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

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 Fat (triacylglycerols)15 (21%)141,000 Protein 6 24,000 Glycogen (muscle) 0.150 600 Glycogen (liver) 0.075 300 Blood glucose0.020 80 Blood fatty acids0.0003 3 Blood triacylglycerols0.003 30 Kg Calories Total 166,000

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

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

7. What is Ketosis? An excessive production of ketones in the blood 3 derivatives of acetyl-CoA Acetoacetate  -hydroxybutyrate Acetone CH 3 CCH 2 COO - O O CH 3 -C-CH 3 CH 3 CCH 2 COO - OH H 

8. OOC-CH 2 -C-CH 2 -C~SCoA O OH CH 3 O OOC-CH 2 -C-CH 2 -C~SCoA OH CH 3 CH 3 -C~SCoA O + OOC-CH 2 -C-CH 3 O CH 3 -C-CH 3 O CO 2 OOC-CH 2 -CH-CH 3 OH NADH + H + NAD + Acetoacetate Acetone  -hydroxybutyrate HMG-CoA Lyase

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 Less carbohydrate means less pyruvate. Less pyruvate means less OAA. Less OAA means less citrate OAA is being used for gluconeogenesis

10. INSULIN Pancreas beta cells5.8 kDa polypeptide Emulates the fed signal Stimulates glycogen synthesis Stimulates glycolysis Stimulates lipid synthesis Lowers blood glucose GLUCAGON Suppresses Glucagon Pancreas alpha cells3.5 kDa polypeptide Emulates the “need” signalRaises blood glucose Stimulates gluconeogenesis Stimulates lipolysis Stimulates glycogen breakdown NO BACKUP GLUCORTICOIDS BACKUP

11. ADIPOSE TISSUE Triacylglycerols 3 Fatty acids + Glycerol Glycerol-PO 4 Blood Glycerol kinase DHAP 3 fatty acids Glucose Missing in adipose tissue Glucagon-stimulated lipase Liver No glucose uptake by adipose Breakdown of adipose lipids grossly accelerated

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

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