• Metabolic effects of Insulin and Glucagon

• Metabolism in the Well fed state

• Metabolism in the Starvation and Diabetes Mellitus

Integration of Metabolism

Metabolism of starvation and diabetesMetabolism of starvation and diabetes*Starvation: Results from inability to obtain food that can be resulted from

A) Intentionally (reduce weight rapidly)

B) Clinical situation in which person cannot eat because of trauma, surgery,

burns,

In the absence of food low glucose, TG, a.a, in blood low insulin / glucagon

ratio and low substrate availability Catabolic period characterized by high

TG degradation, high glycogen and a.a catabolism

*Exchanges between tissues liver, adipose, muscle determined by two

priorities:

A) The need to maintain plasma glucose level to sustain energy for brain and

other glucose-requiring tissues.

B) The need to mobilize fatty acids from adipocytes and keton bodies to supply

energy to all other tissues.

*Fuel stores: Metabolic fuel including glycogen (0.2 kg), Fat(15 kg) and

proteins (6 kg)

- Only 1/3 of proteins can be used as energy safely

*Enzymatic changes in starvation: Determined by 1) Availability by

substrates. 2) Allosteric regulators 3) Covalent modification. 4) Induction-

repression of enzyme synthesis.

*The metabolic changes observed in starvation are generally opposite to

these in well-fed state.

Liver response to starvation

A) Glycogen degradation starts 3 hours

after the last meal and provide the blood with

glucose for about 10-18hours.

Liver glycogen exhausted after 10–18hours.

B) Increase gluconeogenesis:

-Plays essential rule in maintaining

glucose level during both overnight and

prolonged fasting

-Substrates for gluconeogenesis: a.a

(carbon skeletons), Pyruvate, Glycerol

(from TG)

- Gluconeogenesis starts 4–6hours after

last meal and become fully active when

glycogen store is depleted.

I. Liver in starvation

A- CHO metabolism

- Liver first uses glycogen degradation then gluconeogenesis to maintain blood

glucose level to provide energy for brain

*Sources of blood glucose

1- Diet 2- Glycogen 3- Gluconeogenesis

B- Fat metabolism

1) High fatty acid oxidation that derived from TG (adipose tissue) is

the major source of energy in hepatic cells. (glucose is the major source

of energy in case of well-fed state)

2) Increase synthesis of ketone bodies

Ketone bodies synthesis is the favored when concentration of acetyl-CoA is

higher than oxidation capacity of TCA cycle.

Significant synthesis

of ketone bodies starts

in the first days of

starvation.

Circulating ketone

bodies are important

to provide energy for

peripheral tissues

including brain.

II. Adipose tissue in starvation

A- CHO metabolism

- Glucose transport into adipocytes is

reduced decrease glycolysis decrease

fatty acids and TG synthesis because also of

decreased insulin.

B- Fat metabolism

I) Increase degradation of TG

*Hormone sensitive lipase is activated by

1) Low level of insulin.

2) High level of epinephrine and nor-

epinephrine activate TG degeneration

and release of fatty acids

II) Increase release of fatty acid

- Fatty acids released from hydrolysis of

stored TG bound to albumin and transported

to tissues to be used as fuel.

Glycerol that resulted from TG

degredation is used in

gluconeogenesis by liver.

Decrease uptake of fatty acids: by

adipocytes decrease TG synthesis

- In starvation decrease activity of

lipo-protein lipase of adipocytes

circulating TG of lipo-proteins is

decreased.

* Fatty acids are taken by the liver

and degraded by B-oxidation

accumulation of Acetyl CoA

activation of Ketone body formation

increasing the circulatory ketone

bodies

III. Skeletal muscle in starvationA- CHO metabolism

low insulin decrease uptake of glucose by skeletal muscle glucose

metabolism is decreased.

B- Lipid metabolism

During the first two weeks of starvation muscle uses fatty acids from

adipose tissue and ketone bodies as fuel. After three weeks muscle

decrease utilization of ketone bodies and use only fatty acids increase

circulating ketone bodies.C- Protein metabolism

During the first few days of

starvation rapid degradation

of muscle protein providing a.a for

gluconeogenesis.

After several weeks of starvation,

the rate of muscle protein

degradation decrease a decline in

need for glucose as fuel for brain.

IV. Brain in starvation

First days of starvation, brain

uses only glucose (from

gluconeogenesis).

After 2 – 3 weeks, brain starts

using ketone bodies

decrease gluconeogenesis as

source of glucose.

Inter-tissue

relationships

during

starvation.

Diabetis Mellitus- Major health problem

- Heterogeneous group of syndromes characterized by an elevation of FBG

(Fasting Blood Glucose), caused by relative or complete absence of insulin.

(high blood glucose and low insulin)

- Metabolic changes caused by low insulin release and aggregated release

of glucagon.

*Diabetes types:

Insulin Dependent DM (IDDM)

Non-Insulin Dependent DM (NIDDM)

IDDM (Type I Diabetes)

- Requires insulin to avoid life-threatening keto acidosis

- Absolute deficiency of insulin caused by massive autoimmune attack on

the β-cell of pancreas.

* Insulitis

- Rule of T-lymphocytes in IDDM

- Symptoms appear abruptly after 80 – 90% of β-cell has been destroyed

pancreas fail to respond to ingested glucose.

Diagnosis of Type I

- Abrupt appearance of polyurea, polydypsia, polyphagia with fatigue,

weight loss, weakness and with FBG to greater than 140 mg/dl

- Appearance of glucose in urine.

*Metabolic changes in Type I

- Hyperglycemia and Ketoacidosis

- Hyperglycemia is caused by increased hepatic production of glucose

combined with decrease in peripheral utilization.

- These effects due to low insulin and high glucagon.

* Ketosis: increase mobilization of fatty acids from adipocytes compined

with increase hepatic synthesis of ketone bodies.

- Not all fatty acids degraded are oxidized, but can be used in TG

biosynthesis of VLDL released into blood.

- Chylomicrones & VLDL level are elevated because lipoprotein lipase is

inactivated or low in diabetic persons hypertriglyceridemia.

- Low insulin / glucagon increase gluconeogenesis and increase

ketogenesis.

* Metabolic changes in IDDM resemble to changes in starvation except that they are more exaggerated.

* Treatment of IDDM: they have no functional β-cells they depend only on the take of insulin.

* Non-Insulin Dependent Diabetes Melletus (NIDDM) “Type II “

- Most common affecting 80% of diabetic population.

- Develops gradually without obvious symptoms.

- NIDDM patients have functional β-cells and don’t require insulin to sustain life.

- Highly determined by genetic factors.

- Metabolic alterations observed in NIDDM are milder than that of IDDM.

* NIDDM results from:

a) Dysfunctional β-cells.

- β-cells function is reduced insulin can be normal or below normal, but β-cells fail to secrete enough insulin to correct hyperglycemia.

b) Insulin resistance.

- Tissues fail to respond normally to insulin. Usually it is accompanied by target organ insulin resistance.

- Liver resistance to insulin leads to uncontrolled hepatic glucose production.

- Muscle and adipose tissues decrease glucose uptake by these tissues.

- Also type II can be due to number of defects of signal transduction.

* Treatment of Type II

- The goal of treating type II is to maintain normal glucose level.

1. Wight reduction.

2. Dietary modifications.

3. Hypoglycemic agent.

4. Complicated cases insulin is required.

* Chronic effects of Diabetes:

A. Atherosclerosis

B. Retinopathy

C. Nephropathy

D. neuropathy

Comparison of Type I and Type II diabetes

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