Interestingly, in one study, insulin appeared to be acting to stimulate ET-1 production via the insulin-like growth factor (IGF)-I receptor. This may be germane, since endothelial cells express both selleck chemicals insulin and IGF-I receptors, and the insulin concentrations achieved in the obese subjects are at the bottom end of the range that can signal via IGF-I receptors (24). Dose-dependent effects of insulin on endothelin-mediated vasoconstriction have been reported in arterioles isolated from normal rats during concurrent NOS synthase antagonism (9) and in vascular rings from spontaneously hypertensive rats (43). These observations suggest that a second source of vascular dysfunction may be necessary to demonstrate insulin-stimulated vasoconstriction via endothelin.

Although these in vitro data are consistent, effects of insulin infusions on ET-1 levels reported in humans are surprisingly inconsistent. Some authors report reductions in ET-1 with insulin (15, 39, 48, 51), some report neutral effects (21, 31), and others report increases in ET-1 levels (13, 38, 49, 54). Where increases are found, they have been on the order of 30% and are not obviously larger with greater insulin exposure. Interestingly, insulinoma patients do not exhibit elevated levels of ET-1 (38). In the current study, under insulin stimulation, we saw a significant increase in ET-1 flux (Table 2) but nominally less in obese subjects than lean subjects and clearly not proportional to insulinemia.

Regardless of the underlying explanation, the current data argue against the notion of a dose response between insulin and endothelin production or action in humans, at least in physiological concentration ranges under the clamp conditions studied. An alternate hypothesis. We observed matched effects of insulin on endothelin action under the experimental circumstance where insulin’s actions on NO were matched between groups. Regulatory and functional interactions of NO and ET-1 are well documented, including in vivo in humans (1, 7, 30). In particular, acute increases in bioavailable nitrates can acutely suppress ET-1 levels and action (9, 37). The current observations may therefore reflect the matching of insulin’s NO-dependent vascular actions, rather than separate effects via differential hyperinsulinemia. This may explain why the balanced insulin exposure produced equal insulin-stimulated BQ-123-induced vasodilation.

With this perspective, under normal circumstances for subjects with insulin resistance, the failure of insulin to activate NO (or reduced NO bioavailability more generally) would fail to suppress ET-1, leading to augmented ET-1 action. The capacity of insulin to directly stimulate ET-1 may therefore be misleading, and this action may not play an important GSK-3 role in the in vivo determination of ET-1 action.