PGY452 552 Human Physiology Endocrinology 6 Short term metabolic control by insulin glucagon A Insulin anabolism 1 Regulation of secretion 2 Signaling mechanism 3 Anabolic response B Glucagon catabolism C Glucose homeostasis Insulin glucagon are synthesized in the endocrine pancreas Small intestine Pancreas 2 Insulin glucagon are secreted from specialized cells Exocrine cells digestive enzymes Blood flow Islet of Langerhans a cells glucagon 20 b cells insulin amylin 70 10 cells somatostatin cells pancreatic polypeptide cells ghrelin Blood flow on inside to on outside hormones can regulate cell hormones 3 Insulin is the primary anabolic hormone Short term anabolism Glucose o To glycogen o TAGs NEFA TAG Amino acids proteins Anabolism Glycogen TAG Protein Long term anabolism Regulation of adipose stores Growth development We ll get to this in the next topic Fed state absorptive 4 Insulin synthesis typical for a peptide hormone p A B C Synthesized from a higher MW precursor Cleaved in trans golgi to form 3 peptides Insulin A B chains Disulfide linked MW 6000 51 aa 3 mRNA 5 Ribosome 5 proinsulin 3 C H S ER S H S H C peptide S H S S H H S N Insulin A C S S S S B Cleavage ER S S C N C peptide S N S S S S C peptide Activity Marker for secretion trans golgi S A B S S S S S Mature insulin in secretory vesicle 5 Insulin is the primary point of anabolic control Blood glucose primary regulatory influence is key to understanding molecular mechanism of release 6 Molecular mechanism of insulin release Step 1 glucokinase glucose 6 phosphate ATP Glucokinase hexokinase glucose glucose 6 phosphate Hexokinase Muscle adipose Hexokinase muscle adipose 100 activity Glucokinase cells liver physiological range of glucose 0 5 10 15 plasma glucose in mM ADP glycolysis Active at low glucose Always at maximum rate glucose Glucokinase pancreatic cells liver Rate limiting step of glycolysis Overall rate of glycolysis very sensitive to glucose 7 Insulin release Step 2 the K ATP channel I K Ca2 ATP 5 Ca2 GLUT2 1 3 K Glucokinase ATP sensitive K channel Ca 2 Ca 2 Glycolysis I 2 ATP ATP 2 4 Pancreatic cell 8 Insulin release Step 2 The K ATP channel 1 Glucose enters the cell through the GLUT2 transporter 2 As the concentration of glucose increases so does the rate of glucokinase leading to increased glycolysis and a high cellular ATP 3 ATP inhibits the ATP sensitive K channel leading to a change in membrane potential which opens a voltage sensitive Ca2 channel 4 Ca2 enters the cell and activates a Ca2 release channel which releases Ca2 from internal stores 5 That is the calcium that stimulates secretion of insulin 9 The ATP sensitive K channel connects glucose to insulin release ATP 2 Glucokinase Glycolysis Glucokinase activity responds to Glucose Glucokinase activity determines overall glycolysis rate Glycolysis rate determines ATP ATP gates the K channel Channel also known as sulfonylurea receptor Major diabetic drug target ATP Sulfonylurea 10 Two other hormones are critical 1 Glucagon like peptide 1 GLP1 Intestinal L cells Responds to dietary glucose Receptor Glp Same precursor as glucagon 37 amino acid peptide Related to glucagon receptor G S coupled s PKA 11 Two other hormones are critical 2 Glucose dependent insulinotropic peptide AKA o Gastric inhibitory poly peptide o Gastrin inhibitory peptide GIP 42 amino acids From K cells in small intestine Response to glucose G S coupled receptor GIP s PKA 12 GLP1 and GIP have very short half lives Both inactivated by the protease DPP4 GIP Glp DPP4 Inactive peptide fragments 13 The actions of GIP GLP1 are called the incretin effect se co lu lin su se co lu G lin su In G In GI IV glucose Wait 2 hr Levels Oral glucose The difference is GLP1 GIP secreted only during oral glucose ingestion 14 GLP1 GIP increase insulin release Ca I GIP or Glp 2 ATP 2 AC AC s cAMP ATP Ca2 cAMP PKAii cAMP PKA cAMP Ca2 PKAii Pancreatic cell Glucose is required permissive 2 Ca cAMP I ATP Ca2 15 What if the meal does not include glucose Placeholder Intentionally blank 16 Amino acids and lipids can cause insulin release I Ca2 Some dietary amino acids oxidation of NEFA ATP Ca2 I TAG K NEFA Ca2 ATP Ca 2 CoA Electron transport system Ca2 Pancreatic cell O 17 Other factors that influence insulin secretion Anabolic hormones neurotransmitters Usually stimulate insulin release CNS influence critical but poorly understood Catabolic hormones often inhibit insulin release These factors are secondary Key requirement cell glucose 18 Insulin signaling mechanism Comprehensive mechanism involving kinase based enzyme activation and regulation of transcription I P TK TK P Tyr Tyr P 19 The insulin receptor is a receptor tyrosine kinase RTK I I TK TK Inactive TK IRS insulin receptor substrate 8 members Tissue specific Each has 8 tyrosines Responsible for most insulin actions I TK P TK Insulin activates TK by autophosphorylation TK P IRS P P P P P P P IRS P P P P P P P Activation of IRS proteins 20 Insulin signaling is complex Placeholder Intentionally blank 21 The essentials of insulin signaling I I PIP3 PDK PIP2 P P P P P P TK SHC TK P SHC P P P P P P P PDK P P IRS P P P P P P P P P P IRS P P AKT Activates translation protein synthesis Direct phosphorylation of metabolic enzymes anabolism IRS P P P P P P P P P P mTOR P P P P P P P P P P P P P P P P P P P P PI3K AKT IRS P P P P P P IRS P P GRB P P P P P P GRB Cell Growth division Pol II Anabolism Pol II P Pol II P P Catabolism 22 Response to Insulin Anabolism 23 Insulin is the primary anabolic hormone Anabolic effects glucose storage fat storage protein synthesis Nearly all tissues have insulin receptors Major sites of shortterm metabolic effects Liver Skeletal Muscle Adipose tissue 24 Comprehensive control in the liver II 2 P TK 1 TK P Lipid Droplet TAGs Acetyl CoA Pyruvate 3 NEFA O CoA 2 VLDL 4 oxidation Citric acid cycle 25 Comprehensive control in the liver Insulin in the liver 1 Increases the formation of glycogen while inhibiting its breakdown It also inhibits the conversion of glucose 6 phosphate to glucose and stimulates the formation of glucose 6 phosphate by increasing the synthesis of glucokinase 2 The rate of glycolysis is increased and gluconeogenesis is shut down This results in a large amount of pyruvate 3 The conversion of pyruvate to acetyl CoA is enhanced to produce energy and to promote the export of citrate to the cytoplasm and its conversion to acetylCoA 4 Lipogenesis is stimulated resulting in high levels of NEFAs as well as glycerol from