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-A(y) 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-A(y) 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-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose
tissues and systemic glucose metabolism through reductions in body weight.