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Glucose metabolism: key endogenous regulator of β‐cell replication and survival

Recent studies in mice have shown that pancreatic β‐cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β‐cell regeneration is based on the replication of fully differentiated, insulin‐positive β‐cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β‐cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β‐cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β‐cells, and through a signalling cascade that resembles the pathway for glucose‐stimulated insulin secretion. We introduce the concept that the individual β‐cell workload, defined as the amount of insulin that an individual β‐cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell‐autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β‐cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β‐cells may allow for the development of effective regenerative therapies for diabetes.