Hormonal Regulation: glycolysis/gluconeogenesis - glucose homeostasis

1. Hormonal Regulation: glycolysis/gluconeogenesis- glucose homeostasis Reading: • Harper’s Biochemistry Chapter 21 • Lehninger Principles of Biochemistry 3rd Ed. pp. 878-884

2. OBJECTIVES 1. To understand how blood glucose levels are regulated by hormones, especially epinephrine, glucagon, and insulin. 2. To examine metabolic consequences of loss of glucose homeostasis.

3. Some Facts - • The most important metabolic fuels are glucose and fatty acids. • In normal circumstances, glucose is the only fuel the brain uses. • Glucose is also preferentially used by muscle during the initial stages of exercise. • To ensure the continuous provision of glucose to the brain and other tissues, metabolic fuels are stored. • Carbohydrates are stored as glycogen - the amount of available glycogen stored is not large - about 75g in the liver and 400g in the muscles. Liver glycogen can supply glucose for no longer than 16h. • To provide glucose over longer periods, the body transforms non-carbohydrate compounds into glucose through gluconeogenesis.

4. Long-chain fatty acids are the ideal storage fuel • The caloric value of fats (9 Kcal/g) is higher than that of either carbohydrate or protein (4 Kcal/g), and therefore long-chain fatty acids are ideal storage fuel. • The body has a virtually unlimited capacity for the accumulation of fats e.g. a 150 lb. man will have on average 30 lbs. of fat stored as adipose tissue triglycerides. • Fatty acids can support the body’s energy needs over prolonged periods of time. In extreme circumstances, humans can fast for as long as 60-90 days and obese persons longer.

5. The concentration of blood glucose is regulated with narrow limits • Physiological effects of low blood glucose in humans. Blood glucose levels of 40 mg/100ml and below constitute severe hypoglycemia

6. Sources of blood glucose • Diet - most digestible carbohydrates ultimately form glucose and other simple sugars that are transported to the liver via the hepatic portal vein. • Gluconeogenesis - from gluconeogenic compounds. - Net conversion to glucose without significant recycling e.g. certain amino acids and proprionate - compounds which are the products of the partial metabolism of glucose in certain tissues and are conveyed to the liver/kidney and re-synthesized to glucose e.g. lactate via Cori cycle • Glucose is also formed from liver glycogen by glycogenolysis

7. Blood glucose level • The minute-by-minute adjustments that keep the blood glucose level near 4.5 mM involve the integrated actions of several hormones (insulin, glucagon, and epinephrine) on metabolic processes in many tissues, primarily liver, muscle, and adipose tissue. - Insulin - signals that blood glucose concentration is higher than necessary - cells respond by taking up glucose and converting to storage forms. - Glucagon - signals that blood glucose is too low - cells respond by producing glucose through gluconeogenesis and glycogen breakdown. - Epinephrine - released into the blood to prepare the muscles, lungs, and heart for a burst of activity

8. Hormones that affect blood glucose Epinephrine: • Secreted by the adrenal medulla in response to stressful stimuli (fear, excitement, hemorrhage, hypoxia, hypoglycemia, etc) • Leads to glycogen breakdown in the liver and muscle - epinephrinereceptor activates adenylate cyclase cAMP PKA activatedphosphorylates/activates phosphorylase; phosphorylates/inactivates glycogen synthase • Stimulates fat mobilization in adipose tissue, activating (via PKA) triacylglycerol lipase. • Stimulates glucagon secretion and inhibits insulin secretion, reinforcing its effect of mobilizing fuels.

10. Hormones that affect blood glucose Glucagon: • Even in the absence of significant physical activity or stress, several hours after carbohydrate intake, blood glucose levels fall below 4.5 mM because of utilization by brain and other tissues. • Lowered blood glucose triggers secretion of glucagon, a hormone produced by the  cells of the islets of Langerhans. • Glucagon increases blood glucose in several ways: - stimulates breakdown of liver glycogen - inhibits glucose breakdown in liver - stimulates liver gluconeogenesis • Together, these lead to accumulation of liver glucose, allowing its export to blood • Glucagon stimulates fatty acid mobilization in adipose tissue, liberating an alternate fuel for tissues (other than brain)

