Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia

Judith Furth-Lavi, Ayat Hija, Sharona Tornovsky-Babeay, Adi Mazouz, Tehila Dahan, Miri Stolovich-Rain, Agnes Klochendler, Yuval Dor*, Dana Avrahami*, Benjamin Glaser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Diabetogenic ablation of beta cells in mice triggers a regenerative response whereby surviving beta cells proliferate and euglycemia is regained. Here, we identify and characterize heterogeneity in response to beta cell ablation. Efficient beta cell elimination leading to severe hyperglycemia (>28 mmol/L), causes permanent diabetes with failed regeneration despite cell cycle engagement of surviving beta cells. Strikingly, correction of glycemia via insulin, SGLT2 inhibition, or a ketogenic diet for about 3 weeks allows partial regeneration of beta cell mass and recovery from diabetes, demonstrating regenerative potential masked by extreme glucotoxicity. We identify gene expression changes in beta cells exposed to extremely high glucose levels, pointing to metabolic stress and downregulation of key cell cycle genes, suggesting failure of cell cycle completion. These findings reconcile conflicting data on the impact of glucose on beta cell regeneration and identify a glucose threshold converting glycemic load from pro-regenerative to anti-regenerative.

Original languageAmerican English
Article number111719
JournalCell Reports
Volume41
Issue number9
DOIs
StatePublished - 29 Nov 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • CP: Metabolism
  • beta cells
  • cell cycle
  • diabetes
  • glucose toxicity
  • hyperglycemia
  • ketogenic diet
  • regeneration
  • sglt2 inhibitor

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