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 [Ca2+l(i) homeostasis may be the nexus between insulin resistance and increased VSM tone. The genetically obese, hyperinsulinemic, 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+]i could then account, in part, for increased VSM tone characteristic of hypertension associated with non-insulin-dependent 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.