36. Etiology and pathogenesis of 1DM

Basic mechanism behind 1DM?

Destruction of pancreatic ß-cells

- The exact cause of destruction is unknown, but:

• Genetic factors

• Environmental factors

Other endocrine functions of the pancreas are usually maintained

Genetic factors 1DM?

Concordance between identical twins = 40%

- Between parent and child: 5%

= Indicates that genetic factors play a minor role

HLA-DR3 and DR4 are strongly associated w/ DM1

- More than 90% of 1DM patients have HLA haplotype

Environmental factors DM1?

The specific environmental factors that trigger the autoimmunity in 1DM are not well known

CMV & Coxsackie are likely factors, as well as toxic chemicals

What other autoimmune disorders are DM1 associated with?

- Hashimoto

- Celiac disease

- Primary adrenal insufficiency

Pathogenesis 1DM?

The low concordance indicates that environmental factors are essential for the development of the disease

= They can alter structure o MHCII -> which encodes for HLA

Causing immune system to recognize the cells as foreign -> autoimmunity

The immune response in 1DM?

Involves both cellular and humoral mechanisms

- Cytotoxic T-cells

- Antibodies

Causes inflammation of the Langerhans islets (insulitis)

Insulitis?

Will damage the cells of the Langerhans islets

- The cell damage may transform them into neo-antigens, which can cause a "secondary" autoimmune response against the same cells

Molecular mimicry - DM1?

Where pathogen antigens are very similar to the self-antigens

- This may occur in Coxsackie infections

When does clinical symptoms occur in 1DM?

When 90% of ß-cells are destroyed

- Impaired OGTT may develop earlier than impaired Fasting glucose

= After this point: symptoms of DM develop quickly

(The a-cells are normal)

What antibodies may be found in the plasma before manifestation of 1DM?

- Islet cell cytoplasmic antibodies - against the cytoplasm of ß-cells

- Islet cell surface antibodies - against the surface of ß-cells

- Glutamic acid decarboxylase antibodies - against an enzyme in ß-cells

- Insulin antibodies - against insulin itself

Treatment 1DM?

Insulin

- To prevent hypogylcemia, the amount if insulin applied depends on the physical activity and carbohydrate intake

= Can be difficult to manage

Insulin should be given before meals