Mechanisms of hypertension in diabetes

Hypertension in insulin resistance states is gener­ally attributed to hyperinsulinemia, with resulting increases in renal sodium retention and/or sympa­thetic nervous system activity. However, recent data from our laboratory suggest that cellular insulin re­sistance, rather than hyperinsulinemia per se, may lead to hypertension. The basic tenet proposed in this review is that the common mechanism involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of in­sulin at the cellular level. Recent observations sug­gest that impaired cellular response to insulin pre­disposes to increased vascular smooth muscle (VSM) tone (the hallmark of hypertension in the diabetic state). For example, recently reported studies from our laboratory demonstrate that insulin in physio­logical doses attenuates the vascular contractile re­sponse to phenylephrine, serotonin, and potassium chloride. Thus, insulin appears to normally modu­late (attenuate) VSM contractile responses to vaso­active factors, and insulin resistance should accord­ingly be associated with enhanced vascular reactivity. Abnormal VSM cell calcium [Ca24-^ homeostasis may be the nexus between insulin resistance and increased VSM tone. The genetically obese, hyper- insulinemic, insulin-resistant Zucker rat demon­strates increased vascular reactivity, reduced mem­brane Ca²⁺-ATPase activity, increased cellular Ca²⁺ levels, and a marked impairment in vascular smooth muscle Ca²⁺ efflux compared to lean con­trols. Insulin stimulates membrane Ca-ATPase, blocks Ca²⁺ currents, and Ca²⁺-driven action poten­tials. Thus, an insulin-resistant state as exists in the Zucker rat may be associated with increased Ca²⁺ influx through voltage-dependent sarcolemmal Ca²⁺ channels and/or decreased production or acti­vation of the VSM cell Ca-ATPase pump. The re­sulting sustained rise in VSM [Ca²⁺]j could then ac­count, in part, for increased VSM tone characteristic of hypertension associated with non-insulin­dependent diabetes mellitus. Accordingly, we pro­pose that insulin resistance is associated with al­tered VSM membrane Ca²⁺ transport leading to a more sustained rise in VSM [Ca²⁺]i which, in turn, is associated with enhanced VSM contraction.