Informing beta-cell regeneration strategies using studies of heterogeneity

BACKGROUND: Current therapeutic strategies for type 1 (T1DM) and type 2 diabetes mellitus (T2DM) rely on increasing or substituting endogenous insulin secretion in combination with lifestyle changes. beta-cell regeneration, a process whereby new beta-cells arise from progenitors, self-renewal or transdifferentiation, has the potential to become a viable route to insulin self-sufficiency. Current regeneration strategies capture many of the transcriptomic and protein features of native beta-cells, generating cells capable of glucose-dependent insulin secretion in vitro and alleviation of hyperglycemia in vivo. However, whether novel beta-cells display appreciable heterogeneity remains poorly understood, with potential consequences for long-term functional robustness. SCOPE OF REVIEW: The review brings together crucial discoveries in the beta-cell regeneration field with state-of-the-art knowledge regarding beta-cell heterogeneity. Aspects that might aid production of longer-lasting and more plastic regenerated beta-cells are highlighted and discussed. MAJOR CONCLUSIONS: Different beta-cell regeneration approaches result in a similar outcome: glucose-sensitive, insulin-positive cells that mimic the native beta-cell phenotype but which lack normal plasticity. The beta-cell subpopulations identified to date expand our understanding of beta-cell survival, proliferation and function, signposting the direction for future regeneration strategies. Therefore, regenerated beta-cells should exhibit stimulus-dependent differences in gene and protein expression, as well as establish a functional network with different beta-cells, all while coexisting with other cell types on a three-dimensional platform.