JTT-553,a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor,improves glucose metabolism in diet-induced obesity and genetic T2DM mice

Type 2 diabetes mellitus (t2dm) arises primarily due to lifestyle factors and genetics. a number of lifestyle factors are known to be important in the development of t2dm,including obesity. jtt-553,a novel acyl coa:diacylglycerol acyltransferase 1 inhibitor,reduced body weight depending on dietary fat in diet-induced obesity (dio) rats in our previous study. here,the effect of jtt-553 on glucose metabolism was evaluated using body weight reduction in t2dm mice. jtt-553 was repeatedly administered to dio and kk-ay mice. jtt-553 reduced body weight gain and fat weight in both mouse models. in dio mice,jtt-553 decreased insulin,non-esterified fatty acid (nefa),total cholesterol (tc),and liver triglyceride (tg) plasma concentrations in non-fasting conditions. jtt-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in dio mice. in kk-ay mice,jtt-553 decreased glucose,nefa,tc and liver tg plasma concentrations in non-fasting conditions. jtt-553 also decreased glucose,insulin,and tc plasma concentrations in fasting conditions. in addition,jtt-553 decreased tnf-α mrna levels and increased glut4 mrna levels in adipose tissues in kk-ay mice. these results suggest that jtt-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight. © 2015 the authors.