The pancreatic β cell and type 1 diabetes: innocent bystander or active participant?

• T1DM is a multifactorial disease, with both environmental and polygenic risk factors leading to disease development.
• Genome-wide association studies (GWAS) have provided novel loci to consider in the pathogenesis of T1DM.
• >50% of T1DM GWAS loci are expressed in pancreatic β-cells, and are suggestive for a role of the β-cell in the pathogenesis of T1DM.
• The proteins encoded by T1DM loci may play critical roles in pancreatic β-cells, from recruitment and amplification of immune cell responses to reduced insulin secretion and regulation of cell survival.
• We hypothesize that the β-cell plays an active role in its own demise, rather than acting as an innocent bystander to autoimmune attack.

Type 1 diabetes mellitus (T1DM) is a chronic disease resulting from destruction of insulin-producing pancreatic β cells. Genetic and environmental factors contribute to T1DM onset. Use of high-throughput DNA sequencing has allowed geneticists to perform genome-wide association studies (GWAS) to identify novel gene loci associated with T1DM. Interestingly, >50% of these genes encode products that are expressed in β cells. These studies, coupled with emerging molecular evidence that β cells are impaired by gain-of-function or loss-of-function of these loci, suggest an active role for the β cell in eliciting its own demise. Although immune dysregulation plays a vital role in T1DM pathogenesis, understanding the mechanisms contributing to β cell failure may lead to new strategies to preserve or improve β cell function in patients with T1DM.