title: Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics.
abstract: GKAs (glucokinase activators) are promising agents for the therapy of Type 2 diabetes, but little is known about their effects on hepatic intermediary metabolism. We monitored the fate of (13)C-labelled glucose in both a liver perfusion system and isolated hepatocytes. MS and NMR spectroscopy were deployed to measure isotopic enrichment. The results demonstrate that the stimulation of glycolysis by GKA led to numerous changes in hepatic metabolism: (i) augmented flux through the TCA (tricarboxylic acid) cycle, as evidenced by greater incorporation of (13)C into the cycle (anaplerosis) and increased generation of (13)C isotopomers of citrate, glutamate and aspartate (cataplerosis); (ii) lowering of hepatic [Pi] and elevated [ATP], denoting greater phosphorylation potential and energy state; (iii) stimulation of glycogen synthesis from glucose, but inhibition of glycogen synthesis from 3-carbon precursors; (iv) increased synthesis of N-acetylglutamate and consequently augmented ureagenesis; (v) increased synthesis of glutamine, alanine, serine and glycine; and (vi) increased production and outflow of lactate. The present study provides a deeper insight into the hepatic actions of GKAs and uncovers the potential benefits and risks of GKA for treatment of diabetes. GKA improved hepatic bioenergetics, ureagenesis and glycogenesis, but decreased gluconeogenesis with a potential risk of lactic acidosis and fatty liver.
authors.affiliation: Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. nissim@email.chop.edu
authors.forename: Itzhak
authors.initials: I
authors.lastname: Nissim
authors.forename: Oksana
authors.initials: O
authors.lastname: Horyn
authors.forename: Ilana
authors.initials: I
authors.lastname: Nissim
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Daikhin
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Wehrli
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005941:Glucokinase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D044482:Benzeneacetamides; C553963:piragliatin; D005941:Glucokinase