KB-R7785, A NOVEL MATRIX METALLOPROTEINASE INHIBITOR, EXERTS ITS ANTIDIABETIC EFFECT BY INHIBITING TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

It has been suggested that tumor necrosis factot-alpha (TNF-alpha) is a key mediator of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha is synthesized as a membrane-bound precur sor; this is proteolytically processed to an active form by a matrix m etalloproteinase (MMP)-like enzyme. In this study, we have used KKA(y) mice which show insulin resistance like NIDDM to investigate the effe cts of KB-R7785, a novel MMP inhibitor, on blood glucose and insulin l evels. Subcutaneous administration of KB-R7785 at 100 mg/kg twice dail y (Le., 200 mg/kg/day) for 4 weeks resulted in a significant decrease in plasma glucose levels which was observed after 3 weeks. Oral admini stration of pioglitazone (20 mg/kg twice daily or 40 mg/kg/day for 4 w eeks), an agent known to ameliorate insulin sensitivity, significantly decreased plasma glucose levels during the treatment period. KB-R7785 , but not pioglitazone, also significantly decreased plasma insulin le vels. Lipopolysaccharide (LPS) increased plasma TNF-alpha levels to a significantly greater degree in KKA(y) mice than in normal C57BL mice; this was inhibitable in KKA(y) mice by KB-R7785. In contrast, pioglit azone did not affect the LPS-induced increase in plasma TNF-alpha leve ls in KKA(y) mice. These results suggest that KB-R7785 exerts its anti diabetic effect by ameliorating insulin sensitivity through the inhibi tion of TNF-alpha production.