Repair of diverse diabetic defects of β-cells in man and mouse by pharmacological glucokinase activation

Nicolai M. Doliba, Deborah Fenner, Bogumil Zelent, Joseph Bass, Ramakanth Sarabu, Franz M. Matschinsky*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations

Abstract

Glucokinase activators (GKAs) are being developed and clinically tested for potential antidiabetic therapy. The potential benefits and limitations of this approach continue to be intensively debated. To contribute to the understanding of experimental pharmacology and therapeutics of GKAs, we have tested the efficacy of one of these agents (Piragliatin) in isolated islets from humans with type 2 diabetes mellitus (T2DM), from mice with glucokinase (GK) mutations induced by ethyl-nitroso-urea (ENU) as models of Maturity Onset Diabetes of the Young linked to GK and Permanent Neonatal Diabetes Mellitus linked to GK (PNDM-GK) and finally of islets rendered glucose insensitive by treatment with the sulphonyl urea compound glyburide in organ culture. We found that the GKA repaired the defect in all three instances as manifest in increased glucose-induced insulin release and elevated intracellular calcium responses. The results show the remarkable fact that acute pharmacological activation of GK reverses secretion defects of β-cells caused by molecular mechanism that differ vastly in nature, including the little understood multifactorial lesion of β-cells in T2DM of man, the complex GK mutations in mice resembling GK disease and acute sulphonylurea failure of mouse β-cells in tissue culture. The implications of these results are to be discussed on the theoretical basis underpinning the strategy of developing these drugs and in light of recent results of clinical trials with GKAs that failed for little understood reasons.

Original languageEnglish (US)
Pages (from-to)109-119
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume14
Issue numberSUPPL.3
DOIs
StatePublished - Oct 2012

Keywords

  • Diabetes therapy
  • Glucokinase
  • Glucokinase activators
  • β-cells

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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