Impact of genetic and non‐genetic factors in type 1 diabetes

Abstract

Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.

TLR Activation Synergizes with Kilham Rat Virus Infection to Induce Diabetes in BBDR Rats

“…Type 1 diabetes in humans is hypothesized to result from nongenetic environmental factors (e.g., virus) operating in a genetically susceptible host (74,75), but the nature of that genetic susceptibility, apart from MHC haplotype, is poorly understood. The present data suggest that genetically determined differences in innate immunity may be important.…”

LEW.1WR1 Rats Develop Autoimmune Diabetes Spontaneously and in Response to Environmental Perturbation

“…In their aggregate, the characteristics of the LEW.1WR1 rat suggest that it will be useful as a model system in which to test the hypothesis that human type 1 diabetes is caused by nongenetic environmental factors operating in a genetically susceptible host to initiate a destructive immune process (8,9). The LEW.1WR1 and other newer rat models of autoimmune diabetes suggest a promising "environmental genetics" approach to modeling human type 1A diabetes.…”

“…Unfortunately, type 1A diabetes remains refractory to prevention (4 -6) by methods other than immunosuppression (7). This refractoriness may in part result from the possibility that type 1 diabetes is caused by nongenetic environmental factors operating in a genetically susceptible host (8,9). The disease may therefore be due to interaction with the environment of alleles at many loci (10).…”

Association of TNF-α and PTPN22 SNPs with the risk and clinical outcome of type 1 diabetes

“…During T1DM pathogenesis macrophages and lymphocytes infiltrate the islets. Thereby, the intensity of the β-cell destructive process is modulated by the interaction of a large number of susceptibility genes and both known (nutritional factors and viral infection) and unknown environmental factors [1].…”