What is Ketosis?

An excessive production of ketones in the blood

3 derivatives of acetyl-CoA
Acetoacetate
-hydroxybutyrate

Acetone

CH3CCH2COOO

H
CH3CCH2COOOH
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
Fatty Acids

minor

Acetyl-CoA
major

Citrate

Ketone Bodies

CH3C~SCoA
O

CH3C~SCoA
O
HS-CoA

CH2C~SCoA
CH C + O
rearrangement

OH

CH3CCH2C~SCoA
O
O

-Ketothiolase

Acetoacetyl-CoA

CH3CCH2C~SCoA
O
O
HS-CoA

CH3C~SCoA
O

CH2C-OO
CH3CCH2C~SCoA
HO

OH
OOC-CH2-C-CH2-C~SCoA
CH3

HMG-CoA
Synthase

-hydroxy--methyl
glutaryl-CoA
(HMG-CoA)

OH
OOC-CH2-C-CH2-C~SCoA
CH3 O

HMG-CoA

Acetoacetate

CH3-C~SCoA
O
OH
+ 2-C~SCoA HMG-CoA
OOC-CH2-C-CH
Lyase
CH3 O

OOC-CH2-C-CH3
O
CO2
NADH + H+
NAD+
CH3-C-CH3
OOC-CH2-CH-CH3
O
Acetone
-hydroxybutyrate
OH

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

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

INSULIN
Pancreas beta cells
5.8 kDa polypeptide
Emulates the fed signal Lowers blood glucose
Stimulates glycogen synthesis
Stimulates glycolysis
Stimulates lipid synthesis

NO BACKUP

Suppresses Glucagon
GLUCAGON
Pancreas alpha cells 3.5 kDa polypeptide
Emulates the need signal Raises blood glucose
Stimulates glycogen breakdown
Stimulates gluconeogenesis
GLUCORTICOIDS
Stimulates lipolysis
BACKUP

ADIPOSE TISSUE
Triacylglycerols
Glucagon-stimulated
lipase

Glucose

No glucose
uptake by
3 fatty acids
adipose
Glycerol-PO4
DHAP

3 Fatty acids + Glycerol

Glycerol kinase
Missing in
adipose tissue

Blood
Liver

Breakdown of adipose lipids

grossly accelerated

FA

Glucose

Pyruvate

LIVER

Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA

CO2

Ketone bodies
OAA

CITRATE

Glucose

All glucagon-stimulated activities take precedence