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 D Hitosugi, Yogish C Kudva, Aleksey V Matveyenko, Yasuhiro H Ikeda

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 1 2018

Fingerprint

Glucokinase
Nutrition
Medical problems
Diet
High Fat Diet
Glucose
Fats
Insulin
Gene transfer
KATP Channels
Glucose Intolerance
Depolarization
Islets of Langerhans
Inbred C57BL Mouse
Metabolism
Liver
Type 2 Diabetes Mellitus
Chemical activation
Fluxes
Membranes

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)

Cite this

Lu, B., Kurmi, K., Munoz-Gomez, M., Ambuludi, E. J. J., Tonne, J. M., Rakshit, K., ... Ikeda, Y. H. (2018). Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes. DMM Disease Models and Mechanisms, 11(6), [dmm.033316]. https://doi.org/10.1242/dmm.033316

Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes. / Lu, Brian; Kurmi, Kiran; Munoz-Gomez, Miguel; Ambuludi, Egon J.Jacobus; Tonne, Jason M.; Rakshit, Kuntol; Hitosugi, Taro D; Kudva, Yogish C; Matveyenko, Aleksey V; Ikeda, Yasuhiro H.

In: DMM Disease Models and Mechanisms, Vol. 11, No. 6, dmm.033316, 01.06.2018.

Research output: Contribution to journalArticle

Lu B, Kurmi K, Munoz-Gomez M, Ambuludi EJJ, Tonne JM, Rakshit K et al. Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes. DMM Disease Models and Mechanisms. 2018 Jun 1;11(6). dmm.033316. https://doi.org/10.1242/dmm.033316
Lu, Brian ; Kurmi, Kiran ; Munoz-Gomez, Miguel ; Ambuludi, Egon J.Jacobus ; Tonne, Jason M. ; Rakshit, Kuntol ; Hitosugi, Taro D ; Kudva, Yogish C ; Matveyenko, Aleksey V ; Ikeda, Yasuhiro H. / Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes. In: DMM Disease Models and Mechanisms. 2018 ; Vol. 11, No. 6.
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