What is Ketosis?

1
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
Glucose
tolerance
BLOOD
Glucagon
Insulin
HOURS
3
Starvation

• Maintain blood glucose at all cost
• FUEL STORES DEPLETED Glycogen gt Triacylglycerol
  gt 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
Kg Calories

• Fat (triacylglycerols) 15 (21) 141,000
• Protein 6 24,000
• Glycogen (muscle) 0.150 600
• Glycogen (liver) 0.075 300
• Blood glucose 0.020 80
• Blood fatty acids 0.0003 3
• Blood triacylglycerols 0.003 30

Total 166,000
5
Liver Glycogen
18 hr fast
Half the glycogen stores are depleted by 18 hr
7 subjects
6
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
7
What is Ketosis?
An excessive production of ketones in the
blood 3 derivatives of acetyl-CoA
Acetoacetate
??-hydroxybutyrate
Acetone
8
HMG-CoA
HMG-CoA Lyase

Acetone
?-hydroxybutyrate
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
OAA is being used for gluconeogenesis
Less carbohydrate means less pyruvate. Less
pyruvate means less OAA. Less OAA means less
citrate
10
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
11
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
12
LIVER
FA
Glucose
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Pyruvate
Ketone bodies
OAA
CITRATE
Glucose
All glucagon-stimulated activities take precedence
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