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

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.

The TFIID subunit Taf4 is required for pancreatic beta cell function and identity

“…Furthermore, the number of Taf4-expressing BCs did not increase between 34 and 55 weeks arguing against proliferation of non-recombined BCs. Alternatively, Taf4-expressing BCs may arise from trans-differentiation of alpha cells or other islet populations into BCs as has been previously described, for example under conditions of reduced BC-mass [30][31][32][33] , one of the consequences of Taf4 inactivation. Notwithstanding the mechanisms involved, these data showed that despite reduced BC mass through increased apoptosis and an ensuing elevated glycaemia, the BC population was only partially and slowly replaced by newly generated BCs.…”

“…The molecular mechanisms involved particularly at the transcriptional level are however not fully understood 30,32,[45][46][47] . In type 2 diabetes, hyperglycaemia seems to induce BC dedifferentiation with diminished expression BC function genes and key BC transcription factors, but expression of BC forbidden genes and it may involve reversion to a Ngn3-expressing precursor state as a prerequisite to trans-differentiation to alpha or delta cells 33,40,48 . BC transdifferentiation upon loss of Taf4 occurred rapidly in absence of chronic hyperglycaemia and was characterized by loss of BC markers, but not by up-regulated expression of forbidden genes and it did not require passage via a progenitor state.…”

Na dobre i na złe – czyli rola oddziaływania trzustki, śródbłonka i tkanki tłuszczowej w regulacji funkcjonowania komórek β i rozwoju cukrzycy typu 2 związanej z otyłością

“…Pancreatic islets are metabolically limited in their ability to store lipids. The possible mechanisms of irreversible β-cell demise in the setting of T2D progression involve interactions among many branches of cellular metabolism, including inflammation, severe endoplasmic reticulum (ER) and oxidative stress, de novo ceramide synthesis, mitochondrial injury, compromised autophagy, epigenetic changes, β-cell de-differentiation, and loss of β-cell identity [29,30]. Increases in circulating plasma levels of FAs and disturbances in lipid homeostasis emphasize the importance of free FAs during β-cell adaptation and the metabolic control of diabetes [29].…”

Epigenetyczna regulacja ekspresji genów – nowy mechanizm łączący otyłość z rozwojem cukrzycy typu 2

“…The most plausible mechanism to explain the effects of gluco-and lipotoxicity on pancreatic islet decompensation in T2D is massive β-cell death. However, recent genetic and epigenetic studies indicate that both β-cell demise and the loss of pancreatic endocrine cell identities may be major causes of the development of obesity-related T2D [26][27]. Alterations of cell proliferation, survival, transdifferentiation, dedifferentiation, or migration that are related to remodeled cell-cell contacts may result in the reorganization of pancreatic islet microarchitecture.…”