Endocrine Abstracts

Pancreatic β cell dysfunction and death are central in the pathogenesis of type 2 diabetes but the underlying mechanisms are not well understood. Genetic factors predispose to type 2 diabetes but, despite very large scale genome-wide association studies, the heritability of the disease remains largely unexplained. Environmental and lifestyle factors contribute to the pathogenesis of type 2 diabetes and likely explain its rapidly increasing prevalence. Elevated levels of saturated free fatty acids may cause β cell failure in insulin resistant individuals, and our work aims to clarify the molecular mechanisms involved. Epigenetic changes are an additional link for translating environmental exposures into heritable disease mechanisms. Human β cells are long-lived, and have a lifetime to acquire epigenetic alterations.

We have performed the first comprehensive DNA methylation profiling in human islets from type 2 diabetic and non-diabetic donors, identifying differential DNA methylation in genes in pathways affecting β cell function and survival. In parallel, we are mapping the human islet transcriptome by RNA-sequencing, under control condition or following exposure to the saturated fatty acid palmitate. Palmitate modified transcripts related to the endoplasmic reticulum stress response, ubiquitin and proteasome function, autophagy and apoptosis. Several transcription factors controlling β cell phenotype were inhibited by palmitate. In addition, palmitate caused a shift in alternative splicing, pointing to novel mechanisms of palmitate-induced β cell dysfunction and death.

These omic approaches will offer new insights into the pathogenesis of diabetes. A better understanding of the epigenetic dysregulation in type 2 diabetic islets and the mapping of the human islet transcriptome will advance our understanding of disease etiology.