Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass

Abstract

In all forms of diabetes, β cell mass or function is reduced and therefore the capacity of the pancreatic cells for regeneration or replenishment is a critical need. Diverse lines of research have shown the capacity of endocrine as well as acinar, ductal and centroacinar cells to generate new β cells. Several experimental approaches using injury models, pharmacological or genetic interventions, isolation and in vitro expansion of putative progenitors followed by transplantations or a combination thereof have suggested several pathways for β cell neogenesis or regeneration. The experimental results have also generated controversy related to the limitations and interpretation of the experimental approaches and ultimately their physiological relevance, particularly when considering differences between mouse, the primary animal model, and human. As a result, consensus is lacking regarding the relative importance of islet cell proliferation or progenitor differentiation and transdifferentiation of other pancreatic cell types in generating new β cells. In this review we summarize and evaluate recent experimental approaches and findings related to islet regeneration and address their relevance and potential clinical application in the fight against diabetes.

Dysregulated insulin secretion is associated with pancreatic β‐cell hyperplasia and direct acinar‐β‐cell trans‐differentiation in partially eNOS ‐deficient mice

“…The occurrence of β‐cell hyperplasia and acinar‐to‐β‐cell conversion in association with the eNOS+/− genotype prompted us to presume that a common mechanism might be responsible for such concomitant change hypothetically concurring to increase the pancreatic potential for insulin production, even though the functional relevance of the transdifferentiation process is currently debated (Spears et al, 2021 ). On the basis of a number of studies aiming at identifying putative factors involved in β‐cell endogenous regeneration (Aguayo‐Mazzucato & Bonner‐Weir, 2018 ), we envisaged the possible involvement of Notch pathway in the eNOS+/− mouse model.…”

Evaluation of the Effects of Harmine on β-cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis

“…Most studies investigating b-cell proliferation have been performed in rodent models, leading to greater knowledge of the signaling pathways controlling b-cell replication in mice than in humans (19). Human and rodent islets, however, not only exhibit intrinsic differences in structure, composition, and function, but also in proliferative capacity (20)(21)(22). While rodent b-cells follow similar development-and age-related trends as in humans, rodent b-cells have much higher proliferative rates (10-30% neonatally and 1% in adulthood) (22)(23)(24).…”

“…Human and rodent islets, however, not only exhibit intrinsic differences in structure, composition, and function, but also in proliferative capacity (20)(21)(22). While rodent b-cells follow similar development-and age-related trends as in humans, rodent b-cells have much higher proliferative rates (10-30% neonatally and 1% in adulthood) (22)(23)(24). Intriguingly, during periods of high metabolic demand in adulthood, including pregnancy and obesity, b-cell mass increases significantly in both rodents and humans.…”

“…Intriguingly, during periods of high metabolic demand in adulthood, including pregnancy and obesity, b-cell mass increases significantly in both rodents and humans. While rodent studies point to a mechanism of increased b-cell proliferation (25,26), robust data demonstrating increased proliferation rather than neogenesis in humans during pregnancy or obesity is still lacking (27,28), and the precise contribution of proliferation remains controversial (22,(29)(30)(31). As a further illustration, human islets transplanted into mice fed a high-fat diet do not proliferate whereas endogenous mouse islets do (22,31).…”

“…While rodent studies point to a mechanism of increased b-cell proliferation (25,26), robust data demonstrating increased proliferation rather than neogenesis in humans during pregnancy or obesity is still lacking (27,28), and the precise contribution of proliferation remains controversial (22,(29)(30)(31). As a further illustration, human islets transplanted into mice fed a high-fat diet do not proliferate whereas endogenous mouse islets do (22,31). These examples highlight potential fundamental differences in b-cell proliferative capacity between rodents and humans and emphasize the need to focus on human islets for the study of b-cell proliferation.…”