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.
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.
Department of Medical Chemistry, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
Lilla
L
Nagy
Tibor
T
Docsa
Magdolna
M
Szántó
Attila
A
Brunyánszki
Csaba
C
Hegedűs
Judit
J
Márton
Bálint
B
Kónya
László
L
Virág
László
L
Somsák
Pál
P
Gergely
Péter
P
Bai
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007473:Ion Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008112:Liver Glycogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008820:Mice, Obese; D024101:Mitochondrial Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007473:Ion Channels; D008112:Liver Glycogen; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D014508:Urea; D024981:Glycogen Phosphorylase; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D005947:Glucose