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Glucose-stimulated insulin release from pancreas B cell

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Diabetes Mellitus and Starvation

Similarity: Lack of intracellular energy

Difference: What causes the problem

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Cause of the problem

DM: Deficient mechanism to obtain energy

from glucose

- Starvation: Lack of nutrients input for the

provision of fuel substances

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Alternative to obtain energy in DM and

Starvation

a. Switch from carbohydrate to fat

metabolism

b. Switch from gluconeogenesis to ketoneproduction

Consequences (what are they?) have to be

monitored.

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Diabetes Mellitus type1

- Less common than type 2

- Autoimmune destruction of pancreaticB cells

- Severe insulin deficiency

- Diabetic ketoacidosis

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Diabetes Mellitus type 2

- Insulin resistance

- Do not require insulin treatment

- Managed with diet alone or

diet plus medications

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Purpose of medications:

- Enhance endogenous insulin secretion

(sulfonylureas)

- Decrease insulin resistance

- Decrease intestinal carbohydrate

absorption (-glycosidase inhibitors)

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Explain biochemical aspects of:

1. Hyperglycaemia

2. Glucosuria

3. Decreased glycogenesis

4. Decreased fatty acid synthesis

5. Increased lypolysis

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6. Increased fatty acids in blood

7. Ketonaemia

8. Ketonuria

9. Metabolic acidosis

10. Negative Nitrogen Balance

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Explanation of 1-4

Actions of insulin on target tissues

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Hyperglycaemia

- Decreased glucose uptake by insulin

dependent glucose transporter(Glut 4, muscle, adipose tiss)

- Decreased glycogenesis

Not sufficient insulin to activate

phosphodiesterase, enzyme for

conversion of cAMP to AMP, meaning

to decrease cAMP concentration

cAMP inhibiting factor in glycogenesis

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Explanation of 5 6

Due to a switch from utilization ofglucose to

fat for source ofenergy.

Low levels of oxaloacetate (OAA) in liver

Ketone body production increases

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Explanation of 7 8

Increased production of ketone bodies

Less utilization in muscle (low OAA)

Develops ketonaemia in type 1 DM and

type 2 DM with insulinopenia.

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Glucose is insulin secretagogue for insulin secretion

Type 2 DM: Deficient control of insulin secretion

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Explanation 9 - 10

In severe cases of DM,

tissue protein utilized for energy

Cysteine sulphates acid urine

Negative N-balance due to ineffective amino

acid metabolism.

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Complications and Therapy

Advanced glycation end products (AGEs)

A serious complication of diabetes

Glycoprotein = covalent linkage of sugar to protein

Can occur nonenzymatically

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Glycation causes change to protein function

Circulation, joint and vision problems.

Nonenzymatic glycation of Hb (glycated Hb) is

Used to estimate blood glucose over past several

months

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Chronic Complications

Microvascular complications induced by:

1. Polyol pathway

2. AGE formation

3. Protein kinase C (PKC)

4. Hexosamine Pathway

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ad 1. Aldose reductase converts glucose to sorbitol

In hyperglycemia: accumulation of sorbitol

osmotic stress in nerves, endothelial cells,

eye lens (cataract)

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ad 2. AGEs can cause :

- Microvascular damage

- Formation of glycated HbA (= HbA1c)

Used as index of glycemic control over

preceding 2-3 months

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ad 3. Intracellular hyperglycemia in endothelium

increased DAG (diacylglycerol) activates

protein kinase C (PKC) effects on blood

flow and endothelial permeability.

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ad 4. Increase of glucose entering hexosamine

pathway produces substrates that

can bind covalently to transcription

factors stimulate protein expression

e.g. transforming growth factor,

enhancing microvascular damage

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Gluconeogenesis Inhibitors

Metformin improves sensitivity to insulin in type

2 DM

Stimulates glucose uptake by glucose

transporters in peripheral tissues

Increases binding of insulin to insulin receptors

Stimulates tyrosine kinase activity of insulin

reseptorInhibits glukoneogenesis in liver

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REFERENCES1. Medical Biochemistry (MASTER MEDICINE)

Brownie, A.C., Kernohan, J.C. 2nd ed. 2005

2. BIOCHEMISTRY

Garrett, R.H., Grisham, C.M. 3rd ed. 20053. Pathophysiology of Disease

McPhee, S.J., Ganong, W.F. 5th ed. 2006