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To address insulin insufficiency, diabetes research has long focused on techniques for replacing insulin-producing β cells. Studies in mice have suggested that, under some conditions, a cells possess the capacity to transdifferentiate into β cells, although the mechanisms that drive this conversion are unclear. In this issue, Bramswig et al. analyzed the methylation states of purified human α, β, and acinar cells and found α cells exhibit intrinsic phenotypic plasticity associated with specific histone methylation profiles. In addition to expanding our understanding of this potential source of β cells, this compendium of carefully generated human gene expression and epigenomic data in islet cell subtypes constitutes a truly valuable resource for the field.
Introduction
The critical step that results in clinically manifested diabetes mellitus is loss (in type 1 diabetes due to autoimmune destruction) or deterioration (as in type 2 diabetes) of the functional pancreatic ß cell mass required to meet the body's demands for insulin. Understandably, a central goal in diabetes research has been to uncover strategies that could result in the replenishment of these cells. Whether the basic therapeutic approach might be to transplant replacement ß cells grown ex vivo or to induce new ß cell formation in vivo, an appropriate starting cell source must be identified and acceptable manipulations developed to produce normally functioning tissue.
While built on the extensive trove of knowledge of embryonic pancreatic islet development and the specific differentiation of ß cells, most approaches have relied on best-guess trial and error tactics. This applies to both the cell target and the intervention employed. Amazingly, a number of cell and tissue types have been successfully induced to express insulin and exhibit many ß cell characteristics (1) both in vitro (mouse and human embryonic stem cells, ref. 2) and in vivo (in mouse liver, refs. 3, 4; intestine, ref. 5; pancreatic exocrine, ref. 6; and glucagonproducing islet a cells, refs. 7-9). In mice, lineage tracing has confirmed that near total ablation of the ß cell population can induce transdifferentiation of a cells to a ß cell phenotype (7). This was a somewhat unexpected finding because an earlier lineage-tracing study showed that, during development, ß cells do not arise from glucagon-expressing progenitors (10). The a to ß phenotype switch can also be...