1Section V. Carbohydrate metabolismV. Glucose is central to all metabolism• 3 major paths: glycolysis, glycogen synthesis and pentose phosphate (generates NADPH, 5-C sugars) (V.2)• Major diet carbohydrates (starch, sucrose, lactose) are digested to glucose, fructose and galactose (V.1)• Fructose and galactose are converted to intermediates in glucose metabolism (V.3)• Glycolysis plus TCA, ETC; anerobic glycolysis (V.4)• Intermediates in glycolysis, TCA serve biosynthesis of amino acids, fatty acids, glycerol (V.5)Section V cont.• Pentose phosphate path takes glucose to pyruvate:forms NADPH (use for biosynthesis, antioxidant)forms 5-C sugars used for nucleotides (v.6)• UDP-glucose is used in synthesis of glycogen, UDP-galactose, also glycoproteins, glycolipids (V.7)• Glycogenolysis degrades glycogen → glucose• Gluconeogenesis → glucose from glycerol (V.8)• Overview of major paths of glucose metabolism (V.9)• Hormonal control: glucagon vs. insulin to maintain glucose homeostasis (V.10)Insulin vs. glucagon V.10V.10 Pathways regulated by glucagon vs. insulin in response to blood glucose (tissue-specific also)Blood glucose decrease → Glucagon release →↑glycogenolysis ↑gluconeogenesis ↑lipolysis ↓liver glycolysisBlood glucose increase → Insulin release →↑glycogen synthesis ↑fatty acid synthesis ↑triglyceride synthesis ↑liver glycolysisChapt. 26 hormone regulationCh. 26 Regulation by Insulin, glucagon and other hormonesStudent Learning Outcomes:• Describe mechanisms of major hormones insulin and glucagon to control glucose homeostasis• Explain that Homeostasis is balance of fuel mobility and storage: keep glucose 80-100 mg/dL (~5 mM)• Regulate carbohydrate, lipid, aa metabolism• Describe counteracting influences of insulin and glucagon and other counter-regulatory hormones2Insulin vs glucagon and othersFig. 2 Homeostasis requires glucose control:Insulin is anabolic hormone:• from β-cells of pancreas• Glucose entry into tissues• Glucose storage, growthGlucagon counters:• Degradation of glycogen• Gluconeogeneis• Mobilize fatty acids• Stress hormones counter:• Epinephrine, • Cortisol (glucocorticoid)Glucagon mobilizes glucose from tissuesFig. 1, 3 Glucagon activates pathways for glucose mobilization:• Counteracts insulin• Pancreas α-cell• Acts via G-protein-coupled receptor,cAMP, PKAFuel homeostasisFig. 4 Fuel homeostasis requires balance:• Substrate availability and need• Concentration nutrients in blood affects storage• Hormonal messages to target tissue• Neuronal signalshomoeostatisGlucose homeostasis is critical:• Multiple signals• Insulin vs. glucagon• Stress hormones• Epinephrine• CortisolFig. 53Insulin is anabolicFig. 6; + stimulated by insulin; -, inhibited Insulin is major anabolic hormone for fuel storage:• Storage as glycogen• Synthesis of fatty acids• Triacylglycerol storage• Protein synthesis• Tissues of actionGlucagon is fuel metabolismGlucagon is major hormone for fuel metabolism:• Maintain fuel in absence of dietary glucose• Glycogenolysis in liver• Gluconeogenesis in liver• Fatty acids from adipocytes• Tissues of actionFig. 7; + stimulated by glucagon; -, inhibited Pancreas Pancreas has αααα and ββββ cellsα α α α cells make insulin; ββββ cells make glucagonHigh-carbohydrate mealHigh-carbohydrate meal:• Rapid increase of glucose• 80 → >120 mg/dL • Rapid increase of insulin• 5 → >120 µU/mL• Decrease of glucagon• 110 → 90 pg/mLFig. 8 Blood levels after meal4Table 1 Insulin and counterregulatory hormonesHormone functions major metabolic pathsInsulin promotes storage stimulate glucose storage inmuscle, liverpromotes growth stimulates protein synthesis, fatty acid synthesisGlucagon mobilizes fuels activates gluconeogenesis and glycogenolysismaintains blood activates fatty acid release glucose in fastingEpinphrine mobilizes fuels stimulate glycogenolysis in acute stress stimulate fatty acid releaseCortisol changing long term amino acid mobilizationgluconeogenesisInsulin counterregulatory hormonesFig. 9 Major insulin counterregulatory hormones:Stress of low glucose:• Neuronal signals release hormones:• ACTH from pituitary→• Cortisol from adrenal cortex• Epinephrine from adrenal medulla• Norepinephrine from nerves• Minor role release glucagonIII. Synthesis and release of insulin and glucagonFig. 10insulin Insulin is polypeptide of 51 amino acids:• α and β chains, cross-linked• Synthesized as preproinsulin, cleaved in RER to proinsulin• Passed through Golgi, into storage vesicles (also Zinc)• Final protease cleavages forms active insulin• Exocytosis into blood is stimulated by increased glucose in bloodaround β-cellsRelease of insulin by β-cellsRelease of insulin by ββββ-cells:• Stimulated by increased glucose in blood around ββββ-cells• Glucose enters through transporters (GLUT 2)• Hexokinase phosphorylates, TCA, ETC• ATP ↑; inhibit ATP-dep K+ channel• Membrane depolarization • Ca2+ channel opens• [Ca2+] stimulate vesicle fusionFig. 11 release of insulin in response to increased blood glucose5Table 26.2 Regulators of insulin releaseRegulators of insulin release:Major regulators: Effect:Glucose +threshhold ~80 mg/dL, increase proportional to ~300 mg/dLInsulin is removed from blood and degraded in liverNew synthesis of insulin occurs in β-cells after release Minor regulators:Amino acids +Neural input +Gut hormones + (chapt. 43)Table 26.3 Regulators of Glucagon releaseRegulators of glucagon release:Major regulators: Effect:Glucose -Insulin -Amino acids +Minor regulators:Cortisol +Neural input (stress) +Epinephrine +Glucagon is 160-aa preproglucagon in α-cells; converted to proglucagon in RER; mature 29-aa glucagon in vesicles;Rapid half-life of glucagon in plasma Effect of high-protein mealFig. 12 high protein meal High-protein meal:• Stimulates glucagon release• Not much insulin• Blood glucose not changeMixed meals:get some of each hormoneMechanisms of hormone actionsIV. Mechanisms of hormone actionsRecall from Chapt. 11, that hormones can affect activities of enzymes or transport proteins:• Change conformation of enzyme (as phosphorylation), Change amount of protein (induce or repress synthesis), Change allosteric effector concentration• Signal transduction pathways of hormones:• Intracellular receptors (cortisol, thyroid hormone)• Plasma membrane