Glycogen Phosphorylase Inhibitor N-(3,5-Dimethyl-Benzoyl)-N'-(β-D-Glucopyranosyl)Urea Improves Glucose Tolerance under Normoglycemic and Diabetic Conditions and Rearranges Hepatic Metabolism

Lilla Nagy, Tibor Docsa, Magdolna Szántó, Attila Brunyánszki, Csaba Hegedus, Judit Márton, Bálint Kónya, László Virág, László Somsák, Pál Gergely, Péter Bai

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35 Citations (Scopus)

Abstract

Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition - such as enhanced mitochondrial oxidation and mTORC2 signaling - to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored.

Original languageEnglish
Article numbere69420
JournalPloS one
Volume8
Issue number7
DOIs
Publication statusPublished - Jul 25 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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