The FRK tyrosine kinase has previously been shown to transduce -cell cytotoxic signals in response to cytokines and streptozotocin and to promote -cell proliferation and an increased -cell mass. We therefore aimed to further evaluate the effects of overexpression of FRK tyrosine kinase in -cells. A transgenic mouse expressing kinase active FRK under control of the insulin promoter (RIP-FRK) was studied with regard to islet endocrine function and vascular morphology. Mild glucose intolerance develops in RIP-FRK male mice of at least four months of age. This effect is accompanied by reduced glucose-stimulated insulin secretion in vivo and reduced second-phase insulin secretion in response to glucose and arginine upon pancreas perfusion. Islets isolated from the FRK-transgenic mice display a glucose-induced insulin secretory response in vitro similar to that of control islets. However, islet blood flow per islet volume is decreased in the FRK-transgenic mice. These mice also exhibit a reduced islet capillary lumen diameter as shown by electron microscopy. Total body weight and pancreas weight are not significantly affected, but the -cell mass is increased. The data suggest that long-term expression of active FRK in -cells causes an in vivo insulin secretory defect, which may be the consequence of islet vascular abnormalities that yield a decreased islet blood flow.