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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.

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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

Insulin Suppresses

Glucagon secretion

Glucose

tolerance

BLOOD

Glucagon

Insulin

HOURS


Starvation
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
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


Liver Glycogen

18 hr fast

Half the glycogen stores

are depleted by 18 hr

7 subjects


Diabetes
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

CH3CCH2COO-

H

CH3CCH2COO-

O

O

OH

CH3-C-CH3

What is Ketosis?

An excessive production of ketones in the blood

3 derivatives of acetyl-CoA

Acetoacetate

-hydroxybutyrate

Acetone


CH3-C~SCoA

OH

OOC-CH2-C-CH2-C~SCoA

Acetoacetate

CH3

OH

O

O

O

O

O

OOC-CH2-C-CH3

NADH + H+

OOC-CH2-C-CH2-C~SCoA

CO2

NAD+

CH3

CH3-C-CH3

OOC-CH2-CH-CH3

OH

HMG-CoA

HMG-CoA

Lyase

+

Acetone

-hydroxybutyrate


Diabetes and lipid metabolism
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

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


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


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


Summary
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


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