Control of liver glucokinase activity: a potential new target for incretin hormones?

FRANCINI F; MASSA ML; POLO MP; VILLAGARCÍA H; CASTRO MC; GAGLIARDINO JJ

PEPTIDES

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2015 vol. 74 p. 57 - 63

0196-9781

We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-inducedincrease in liver glucokinase activity in rats with impaired glucose toleranceand the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructosein 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 activityand 3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatasemRNA and protein levels. Fructose fed rats had: hypertriglyceridemia,hyperinsulinemia and high liver glucokinase activity (mainly located in thecytosolic fraction) together with higher glucokinase and6-phosphofructo-2-kinase/fructose-2,6-biphosphatase  mRNA and proteinconcentrations compared to control rats. Co-administration of either exendin-4or des-fluoro-sitagliptin prevented serum and liver changes except glucokinaseprotein expression. Exendin-4 also prevented fructose-induced increase inglucokinase activity in cultured HepG2 cells, effect blunted by co-incubationwith exendin-9-36. In conclusion exendin-4/des-fluro-sitagliptin preventedfructose-induced effect on glucokinase activity, mainly affecting enzymeactivity modulators. Exendin 9-39 blunted invitro protective exendin-4 effect on glucokinase activity, thus suggestinga direct effect of the later on hepatocytes through GLP-1 receptor. Alterationsof glucokinase activity modulators could play a role in the pathogenesis ofliver dysfunction, becoming a potential new treatment target for GLP-1 receptoragonists.