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NORMAL METABOLISM

NORMAL METABOLISM. 1. After a meal glucose levels rise, insulin is produced. 2. Insulin suppresses glucagon secretion. 3. Insulin stimulates glycogen synthase I form. 4. Insulin stimulates acetyl-CoA carboxylase. 5. Fat synthesis accelerated.

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NORMAL METABOLISM

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  1. NORMAL METABOLISM 1. After a meal glucose levels rise, insulin is produced 2. Insulin suppresses glucagon secretion 3. Insulin stimulates glycogen synthase I form 4. Insulin stimulates acetyl-CoA carboxylase 5. Fat synthesis accelerated 6. Insulin stimulates glucose uptake into muscle, adipose 7. Glucose falls, glucagon secretion restored 8. cAMP activates glycogen phosphorylase, lipase 9. Liver switches to gluconeogenic mode

  2. GLUCOSE Insulin Suppresses Glucagon secretion Glucose tolerance BLOOD Glucagon Insulin HOURS

  3. Starvation • Maintain blood glucose at all cost • FUEL STORES DEPLETED: Glycogen > Triacylglycerol > Muscle Protein • Lipolysis, -oxidation, ketogenesis, proteolysis, gluconeogenesis all increased • OAA, citric acid cycle, electron transport all decreased

  4. Fuel Reserves for 70 kg (154 lb) Person Kg Calories • Fat (triacylglycerols) 15 (21%) 141,000 • Protein 6 24,000 • Glycogen (muscle) 0.150 600 • Glycogen (liver) 0.075 300 • Blood glucose 0.020 80 • Blood fatty acids 0.0003 3 • Blood triacylglycerols 0.003 30 Total 166,000

  5. Liver Glycogen 18 hr fast Half the glycogen stores are depleted by 18 hr 7 subjects

  6. Diabetes Insufficient insulin production (Type I) Ineffective or impaired insulin function (Type II) Main Characteristics Failure to transport glucose into muscle and adipose tissue Failure to catabolize glucose at a normal rate in liver Excessive oxidation of fatty acids leading to ketosis

  7. CH3CCH2COO-  H CH3CCH2COO- O O OH CH3-C-CH3 What is Ketosis? An excessive production of ketones in the blood 3 derivatives of acetyl-CoA Acetoacetate -hydroxybutyrate Acetone

  8. CH3-C~SCoA OH OOC-CH2-C-CH2-C~SCoA Acetoacetate CH3 OH O O O O O OOC-CH2-C-CH3 NADH + H+ OOC-CH2-C-CH2-C~SCoA CO2 NAD+ CH3 CH3-C-CH3 OOC-CH2-CH-CH3 OH HMG-CoA HMG-CoA Lyase + Acetone -hydroxybutyrate

  9. Diabetes and Lipid Metabolism Whenever carbohydrates are not available for metabolism, fatty acid oxidation is accelerated A more rapid degradation of fatty acids augments production of acetoacetyl-CoA and acetyl CoA OAA is being used for gluconeogenesis Less carbohydrate means less pyruvate. Less pyruvate means less OAA. Less OAA means less citrate

  10. INSULIN Pancreas beta cells 5.8 kDa polypeptide Emulates the fed signal Lowers blood glucose Stimulates glycogen synthesis Stimulates glycolysis NO BACKUP Stimulates lipid synthesis Suppresses Glucagon GLUCAGON Pancreas alpha cells 3.5 kDa polypeptide Emulates the “need” signal Raises blood glucose Stimulates glycogen breakdown Stimulates gluconeogenesis GLUCORTICOIDS BACKUP Stimulates lipolysis

  11. ADIPOSE TISSUE Glucose Triacylglycerols No glucose uptake by adipose 3 fatty acids Glucagon-stimulated lipase Glycerol-PO4 DHAP Glycerol kinase 3 Fatty acids + Glycerol Missing in adipose tissue Blood Breakdown of adipose lipids grossly accelerated Liver

  12. LIVER FA Glucose Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Pyruvate Ketone bodies OAA CITRATE Glucose All glucagon-stimulated activities take precedence

  13. Summary • Failure of insulin puts glucagon in charge • Glucose absorption by muscle, adipose blocked • Liver is put into gluconeogenic mode • Triacylglycerol synthesis by adipocytes halted • Triacylglycerol breakdown unabated • Low pyruvate means low OAA • Low OAA means low citrate • Low citrate means high acetyl CoA • High acetyl CoA mean ketosis

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