37. Etiology and pathogenesis of 2DM

Genetic factors - 2DM?

Concordance bw identical twins: 80%

- Indicating a stronger genetic factor than 1DM

- Specific genetic factors involved are not well known in DM2

Possible genes that are mutated in 2DM?

- GLUT2

- PPAR-y

- GLUT4

- GCGR - glucagon receptor gene

- TCF7L2 - most significant gene associated w/2DM - a transcription factor active in ß-cells

- ATP-gated K+ channel - channel found on surface of ß-cells that is involved in glucose sensing

Gene mutations in MODY?

In the gene for glucokinase

Also HNF gene mutation is seen in MODY

Environmental factors 2DM?

- Obesity

- Physical activity

- Diet high in sugar & saturated fats

- Hypertension

- Dyslipidemia

- History of gestational diabetes

= risk factors for developing 2DM

Pathogenesis 2DM?

3 factors are in the background of 2DM:

1. Insulin resistance - peripheral tissues' inability to react to insulin

2. Impaired insulin release from ß-cells

3. Increased hepatic glucose output

Insulin resistance?

Cells lose their sensitivity to insulin

- Every time a cell is exposed to insulin, the production of GLUT4 decreases a little

= Slightly more resistance

Insulin resistance also occurs through the PKB-decreased-signal-propagation

Insulin insensitivity vs 2DM?

Most obese people will develop some degree of insulin resistance, but diabetes only develop when the ß-cells cannot produce the extra amount of insulin that is needed to overcome the resistance

Obesity and its relation to diabetes type 2?

- Obesity leads to an increased mobilization of Free Fatty Acids

= Is associated with insulin resistance & ß-cell dysfunction

- Obesity is a chronic inflammatory condition

= Abundance of inflammatory cells & cytokines, may contribute to development of diabetes

PPAR-y and diabetes?

Is a nuclear receptor that

- Increases insulin sensitivity

- Decreases plasma glucose

WHEN ACTIVATED

Can be targeted in treatment of DM2

Three phases of pathogenesis of DM2?

1. Insulin resistance develops - insulin secretion increases to overcome the increased resistance

2. ß-cells eventually become exhausted & insulin secretion starts to decrease

3. Insulin secretion eventually becomes insufficient to overcome increased resistance

When does impaired fasting glucose develop?

Not until the 3rd phase og the pathogenesis

- OGTT is impaired already at the first stage

Treatment - diabetes type 2?

Lifestyle change like:

- Weight reduction

- Physical exercise

- Change of diet

If it does not work, oral antidiabetic drugs may be used

- Metformin (1st choice)

- Sulfonylureas (a-glucosidase inhibitor)

Metformin?

Increases peripheral insulin sensitivity

- Decreases hepatic gluconeogenesis

- Decreases intestinal glucose absorption