Type 1 Diabetes Mellitus: Aetiology And Pathogenesis

T1DM is allied with the selective destruction of insulin-producing β-cells in the pancreas. The commencement of clinical disease signifies the end stage of β-cell destruction which leads to T1DM. There is marked heterogeneity of the pancreatic lesions, which makes it difficult to follow the pathogenesis of selective β-cell destruction within the islet in T1DM¹.

Following are the features which characterise T1DM as an autoimmune disease:

1. Presence of accessory and immuno-competent cells in the infiltrated pancreatic islets
2. Association of the predisposition to disease with the class II genes of the major histocompatibility complex
3. The existence of islet cell-specific autoantibodies
4. Alterations of T cell-mediated immunoregulation, in particular in CD4+T cell compartment
5. The contribution of TH1 cells producing interleukins and monokines in the disease process
6. Response to immunotherapy
7. The frequent occurrence of other organs specific autoimmune diseases in affected individuals or in their family members¹

Causes Of T1DM

1. Autoimmunity
2. Diet (high occurrence in siblings shows malpractice by parents)
3. Lifestyle (high occurrence in siblings shows malpractice by parents)
4. History of other autoimmune disorders
5. Environment² (location)
6. Genetic²
7. Viruses (enterovirus, rotavirus, rubella)²

Role Of Extracellular matrix (ECM) In T1DM

ECM is an important player in T1DM. In T1DM, it has abnormalities, particularly in the extended vascular-ductal pole adjacent to the actual islet. During fetal life and postnatal periods, the vascular-ductal pole is involved in the generation of islets³.

Myeloid cells (which degrade EMC) and macrophages start to accumulate at the vascular-ductal pole as the first sign of insulitis and to encircle the islet later at the islet edges. Myeloid cells and macrophages are involved in normal islet development and for sufficient numbers of insulin-producing cells³.

Autoantigens In T1DM

Two new autoantigens (β-cell proteins) for CD4T cells in T1D⁴:

• Chromogranin A (Chg A)
• Islet amyloid polypeptide (IAPP)

Targets For Preventive Strategies

1. T cells
2. Induction of tolerance to the β-cell proteins such as insulin that is inappropriately recognised (HIPs)
3. β-cell replacement²

Role Of Human Leukocyte Antigen In T1DM

T1D has an association with Human Leukocyte Antigen (HLA). The increase in T1D has been accompanied by a concomitant widening of the HLA risk profile. HLA on chromosome 6 is associated with T1D. This contributes to about half of the familial basis of T1D. There is a combination of HLA genes²:

1. DR₄-DQ₈ and DR₃-DQ₂
• Present in 90% of children with T1D
• Contributes to a greater risk of T1D and is most common in children in whom the disease develops very early in life
2. DR₁₅-DQ₆
• Found in less than 1% of children with T1D

First degree relatives of children with DR4-DQ8 and DR3-DQ2 are at greater risk of T1D than are the relatives of children in whom the disease develops later².

Protective Role Of Vitamin D In T1DM

Some epidemiologic observations support a protective role for vitamin D in T1D2.

• Maternal intake during pregnancy
• High doses of vitamin D supplements early in life

(Safety studies of vitamin D doses in pregnancy are required)

References

1. Ozougwu JC, Obimba KC, et al. The Pathogenesis and Pathophysiology of Type 1 and type 2 Diabetes Mellitus. Journal of Physiology and Pathophysiology. 2013.
2. Kathleen M. Gillespie. Type 1 diabetes: Pathogenesis and prevention.
3. Hemmo A. Drexhage, Wim A. Dik, Pieter J. M. Leenen, Marjan A. Versuel. The Immune Pathogenesis of Type 1 Diabetes: Not Only Thinking Outside the Cell but Also Outside the Islet and Out of the Box. Diabetes. 2016;65: 2130-2133. Doi: 10.2337/dbi16-0030. (Alma’s paper).
4. . Thomas Delong, Timothy A. Wiles et al. Pathogenic CD4T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351(6274).