12. Hormones that affect blood glucose Insulin: • Insulin plays a central role in regulating blood glucose concentration • It is produced by the  cells of the islets of Langerhans in the pancreas, as a direct response to the degree of hyperglycemia • It is a heterodimeric polypeptide consisting of two chains linked by disulfide bridges. • It is synthesized as pre-proinsulin, stored in secretory granules as proinsulin, and released as mature insulin

14. Insulin stimulates glucose uptake in muscle and liver, and activates glycogen synthesis, so that glucose is channeled into storage. • As a consequence of accelerated uptake of blood glucose, the concentration falls to the normal range, slowing insulin release from the pancreas. • There is a closely adjusted feedback mechanism between the rate of insulin secretion and blood glucose concentration which holds blood glucose nearly constant despite large fluctuations in dietary intake • Insulin also stimulates the storage of excess fuel as fat - it promotes glycolysis and thereby acetyl-CoA production used for fatty acid synthesis

16. Effects of insulin are mediated by insulin receptor, a transmembrane tyrosine kinase • Relationship of the insulin receptor to insulin action. Insulin binds to its membrane receptor, and this interaction generates one or more transmembrane signals. This signal (or signals) modulates a wide variety of intracellular events

17. Diabetes is a defect of insulin production or action • Diabetes mellitus - group of metabolic diseases characterized by hyperglycemia due to defective insulin activity

18. Symptoms of Diabetes • Excessive thirst; frequent urination (polyuria); large intake of water (polydipsia). These changes are due to excretion of large amounts of glucose in the urine (glucosuria). • Excessive but incomplete oxidation of fatty acids in the liver, resulting in overproduction of the ketone bodies acetoacetate and -hydroxybutyrate. Acetoacetate can convert to acetone, found in the blood of diabetics (breath odor like ethanol). • The overproduction of ketone bodies is called ketosis, and their production is accompanied by decreased blood pH, (acidosis) or ketoacidosis, potentially life-threatening.

19. Treatment of diabetes • Type 1 - insulin injections daily, or insulin infusion from pump. • Type 2 - do not usually require insulin treatment because insulin synthesis partially preserved. Treatment relies on diet and oral hypoglycemic agents

20. Treatment of diabetes • A sensitive diagnostic criterion is provided by the glucose-tolerance test. • Glucose tolerance test. Blood glucose curves of a normal and a diabetic individual after oral administration of 50 g of glucose. Note the initial raised concentration in the diabetic. A criterion of normality is the return of the curve to the initial value within 2 hours.

21. Fasting and starvation • Fuel reserves in normal human adult are: - glycogen in liver and muscle (small amounts) - triacylglycerols in adipose tissue - tissue proteins, which can be degraded if needed.

22. Fuel metabolism in the liver during prolonged starvation. After depletion of stored carbohydrates, proteins become an important source of glucose, produced from glucogenic amino acids by gluconeogenesis (steps  through), fatty acids imported from adipose tissue are converted into ketone bodies for export to the brain (steps  through). Broken arrows represent reactions through which there is reduced flux during starvation.

23. Alcohol excess can lead to hypoglycemia Case study • middle-aged man, emaciated, chronic alcoholic, collapses in bar at 11 a.m. • Physical exam reveals clammy skin, rapid breathing, rapid heart beat. • Lab test: blood glucose = 2.5 mM; blood alcohol = 0.2%; creatine phosphokinase - normal; serum aspartate aminotransferase (indicative of liver damage)- high; slightly acidic blood; low pCO2; high blood lactate. • After an infusion of glucose, he regained consciousness, had some food, and was referred to a counselor. • What happened?

24. Explanation • Poor diet, low glycogen stores • Dependent on gluconeogenesis • Gluconeogenesis compromised by liver damage and limited muscle mass • Alcohol metabolized primarily in the liver via NAD+ reduction CH3CH2OH CH3CHO CH3COOH • Oxidation of ethanol reduces NAD+ and increases NADH • Redox imbalance inhibits the flux of major substrates into gluconeogenesis • Low blood glucose leads to a stress response • Rapid breathing is a response to metabolic acidosis from lactic acid accumulation NAD+ NADH NAD+ NADH