Insulin sensitizer YM268 ameliorates insulin resistance by normalizing the decreased content of GLUT4 in adipose tissue of obese Zucker rats

Abstract

Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue. European Journal of Endocrinology 137 693-700

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

“…This finding is compatible with previous reports using 3T3L1 adipocytes [37,38]. It has also been reported that thiazolidinediones restore the decreased GLUT4 expression in obese Zucker rat in vivo [39]. We speculate that the effect of thiazolidinediones in returning PPARg expression to normal observed in our study is related to one of the mechanisms for the restoration of the suppression of GLUT4 expression by thiazolidinediones induced by TNF-a.…”

Adipose tissue sensitization to insulin induced by troglitazone and MEDICA 16 in obese Zucker rats in vivo

“…3A) when expressed per animal. An increase in primary adipose reesterification by insulin sensitizers may be ascribed to the higher availability of lipolyzed FFA, to GLUT4 recruitment (34), putative increase in glyceroneogenesis resulting from PPAR␥-induced adipose phosphoenolpyruvate carboxykinase (10), and in glycerol 3-phosphate resulting from PPAR␥-induced adipose glycerol kinase (15). It is worth noting, however, that primary adipose reesterification calculated by the difference between 3ϫ R a glycerol and R a FFA represents fatty acid esterification of glycerol 3-phosphate derived from glucose or from glycolytic three-carbon precursors, but not fatty acid reesterification of glycerol 3-phosphate derived from glycerol via adipose glycerol kinase activity.…”

“…Thus lipolysis is suppressed (16), whereas glucose uptake is increased (6). Previous data have pointed to TZD-induced glucose uptake in isolated adipocytes (26) mediated by GLUT4 recruitment (34). However, evidence for the effect of insulin sensitizers on adipose tissue glucose uptake in vivo is still lacking.…”

Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter.

“…GLUT1 mRNA and protein were increased in the cultures of human skeletal muscle by troglitazone (15). Also, troglitazone analog YM268 could normalize the decreased GLUT4 protein in adipose tissue of Zucker diabetic fatty (ZDF) rats (16). These results strongly suggest that troglitazone can directly increase glucose transporter expression, which con-tributes to glucose disposal in peripheral tissue.…”