Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators

We recently described the identification of a non-peptidyl fungal metabolit e (L-783,281, compound I), which induced activation of human insulin recept or (Ht) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zha ng, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diet, M T., Pelaez, F., Ruby, C., Kendall, R. L., Mao, X., Griffin, P. , Calaycay, J., Zierath, J. R., Heck, J. V., Smith, R, G. & Moller, D. E. ( 1999) Science 284, 974-977). Here we report the characterization of an acti ve analog (compound 2) with enhanced IR kinase activation potency and selec tivity over related receptors (insulin-Like growth factor I receptor, epide rmal growth factor receptor, and platelet-derived growth factor receptor). The IR activators stimulated tyrosine kinase activity of partially purified native IR and recombinant IR tyrosine kinase domain. Administration of the IR activators to mice was associated with increased IR tyrosine kinase act ivity in liver. In vivo oral treatment with compound 2 resulted in signific ant glucose lowering in several rodent models of diabetes. In db/db mice, o ral administration of compound 2 elicited significant correction of hypergl ycemia, In a streptozotocin-induced diabetic mouse model, compound 2 potent iated the glucose-lowering effect of insulin. In normal rats, compound 2 im proved oral glucose tolerance with significant reduction in insulin release following glucose challenge. A structurally related inactive analog (compo und 3) was not effective on insulin receptor activation or glucose lowering in db/db mice. Thus, small molecule IR activators exert insulin mimetic an d sensitizing effects in cells and in animal models of diabetes. These resu lts have implications for the future development of new therapies for diabe tes mellitus.