Biphasic dynamics of beta cell mass in a mouse model of congenital hyperinsulinism: implications for type 2 diabetes

Sharona Tornovsky-Babeay, Noa Weinberg-Corem, Rachel Ben-Haroush Schyr, Dana Avrahami, Judith Lavi, Eseye Feleke, Klaus H. Kaestner, Yuval Dor*, Benjamin Glaser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Aims/hypothesis: Acute hyperglycaemia stimulates pancreatic beta cell proliferation in the mouse whereas chronic hyperglycaemia appears to be toxic. We hypothesise that this toxic effect is mediated by increased beta cell workload, unrelated to hyperglycaemia per se. Methods: To test this hypothesis, we developed a novel mouse model of cell-autonomous increased beta cell glycolytic flux caused by a conditional heterozygous beta cell-specific mutation that activates glucokinase (GCK), mimicking key aspects of the rare human genetic disease GCK-congenital hyperinsulinism. Results: In the mutant mice, we observed random and fasting hypoglycaemia (random 4.5–5.4 mmol/l and fasting 3.6 mmol/l) that persisted for 15 months. GCK activation led to increased beta cell proliferation as measured by Ki67 expression (2.7% vs 1.5%, mutant and wild-type (WT), respectively, p < 0.01) that resulted in a 62% increase in beta cell mass in young mice. However, by 8 months of age, mutant mice developed impaired glucose tolerance, which was associated with decreased absolute beta cell mass from 2.9 mg at 1.5 months to 1.8 mg at 8 months of age, with preservation of individual beta cell function. Impaired glucose tolerance was further exacerbated by a high-fat/high-sucrose diet (AUC 1796 vs 966 mmol/l × min, mutant and WT, respectively, p < 0.05). Activation of GCK was associated with an increased DNA damage response and an elevated expression of Chop, suggesting metabolic stress as a contributor to beta cell death. Conclusions/interpretation: We propose that increased workload-driven biphasic beta cell dynamics contribute to decreased beta cell function observed in long-standing congenital hyperinsulinism and type 2 diabetes. Graphical abstract: [Figure not available: see fulltext.]

Original languageAmerican English
Pages (from-to)1133-1143
Number of pages11
JournalDiabetologia
Volume64
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Keywords

  • Beta cell
  • Glucokinase
  • Glucose intolerance
  • Glucotoxicity
  • Hyperglycaemia
  • Hypoglycaemia
  • Insulin secretion
  • Mouse model
  • Type 2 diabetes

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