Carbenoxolone enhances peripheral insulin sensitivity and GLUT4 expression in skeletal muscle of obese rats: Potential participation of UBC9 protein

Abstract

AimThis study investigates the insulin sensitizer effect of carbenoxolone (CBX) and potentially involved peripheral mechanisms. Main methodsTaking glucose transporter 4 (GLUT4) as a marker of glucose disposal, we investigated the CBX effects on whole-body insulin sensitivity and solute carrier 2a4 (Slc2a4)/GLUT4 expression in visceral (VAT) and subcutaneous (SAT) adipose tissues and soleus muscle of monosodium glutamate (MSG)-induced obese rats. Sterol regulatory element binding protein (SREBP1), an enhancer of Slc2a4 expression was analyzed through mRNA content and SREBP1-binding to Slc2a4 promoter. Finally, the small ubiquitin-modifier conjugating enzyme 9 (UBC9), whose low content indicates accelerated GLUT4 degradation was analyzed in soleus. Key findingsHypercorticosteronemia, hyperinsulinemia and low glucose decay rate in the insulin tolerance test of obese rats were restored by CBX (P < 0.05). Slc2a4/GLUT4 increased in SAT (P < 0.05) and decreased in VAT (P < 0.01) of obese rats. In soleus, obesity increased Slc2a4 but decreased GLUT4 (P < 0.01), possibly by accelerating GLUT4 degradation, as suggested by decreased UBC9 (P < 0.01). CBX restored both UBC9 and GLUT4 contents. SREBP1 did not participate in the Slc2a4 transcriptional regulation. SignificanceThe insulin sensitizer effect of CBX involves the increase of GLUT4 expression in soleus, indicating an increased glucose disposal in skeletal muscle. This observation reinforces the skeletal muscle as the main site of insulin-induced glucose uptake and sheds new light on the metabolic effects of 11βHSD1 inhibitors, since most of the studies so far have focused on its effects on liver and adipose tissues.