期刊
FRONTIERS IN GENETICS
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2017.00035
关键词
diabetes mellitus; type 2; beta-cell; dedifferentiation; trans-differentiation; epigenetics; transcription factors; islets of Langerhans
资金
- National Institute of Diabetes and Digestive Kidney Diseases [K01DK094842, R01DK050203, R01DK090570]
- American Diabetes Association [1-16-JDF-044]
The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet beta-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated beta-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, beta-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of beta-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e.g., insulin and transcription factors like MAFA, PDX1, and NKX6.1), as well as (2) de-differentiation, defined by regression to a progenitor or stem cell-like state. New technologies have allowed the field to compare islet cell characteristics from normal human donors to those under pathophysiological conditions by single cell RNA-Sequencing and through epigenetic analysis. This has revealed a remarkable level of heterogeneity among histologically defined insulin-positive beta-cells. These results not only suggest that these beta-cell subsets have different responses to insulin secretagogues, but that defining their unique gene expression and epigenetic modification profiles will offer opportunities to develop cellular therapeutics to enrich/maintain certain subsets for correcting pathological glucose levels. In this review, we will summarize the recent literature describing how beta-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention.
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