Section V. Carbohydrate metabolism V. 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.10 V.10 Pathways regulated by glucagon vs. insulin in response to blood glucose (tissue-specific also) Blood glucose decrease → Glucagon release → ↑ glycogenolysis ↑gluconeogenesis ↑lipolysis ↓liver glycolysis Blood glucose increase → Insulin release → ↑glycogen synthesis ↑fatty acid synthesis ↑triglyceride synthesis ↑liver glycolysis

Chapt. 26 hormone regulation Ch. 26 Regulation by Insulin, glucagon and other hormones Student 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 mg/dL (~5 mM) Regulate carbohydrate, lipid, aa metabolism Describe counteracting influences of insulin and glucagon and other counter-regulatory hormones

Insulin vs glucagon and others Fig. 2 Homeostasis requires glucose control: Insulin is anabolic hormone: from  -cells of pancreas Glucose entry into tissues Glucose storage, growth Glucagon counters: Degradation of glycogen Gluconeogeneis Mobilize fatty acids Stress hormones counter: Epinephrine, Cortisol (glucocorticoid )

Glucagon mobilizes glucose from tissues Fig. 1, 3 Glucagon activates pathways for glucose mobilization: Counteracts insulin Pancreas  -cell Acts via G-protein- coupled receptor, cAMP, PKA

Fuel homeostasis Fig. 4 Fuel homeostasis requires balance: Substrate availability and need Concentration nutrients in blood affects storage Hormonal messages to target tissue Neuronal signals

homoeostatis Glucose homeostasis is critical: Multiple signals Insulin vs. glucagon Stress hormones Epinephrine Cortisol Fig. 5

Insulin is anabolic Fig. 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 action

Glucagon is fuel metabolism Glucagon 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 action Fig. 7; + stimulated by glucagon; -, inhibited

Pancreas Pancreas has  and  cells  cells make insulin;  cells make glucagon

High-carbohydrate meal High-carbohydrate meal: Rapid increase of glucose 80 → >120 mg/dL Rapid increase of insulin 5 → >120  U/mL Decrease of glucagon 110 → 90 pg/mL Fig. 8 Blood levels after meal

Table 1 Insulin and counterregulatory hormones Hormonefunctionsmajor metabolic paths Insulinpromotes storagestimulate glucose storage in muscle, liver promotes growthstimulates protein synthesis, fatty acid synthesis Glucagonmobilizes fuelsactivates gluconeogenesis and glycogenolysis maintains bloodactivates fatty acid release glucose in fasting Epinphrinemobilizes fuelsstimulate glycogenolysis in acute stressstimulate fatty acid release Cortisolchanging long termamino acid mobilization gluconeogenesis

Insulin counterregulatory hormones Fig. 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 glucagon

III. Synthesis and release of insulin and glucagon Fig. 10 insulin Insulin is polypeptide of 51 amino acids:  and  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 blood around  -cells

Release of insulin by  -cells Release of insulin by  -cells: Stimulated by increased glucose in blood around  -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 fusion Fig. 11 release of insulin in response to increased blood glucose

Table 26.2 Regulators of insulin release Regulators of insulin release: Major regulators:Effect: Glucose+ threshhold ~80 mg/dL, increase proportional to ~300 mg/dL Insulin is removed from blood and degraded in liver New synthesis of insulin occurs in  -cells after release Minor regulators: Amino acids+ Neural input+ Gut hormones+ (chapt. 43)

Table 26.3 Regulators of Glucagon release Regulators of glucagon release: Major regulators:Effect: Glucose- Insulin- Amino acids+ Minor regulators: Cortisol+ Neural input (stress)+ Epinephrine + Glucagon is 160-aa preproglucagon in  -cells; converted to proglucagon in RER; mature 29-aa glucagon in vesicles; Rapid half-life of glucagon in plasma

Effect of high-protein meal Fig. 12 high protein meal High-protein meal: Stimulates glucagon release Not much insulin Blood glucose not change Mixed meals: get some of each hormone

Mechanisms of hormone actions IV. Mechanisms of hormone actions Recall 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 receptors: G-protein coupled receptors (adenylyl cyclase, cAMP) Receptor tyrosine kinases and Ras/Raf, MAPK PIP2, DAG signaling from both

Plasma membrane hormone receptors 2 major plasma membrane hormone receptors: G-protein coupled heptahelical - glucagon Tyrosine kinase receptors - insulin Figs. 11.9, 11.10

RTK Insulin receptor has several signaling paths Fig Insulin signaling: PLC - phospholipase PIP – phosphatidyl inositol forms PI 3-kinase signals through protein kinase B (Fig ) * Insulin receptor signals through several paths: Binding of hormone causes autophosphorylation Binds IRS (insulin receptor substrates), PO 4 those: Grb2 can signal through Ras and MAPK path Other proteins bind, interact with PIPs in membrane

Signal transduction by insulin Signal transduction by insulin: 5 categories of tissue specific responses: Reverses glucagon-stimulated phosphorylation Phosphorylation cascade stimulates phosphorylation of several enzymes Induces and represses synthesis of some enzymes Growth factor, stimulation of protein synthesis Stimulates glucose and amino acid transport into cells

Signal transduction by glucagon Signal transduction by glucagon: Glucagon receptor is G-protein coupled (G s ) Activate adenylyl cyclase → cAMP → activate PKA PKA phosphorylates enzymes on ser: Activates some enzymes, inhibits others Especially affects kinases, phosphatases cAMP rapidly degraded to AMP Hormone signal terminated by phosphatases remove the PO 4 from enzymes Skeletal muscle does not have glucagon receptor, but liver and other tissues do

Signal transduction by cortisol, intracellular receptors Cortisol and thyroid hormone bind intracellular receptors: Binding of hormone causes hormone-receptor complex to bind specific DNA sequences, increase transcription from target genes. Figs. 11.7,8

Signal transduction by epinephrine, norepinephrine Fig. 13 Epinephrine, norepinephrine are catecholamines Neurotransmitters or hormones Stress hormones increase fuel mobilization Adrenergic receptors (autonomic) 9 different receptors: 6 , 3   receptors work through G-protein coupled, adenylyl cyclase, cAMP, PKA Different receptors on tissues Mobilize fuels Stimulate muscle contractions

Key concepts Key concepts: Glucose homeostasis maintains blood glucose levels Insulin and glucagon are two major hormones regulating levels of glucose – opposing effects Excess fuel is stored as glycogen or fat; stored fuels are mobilized when demanded Insulin promote glucose utilization, storage; secretion regulated by blood glucose levels Insulin binds to RTK receptor Glucagon promotes glucose production, mobilization of glycogen, gluconeogenesis Glucagon binds G-protein coupled receptor, cAMP

Review questions Review question: 2. Caffeine is a potent inhibitor of the enzyme cAMP phosphodiesterase. Which of the following consequences would you expect to occur in the liver after drinking two cups of strong espresso coffee? a.A prolonged response to insulin b.A prolonged response to glucagon c.An inhibition of protein kinase A d.An enhancement of glycolytic activity e.A reduced rate of glucose export to circulation