Pathogenesis of type 1 diabetes: lessons from natural history studies of high-risk individuals

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by known genetic risk factors with T cell-mediated infiltration and destruction of the beta cells within pancreatic islets. Autoantibodies are the most significant preclinical marker of T1D, and birth cohort studies have provided important insights into the natural history of autoimmunity and T1D. While HLA remains the strongest genetic risk factor, a number of novel gene variants associated with T1D have been found through genome-wide studies, some of which have been linked to suspected environmental risk factors. Multiple environmental factors that have been suggested to play a role in the development of T1D await confirmation. Current risk-stratification models for T1D take into account genetic risk factors and autoantibodies. In the future, metabolic profiles, epigenetics, as well as environmental risk factors may be included in such models.

Figure 1

Cumulative incidence of persistent islet autoimmunity in siblings or offspring of a person with T1D. The above figure represents the cumulative incidence of persistent islet autoimmunity among siblings (sib) or offspring (off) of individuals with T1D in the DAISY cohort. The high-risk group consists of those with the genotype HLA-DR3/4,DQB1* 0302, the moderate-risk with HLA-DR3/3 or DR4/4,DQB1*0302 or DR1,DQB1*0101/4,DQB1*0302, or DR8, DQB1*0402/4, DQB1*0302, DR4,DQB1*302/DR9,DQB1*303 genotypes, and the low-risk with all other genotypes. Below the figure is the number of subjects in each group at each age.