title: Glucose metabolism: key endogenous regulator of β-cell replication and survival.
abstract: 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.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Dadon
authors.forename: S
authors.initials: S
authors.lastname: Tornovsky-Babaey
authors.forename: J
authors.initials: J
authors.lastname: Furth-Lavi
authors.forename: D
authors.initials: D
authors.lastname: Ben-Zvi
authors.forename: O
authors.initials: O
authors.lastname: Ziv
authors.forename: R
authors.initials: R
authors.lastname: Schyr-Ben-Haroush
authors.forename: M
authors.initials: M
authors.lastname: Stolovich-Rain
authors.forename: A
authors.initials: A
authors.lastname: Hija
authors.forename: S
authors.initials: S
authors.lastname: Porat
authors.forename: Z
authors.initials: Z
authors.lastname: Granot
authors.forename: N
authors.initials: N
authors.lastname: Weinberg-Corem
authors.forename: Y
authors.initials: Y
authors.lastname: Dor
authors.forename: B
authors.initials: B
authors.lastname: Glaser
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006019:Glycolysis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels