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, T. Docsa, Magdolna Szántó, Attila Brunyánszki, Csaba Hegedus, I. Márton, Bálint Kónya, L. Virag, L. Somsák, P. Gergely, P. Bai

Research output: Contribution to journalArticle

32 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

Fingerprint

Glycogen Phosphorylase
phosphorylase
glucose tolerance
Metabolism
glycogen
Urea
urea
Glucose
liver
glucose
metabolism
Liver
Glycogen
mice
Obese Mice
Medical problems
Oxygen Consumption
oxygen consumption
diabetes
Animals

ASJC Scopus subject areas

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

Cite this

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. / Nagy, Lilla; Docsa, T.; Szántó, Magdolna; Brunyánszki, Attila; Hegedus, Csaba; Márton, I.; Kónya, Bálint; Virag, L.; Somsák, L.; Gergely, P.; Bai, P.

In: PLoS One, Vol. 8, No. 7, e69420, 25.07.2013.

Research output: Contribution to journalArticle

@article{041ae284f2fe483bb9a1573db8bce7d5,
title = "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",
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.",
author = "Lilla Nagy and T. Docsa and Magdolna Sz{\'a}nt{\'o} and Attila Bruny{\'a}nszki and Csaba Hegedus and I. M{\'a}rton and B{\'a}lint K{\'o}nya and L. Virag and L. Soms{\'a}k and P. Gergely and P. Bai",
year = "2013",
month = "7",
day = "25",
doi = "10.1371/journal.pone.0069420",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - 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

AU - Nagy, Lilla

AU - Docsa, T.

AU - Szántó, Magdolna

AU - Brunyánszki, Attila

AU - Hegedus, Csaba

AU - Márton, I.

AU - Kónya, Bálint

AU - Virag, L.

AU - Somsák, L.

AU - Gergely, P.

AU - Bai, P.

PY - 2013/7/25

Y1 - 2013/7/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84880807739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880807739&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0069420

DO - 10.1371/journal.pone.0069420

M3 - Article

C2 - 23936011

AN - SCOPUS:84880807739

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e69420

ER -