43. Etiology and pathogenesis of 1DM

Etiology

The basic mechanism behind 1DM is a destruction of pancreatic β-cells. The other endocrine functions of the pancreas are usually maintained. The exact cause of the destruction isn’t completely understood. There are both genetic and environmental factors.

Genetic factors: Concordance between identical twins is only 40% and between parent and child only 5%. This indicates that genetic factors play only a minor role. Certain types of HLA, especially HLA-DR3 and HLA-DR4 are strongly associated with the development of 1DM. These genes are located on chromosome 6. More than 90% of 1DM patients have a characteristic HLA haplotype.

Environmental factors: The specific environmental factors that trigger the autoimmunity in 1DM are not well known. However, viral infections like CMV and Coxsackie are likely factors. Toxic chemicals may be other factors.

1DM is associated with other autoimmune diseases, like Hashimoto thyroiditis, coeliac disease, primary adrenal insufficiency and others.

Pathogenesis

The relatively low concordance of 1DM indicates that an environmental factor is essential for the development of the disease. Environmental factors can alter the structure of the MHC II molecule, which is encoded by HLA genes. This alteration causes the immune system to recognize the cells as foreign, causing autoimmunity. The immune response involves both cellular and humoral mechanisms, including cytotoxic T-cells and antibodies. This causes inflammation of the Langerhans islets, which is called insulitis (from insula, not insulin).

The insulitis will damage the cells of the Langerhans islets. This cell damage may transform them into neoantigens, which may cause a “secondary” autoimmune response against the same cells.

Molecular mimicry, where pathogen antigens are very similar in structure to self-antigens, may be involved in Coxsackie infections. Antibodies produced against these pathogen antigens also bind to self-antigens due to their similar structure.

Manifest clinical symptoms appear when 90% of β-cells are destroyed. Impaired glucose tolerance may develop earlier and develops earlier than impaired fasting glucose. After this point the symptoms of DM develop quickly. The mass of α-cells is normal.

Certain characteristic antibodies may be found in the plasma even before the manifestation of 1DM. These are:

  • Islet cell cytoplasmic antibodies – against the cytoplasm of β-cells
  • Islet cell surface antibodies – against the surface of β-cells
  • Glutamic acid decarboxylase antibodies – against an enzyme in β-cells
  • Insulin antibodies – against insulin itself
Treatment

The treatment of 1DM is the regular application of insulin. The problem with this is that to prevent hypoglycaemia the amount of insulin to be applied depends to the physical activity and carbohydrate intake, which can be difficult to manage. Extra insulin should be applied before meals. The easiest solution to this is to use an automated insulin pump.


Previous page:
42. General pathobiochemistry of diabetes mellitus syndrome

Next page:
44. Etiology and pathogenesis of 2DM

Leave a Reply

Only the "Comment" field must be filled in. It is not compulsory to fill out your name; you can remain anonymous. Do not fill out e-mail or website; if you do, your comment will not be published.