Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes

Brian Lu, Kiran Kurmi, Miguel Munoz-Gomez, Egon J.Jacobus Ambuludi, Jason M. Tonne, Kuntol Rakshit, Taro Hitosugi, Yogish C. Kudva, Aleksey V. Matveyenko, Yasuhiro Ikeda

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear. Here, we employed a β-cell-targeted gene transfer vector and determined the impact of β-cell-specific increase in GCK expression on β-cell function and glucose handling in vitro and in vivo. Overexpression of GCK enhanced glycolytic flux, ATP-sensitive potassium channel activation and membrane depolarization, and increased proliferation in Min6 cells. β-cell-targeted GCK transduction did not change glucose handling in chow-fed C57BL/6 mice. Although adult mice fed a HFD showed reduced islet GCK expression, impaired glucose tolerance and decreased glucose-stimulated insulin secretion (GSIS), β-celltargeted GCK transduction improved glucose tolerance and restored GSIS. Islet perifusion experiments verified restored GSIS in isolated HFD islets by GCK transduction. Thus, our data identify impaired β-cell GCK expression as an underlying mechanism for dysregulated β-cell function and glycemic control in HFD-induced diabetes. Our data also imply an etiological role of GCK in diet-induced diabetes.

Original languageEnglish (US)
Article numberdmm.033316
JournalDMM Disease Models and Mechanisms
Volume11
Issue number6
DOIs
StatePublished - Jun 2018

Keywords

  • Diet-induced diabetes
  • Gene therapy
  • Glucokinase
  • Insulin secretion
  • Islet biology

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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