Genetic Determination and Immunopathogenesis of Type 1 Diabetes Mellitus in Humans

Abstract

A b s t r a c t Type 1 diabetes comprises autoimmune-mediated and idiopathic beta-cell destruction of the pancreatic islets of Langerhans¢ resulting to absolute insulin deficiency. Susceptibility to T1D is influenced by both genetic and environmental factors. It is generally believed that environmental agents, such as viral infections, dietary factors in early infancy or climatic influences, trigger disease development in genetically susceptible individuals. Many candidate regions for diabetes genes have been reported, the insulin, glutamic acid 65, insuloma associated antigen 2, and zinc transporter ZnT8 genes being among the most important. The destruction of b cells is mediated mainly by cellular mechanisms; antibodies seem to reflect the ongoing autoimmune process only, not being directly involved in tissue damage. They, however, appear prior to the onset of insulin deficiency what makes us to profit from in prevention of the disease.

Enfermedades autoinmunitarias asociadas a diabetes mellitus tipo 1A

“…Finalmente, algunas regiones que pueden predisponer a DM1A son IDDM4 que codifica para FADD (Fas-associated death domain containing protein) involucrada en apoptosis, IDDM7 involucrada en la morfogénesis de las células b e IDDM13 que codifica una proteína de resistencia bacteriana en los macrófagos 16,17 . A pesar del amplio conocimiento que se tiene de los factores implicados en la susceptibilidad genética, ésta es insuficiente para explicar la patogénesis de la enfermedad.…”

“…Hasta 40% de los individuos con DM1A son portadores de la combinación de haplotipos DQA1*0501-DQB1*0201 (DQ2), usualmente heredado junto con DRB1*0301 (DR3) y DQA1*0301-DQB1*0302 (DQ8) que se hereda junto con DRB1*0401 o DRB1*0402 (DR4). Por otra parte, se ha encontrado que el haplotipo DQA1*0102/DQB1*0602/DRB1*1501 confiere protección 15,16 . Otro gen implicado es el de la insulina, el cual está codificado en el cromosoma 11p15.5.…”

Concise review: Hematopoietic stem cell transplantation to treat insulin-dependent diabetes mellitus

“…In addition IDDM1 and IDDM2, there are many other genes related to susceptibility to T1D; these include cytotoxic T-lymphocyte antigen-4 (IDDM12), protein tyrosine phosphatase non-receptor type 22 (PTPN22), the gene encoding the alpha chain of the IL-2 receptor, and so on (Kantarova and Buc, 2007). Although patients have autoantibodies against islet antigens, it may take several months to several years for hyperglycemia to occur (van Belle et al, 2011).…”

“…The IDDM2 locus is the insulin gene region on chromosome 11. It is a variable number of tandem repeat (VNTR) polymorphisms that account for the high risk of T1D (Kantarova and Buc, 2007).…”

The Relationship between insulin variable number of tandem repeats (INS-VNTR) -23 A/T and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) +49 A/G polymorphisms with islet autoantibodies in persons with diabetes

“…In the endoplasmic reticulum, the molecule contains alanine at position 17 is abnormally glycosylated that leads to moving backwards of the molecules into the cytoplasm for degradation. This finally results in low amount of CTLA-4 (molecule contains alanine at position 17) at the cell surface and reduce the inhibitory function of CTLA-4 reported in patients with +49G allele (9,10).…”