organised with a2 cortical (~15%), then d (~10%), b medullary (~75%) i. a2, b and d work together as a functional secretory unit (1) many gap junctions / tight junctions between cells (2) releases suitable proportions of glucagon and insulin to regulate minute-to-minute [glucose] (a) modulate metabolism toward anabolism or catabolism in accordance with physiological needs ii. innervated by sympathetic (from VMH; NE) & parasympathetic (VLH; ACh) B. Insulin 1. Stimulated by Glucose, aa, fatty acids a. Glucose is transported into b cells via GLUT2 glucose transporters i. ATP induces closure of ATP-sensitive K+ channels (1) cell membrane depolarization. b. voltage-gated Ca++ channels open c. Ý intracellular Ca++ ® exocytosis of insulin i. incretins ® Ý cAMP Ý cytosolic Ca++ (1) incretins are peptide hormones released from the gut ii. glucose also Ý biosynthesis of insulin 2. Insulin is stimulated by the parasympathetic NS: VLH ® Vagal N. ® vagus nerve Ý ACh a. inhibits glucagon b. hypothalamus integrates balance of sympathetic/parasympathetic regulation of islet 3. Insulin is passively Ý by GIP (during hyperglycemia) a. also by glucagon 4. Insulin is inhibited by NE, Epi, galanin, pancreostatin (Pst) & somatostatin a. and insulin 5. Insulin membrane receptor of 2 x 2 polypeptide chains from a single chain precursor a. insulin (2) binds to two a subunits i. results phosphorylation of the b (2x): tyrosine PK (1) substrate is IRS1 (insulin receptor substrate 1) (a) IRS1 activates phosphatidylinositol 3 kinase (PI3-K) (b) and GRB2 (growth factor receptor bound protein-2) which activates the Sos gene product PI3-K ® PI-3,4,5-P æ (c) Sos ® Ras ® Raf1 ® MEK ® MAP K (d) MAP K ® Phosphatase 1 ® ® Glycogen synthase ® glucose storage æ transcription factors æ Ý glycogen ii. receptor also binds G protein ® Ý PDE (1) degrades cAMP, blocks glycogen conversion to glucose b. Ý glucose uptake follows I-R ® PI3-K + TC10 (GTP binding protein) ® ® translocating GLUT4 to membrane c. I-R desensitization results in type II diabetes d. insulin receptor family includes the receptor of IGF1 C. Glucagon 1. inverse relationship between extracellular [glucose] and glucagon secretion a. inhibited by fatty acids and somatostatin b. stimulated by aa, c. Ý by NE, Epi from sympathetic NS, via VMH ® N.Solitary Tract ® splanchnic nerve ® ® celiac ganglion ® mixed pancreatic nerve d. paracrine insulin inhibits, endocrine insulin stimulates 2. membrane receptor: Gs/AC/cAMP/PKA D. Function: Insulin and Glucagon have opposing actions 1. insulin stimulates anabolism, energy storage; glucagon ® catabolism and energy mobilization a. insulin ® Ý glycogen, protein, & lipid synthesis i. blood sugar ¯ b. glucagon ® Ý glycogenolysis, gluconeogenesis, ketogenesis, proteolysis i. blood sugar Ý c. in the liver, but also in muscle and adipose tissue 2. Diabetes mellitus (running through honey) a. Type 1 = Insulin-dependent (juvenile-onset) i. islet b-cells destroyed ® insulin deficiency (1) primarily via autoimmune reaction b. Type 2 = insulin-independent (maturity-onset) i. b-cells still functional ® elevated insulin secretion ii. decreased sensitivity to insulin = insulin resistance (1) ¯ I-R c. Other types = secondary d. gestational