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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
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What is the Significance of ketosis
Acidosis Excessive acid in the blood Overflow Excessive oxidation of fatty acids Metabolic Problem Faulty Carbohydrate Metabolism
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Metabolic fate of Acetyl CoA
Pyruvate minor Acetyl-CoA Fatty Acids Ketone Bodies major Citrate
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-Ketothiolase Acetoacetyl-CoA CH3C~SCoA O CH3C~SCoA O HS-CoA
+ -Ketothiolase rearrangement OH CH3CCH2C~SCoA O Acetoacetyl-CoA
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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)
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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
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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
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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
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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
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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
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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
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