Background: The effects of a new AT(1) receptor blocker (ARB), TAK-536, on insulin resistance were explored using type 2 diabetic KK-A(y) mice and compared with those of candesartan cilexetil (candesartan).
Methods: Male KK-A(y) mice were treated with TAK-536 or candesartan at doses of 0.0005%, 0.001%, and 0.005% in laboratory chow for 2 weeks. Results of an oral glucose tolerance test (OGTT) and tissue glucose uptake were examined. Expression of markers for insulin resistance and adipocyte differentiation was measured by quantitative reverse transcriptase-polymerase chain reaction.
Results: Both TAK-536 and candesartan suppressed the increase in plasma glucose level in the OGTT without significant change in insulin concentration and improved insulin sensitivity. Both ARBs also increased tissue glucose uptake, especially in skeletal muscle and adipose tissue. These effects of TAK-536 on glucose intolerance were stronger than those of candesartan. In skeletal muscle, TAK-536 but not candesartan decreased the expression of TNF-alpha at doses of 0.001%. In adipose tissue, TAK-536 and candesartan reduced TNF-alpha expression but increased the expression of adiponectin, PPARgamma, C/EBalpha, and aP2. The effects of TAK-536 on these parameters were also greater than those of candesartan. Adipose tissue weight and cell size were decreased by TAK-536 at 0.005%.
Conclusions: These results indicate the greater beneficial effects of TAK-536 in improving glucose intolerance, insulin sensitivity, and induction of adipocyte differentiation, and suggest that TAK-536 is advantageous as a new ARB for treatment of metabolic syndrome.