Modified redox signaling in vasculature after chronic infusion of the insulin receptor antagonist, S961

Background Type 2 diabetes and associated vascular complications cause substantial morbidity and mortality. It is important to investigate mechanisms and test therapies in relevant physiological models, yet few animal models adequately recapitulate all aspects of the human condition. Objective We sought to determine the potential of using an insulin receptor antagonist, S961, in mice for investigating vascular pathophysiology. Methods S961 was infused into mice for 4 weeks. Blood glucose was monitored, and insulin was measured at the end of the protocol. Blood pressure and pressor responses to vasodilators were measured in cannulated mice, and vascular reactive oxygen and nitrogen species were measured in isolated tissue. Results S961 infusion-induced hyperglycemia and hyperinsulinemia. There was evidence of increased vascular reactive oxygen and nitrogen species and modification of NO-mediated signaling. Pressor responses to a NO donor were attenuated, but responses to bradykinin were preserved. Conclusions Infusion of S961, an insulin receptor antagonist, results in the production of a mouse model of type 2 diabetes that may be useful for investigating redox signaling in the vasculature of insulin-resistant mice over the short term. It is limited by both the transient nature of the hyperglycemia and incomplete functional analogy to the human condition.