Glucose metabolism: Key endogenous regulator of β-cell replication and survival

D. Dadon, S. Tornovsky-Babaey, J. Furth-Lavi, D. Ben-Zvi, O. Ziv, R. Schyr-Ben-Haroush, M. Stolovich-Rain, A. Hija, S. Porat, Z. Granot, N. Weinberg-Corem, Y. Dor, B. Glaser*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

32 Scopus citations

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.

Original languageAmerican English
Pages (from-to)101-108
Number of pages8
JournalDiabetes, Obesity and Metabolism
Volume14
Issue numberSUPPL.3
DOIs
StatePublished - Oct 2012

Keywords

  • Activating mutations
  • Diabetes
  • Glucokinase
  • Glucokinase activators
  • Glucose metabolism
  • Glucotoxicity
  • β-cell regeneration
  • β-cell replication

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