title: Control of liver glucokinase activity: A potential new target for incretin hormones?
abstract: We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-induced increase in liver glucokinase activity in rats with impaired glucose tolerance and the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructose in the presence/absence of exendin-9-39. After 3 weeks of in vivo fructose administration we measured: (1) serum glucose, insulin and triglyceride levels; (2) liver and HepG2 cells glucokinase activity and (3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein levels. Fructose fed rats had: hypertriglyceridemia, hyperinsulinemia and high liver glucokinase activity (mainly located in the cytosolic fraction) together with higher glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein concentrations compared to control rats. Co-administration of either exendin-4 or des-fluoro-sitagliptin prevented serum and liver changes except glucokinase protein expression. Exendin-4 also prevented fructose-induced increase in glucokinase activity in cultured HepG2 cells, effect blunted by co-incubation with exendin-9-36. In conclusion exendin-4/des-fluro-sitagliptin prevented fructose-induced effect on glucokinase activity, mainly affecting enzyme activity modulators. Exendin 9-39 blunted in vitro protective exendin-4 effect on glucokinase activity, thus suggesting a direct effect of the later on hepatocytes through GLP-1 receptor. Alterations of glucokinase activity modulators could play a role in the pathogenesis of liver dysfunction, becoming a potential new treatment target for GLP-1 receptor agonists.
authors.affiliation: CENEXA (UNLP-CONICET CCT LA PLATA), PAHO/WHO Collaborating Centre for Diabetes, National University of La Plata School of Medicine, La Plata, Argentina. Electronic address: f_francini@yahoo.com.
authors.forename: Flavio
authors.initials: F
authors.lastname: Francini
authors.affiliation: CENEXA (UNLP-CONICET CCT LA PLATA), PAHO/WHO Collaborating Centre for Diabetes, National University of La Plata School of Medicine, La Plata, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Massa
authors.affiliation: INIBIOLP (UNLP-CONICET CCT LA PLATA), La Plata, Argentina.
authors.forename: Mónica Patricia
authors.initials: MP
authors.lastname: Polo
authors.affiliation: CENEXA (UNLP-CONICET CCT LA PLATA), PAHO/WHO Collaborating Centre for Diabetes, National University of La Plata School of Medicine, La Plata, Argentina.
authors.forename: Hernán
authors.initials: H
authors.lastname: Villagarcía
authors.affiliation: CENEXA (UNLP-CONICET CCT LA PLATA), PAHO/WHO Collaborating Centre for Diabetes, National University of La Plata School of Medicine, La Plata, Argentina.
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Castro
authors.affiliation: CENEXA (UNLP-CONICET CCT LA PLATA), PAHO/WHO Collaborating Centre for Diabetes, National University of La Plata School of Medicine, La Plata, Argentina.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Gagliardino
mesh_terms: D000818:Animals; D000077270:Exenatide; D005632:Fructose; D015870:Gene Expression; D005941:Glucokinase / Q000187:drug effects* / Q000235:genetics; D018149:Glucose Intolerance / Q000503:physiopathology; D056945:Hep G2 Cells; D006801:Humans; D054795:Incretins / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068900:Sitagliptin Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D054795:Incretins; D010455:Peptides; D014688:Venoms; D005632:Fructose; D000077270:Exenatide; D005941:Glucokinase; D000068900:Sitagliptin Phosphate
keywords: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase; Des-fluoro-sitagliptin; Exendin-4; Fructose-rich diet; GLP-1 receptor agonist; Liver glucokinase; Prediabetes