Download What is Ketosis?

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
GLUCOSE
BLOOD
Glucose
tolerance
Glucagon
Insulin
Insulin Suppresses
Glucagon secretion
HOURS
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
Fuel Reserves for 70 kg (154 lb)
Person
•
•
•
•
Fat (triacylglycerols)
Protein
Glycogen (muscle)
Glycogen (liver)
• Blood glucose
• Blood fatty acids
• Blood triacylglycerols
Kg
Calories
15 (21%)
6
0.150
0.075
141,000
24,000
600
300
0.020
0.0003
0.003
Total
80
3
30
166,000
Liver Glycogen
18 hr fast
Half the glycogen stores
are depleted by 18 hr
7 subjects
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
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
OH
OOC-CH2-C-CH2-C~SCoA
HMG-CoA
Acetoacetate
CH3
O
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
OH
-hydroxybutyrate
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
Ketone bodies
OAA
CITRATE
Glucose
All glucagon-stimulated activities take precedence
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