Pancreatic β‐cell identity in diabetes

Abstract

Recovery of functional β-cell mass continues to be an ongoing challenge in treating diabetes. Initial work studying β-cells suggested apoptotic β-cell death as a main contributor for the loss of β-cell mass in diabetes. Restoration of β-cells either by transplant or stimulating proliferation of remaining β-cells or precursors would then logically be a viable therapeutic option for diabetes. However, recent work has highlighted the inherent β-cell plasticity and the critical role of loss of β-cell identity in diabetes, and has suggested that β-cells fail to maintain a fully differentiated glucose-responsive and drug-responsive state, particularly in diabetic individuals with poorly-controlled, long-lasting periods of hyperglycemia. Understanding the underlying mechanisms of loss of β-cell identity and conversion in other cell types, as well as how to regain their mature differentiated functional state, is critical to develop novel therapeutic strategies to prevent or reverse these processes. In this review, we discuss the role of plasticity and loss of β-cell identity in diabetes, the current understanding of mechanisms involved in altering this mature functional β-cell state, and potential progresses to identify novel therapeutic targets providing better opportunities for slowing or preventing diabetes progression.

Comprehensive analysis of body composition and insulin traits associated with intra‐pancreatic fat deposition in healthy individuals and people with new‐onset prediabetes/diabetes after acute pancreatitis

“…Future studies are warranted to investigate whether the inter-relationship between IFD and insulin sensitivity is an epiphenomenon or a driving force for altered insulin traits in relation to subsequent NODAP. [20][21][22] The present study has several limitations. First, the crosssectional nature of the study did not allow inference of causality.…”

“…The finding of higher IFD in participants with NODAP and an inverse association between IFD and insulin sensitivity suggest that IFD might be involved in the pathogenesis of NODAP (Appendix S1 and Figure S2) and associated metabolic abnormalities. Future studies are warranted to investigate whether the inter‐relationship between IFD and insulin sensitivity is an epiphenomenon or a driving force for altered insulin traits in relation to subsequent NODAP …”

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“…β-cell regeneration presumably through β-cell neogenesis but not replication. However, the exact mechanism of the others islet cells contribute to this phenomenon is not completely understood [29]. Glucose is the main mediator for the replication process of pancreatic β-cells.…”

β Cells led astray by transcription factors and the company they keep

“…β Cell plasticity A growing body of evidence from studies in mice and humans indicates that dedifferentiation or partial transdifferentiation/reprogramming of β cells into alternate endocrine cell fates can alter glucose homeostasis (1)(2)(3)(4)(5). β Cell dedifferentiation is generally characterized by the loss of insulin content and gene expression, as well as decreased expression of genes encoding β cell-specific transcription factors (TFs), such as NK6 homeobox 1 (NKX6.1), pancreatic and duodenal homeobox 1 (PDX1), forkhead box protein O1 (FOXO1), neuronal differentiation 1 (NEUROD1), and MAF bZIP transcription factor A (MAFA) (6), and reactivation of endocrine progenitor cell markers such as neurogenin 3 (NGN3) (4,7).…”

“…β Cell dedifferentiation is generally characterized by the loss of insulin content and gene expression, as well as decreased expression of genes encoding β cell-specific transcription factors (TFs), such as NK6 homeobox 1 (NKX6.1), pancreatic and duodenal homeobox 1 (PDX1), forkhead box protein O1 (FOXO1), neuronal differentiation 1 (NEUROD1), and MAF bZIP transcription factor A (MAFA) (6), and reactivation of endocrine progenitor cell markers such as neurogenin 3 (NGN3) (4,7). Similarly, adult β cells can also become transdifferentiated or partially reprogrammed to adopt alternate islet cell properties, such as the capacity for glucagon and/or somatostatin production, accompanied by defects in the expression or regulation of β cell TFs as well (4,5). An understanding of the mechanisms that drive β cell dedifferentiation and partial transdifferentiation into α, pancreatic polypeptide (PP), or δ cell fates in response to various insults is only beginning to emerge.…”