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

What is the Significance of ketosis Acidosis Excessive acid in the blood Overflow Excessive oxidation of fatty acids Metabolic Problem Faulty Carbohydrate Metabolism

Metabolic fate of Acetyl CoA Pyruvate minor Acetyl-CoA Fatty Acids Ketone Bodies major Citrate

-Ketothiolase Acetoacetyl-CoA CH3C~SCoA O CH3C~SCoA O HS-CoA + -Ketothiolase rearrangement OH CH3CCH2C~SCoA O Acetoacetyl-CoA

HMG-CoA Synthase -hydroxy--methyl glutaryl-CoA CH3CCH2C~SCoA O HS-CoA CH3CCH2C~SCoA CH2C-O- O HO HMG-CoA Synthase OOC-CH2-C-CH2-C~SCoA O OH CH3 -hydroxy--methyl glutaryl-CoA (HMG-CoA)

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

Diabetes Main Characteristics 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

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

Emulates the fed signal Lowers blood glucose 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

Breakdown of adipose lipids grossly accelerated 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

Acetyl-CoA LIVER Acetyl-CoA Acetyl-CoA Acetyl-CoA FA Glucose Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Pyruvate CO2 Ketone bodies OAA CITRATE Glucose All glucagon-stimulated activities take precedence