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Review
. 2017 Mar 29:8:35.
doi: 10.3389/fgene.2017.00035. eCollection 2017.

Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

Chad S Hunter  1 , Roland W Stein  2
Affiliations
Review

Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

Chad S Hunter et al. Front Genet. .

Abstract

The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-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 β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-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" β-cells. These results not only suggest that these β-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 β-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention.

Keywords: dedifferentiation; diabetes mellitus; epigenetics; islets of Langerhans; trans-differentiation; transcription factors; type 2; β-cell.

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Figures

Figure 1
Figure 1
Model depicting both endocrine progenitor differentiation into a heterogeneous population of β-cells within human islets, and potential pathways of cell inactivation recently described in T2D. Inactivation likely involves mechanisms that result in loss/reduction β-cell identity marker expression (e.g., MafA, Nkx6.1, Pdx1, insulin) as well induction of cell failure signatures (e.g., ALDH1A3; Kim-Muller et al., 2016). β1–4 cells represent at least some of the functionally distinct β-cell populations in human islets, with our model suggesting that failing T2D islets will be composed of several (e.g., β3 and β4; Dorrell et al., 2016). In addition, there is evidence in (at least) mouse islets that failing β-cells can de-differentiate to progenitor-like cells expressing Ngn3, Nanog, L-Myc, and Oct4 (Talchai et al., 2012).
Figure 2
Figure 2
Schematic illustrating the possible outcomes on human insulin-positive cell production during islet (e.g., α- or δ-cell; Thorel et al., ; Chera et al., 2014) and ES/iPS cell differentiation (Pagliuca et al., ; Rezania et al., 2014). Extensive characterization needs to be performed on these newly-generated insulin-producing cells to determine their functional and molecular characteristics in relation to existing human islet β-cell populations.
See this image and copyright information in PMC

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