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

HOURS

BLOOD

GLUCOSE

Insulin

Glucagon

Glucosetolerance

Insulin SuppressesGlucagon secretion

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) 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

Kg Calories

Total 166,000

18 hr fast

Liver Glycogen

7 subjects

Half the glycogen stores are depleted by 18 hr

Diabetes

Failure to transport glucose into muscle and adipose tissue

Insufficient insulin production (Type I)

Ineffective or impaired insulin function (Type II)

Excessive oxidation of fatty acids leading to ketosis

Main Characteristics

Failure to catabolize glucose at a normal rate in liver

What is Ketosis?An excessive production of ketones in the blood

3 derivatives of acetyl-CoA

Acetoacetate

-hydroxybutyrate

Acetone

CH3CCH2COO-

O

O

CH3-C-CH3

CH3CCH2COO-

OH

H

OOC-CH2-C-CH2-C~SCoAO

OH

CH3

OOOC-CH2-C-CH2-C~SCoA

OH

CH3

CH3-C~SCoAO

+

OOC-CH2-C-CH3

O

CH3-C-CH3

O

CO2

OOC-CH2-CH-CH3

OH

NADH + H+

NAD+

Acetoacetate

Acetone-hydroxybutyrate

HMG-CoA

HMG-CoALyase

Diabetes and Lipid MetabolismWhenever carbohydrates are not available formetabolism, fatty acid oxidation is accelerated

A more rapid degradation of fatty acidsaugments production of acetoacetyl-CoA

and acetyl CoA

Less carbohydrate means less pyruvate. Less pyruvate means less OAA. Less OAA means less citrate

OAA is being used for gluconeogenesis

INSULINPancreas beta cells 5.8 kDa polypeptide Emulates the fed signal

Stimulates glycogen synthesisStimulates glycolysisStimulates lipid synthesis

Lowers blood glucose

GLUCAGON

Suppresses Glucagon

Pancreas alpha cells 3.5 kDa polypeptideEmulates the “need” signal Raises blood glucose

Stimulates gluconeogenesisStimulates lipolysis

Stimulates glycogen breakdown

NO BACKUP

GLUCORTICOIDSBACKUP

ADIPOSE TISSUE

Triacylglycerols

3 Fatty acids + Glycerol

Glycerol-PO4

Blood

Glycerol kinase

DHAP

3 fatty acids

Glucose

Missing in adipose tissue

Glucagon-stimulatedlipase

Liver

No glucoseuptake by adipose

Breakdown of adipose lipids grossly accelerated

OAA CITRATE

Pyruvate Acetyl-CoAAcetyl-CoAAcetyl-CoAAcetyl-CoAAcetyl-CoA

FAGlucose

All glucagon-stimulated activities take precedence

Glucose

Ketone bodies

LIVER

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