Although hyperuricemia is a frequent finding in insulin-resistant states, insulin's effect on renal uric acid (UA) handling is not known. In 20 healthy volunteers, diastolic blood pressure, body weight, and fasting plasma insulin were positively (and age was negatively) related to fasting plasma UA concentrations, together accounting for 53% of their variability. During an insulin clamp, urine flow was lower than during fasting conditions (1.01 +/- 0.12 vs. 1.56 +/- 0.32 ml/min, P = 0.04), whereas creatinine clearance was unchanged (129 +/- 7 and 131 +/- 9 ml/min, P = not significant). Hyperinsulinemia did not alter serum UA concentrations (303 +/- 13 vs. 304 +/- 12 microM) but caused a significant decrease in urinary UA excretion [whether expressed as absolute excretion rate (1.66 +/- 0.21 vs. 2.12 +/- 0.23 mumol/min, P = 0.03), clearance rate (5.6 +/- 0.8 vs. 7.3 +/- 0.8 ml/min, P = 0.03), or fractional excretion (4.48 +/- 0.80 ml/min vs. 6.06 +/- 0.64%, P < 0.03)]. Hyperinsulinemia was also associated with a 30% (P < 0.001) fall in urine Na excretion. Fractional UA excretion was related to Na fractional excretion under basal conditions (r = 0.59, P < 0.01) and during the insulin period (r = 0.53, P < 0.02). Furthermore, the insulin-induced changes in fractional UA and Na excretion correlated with one another (r = 0.66, P < 0.001). Physiological hyperinsulinemia acutely reduces urinary UA and Na excretion in a coupled fashion.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

IntroductionInsulin-mediated vasodilation has been proposed as a determinant of in vivo insulin sensitivity. We tested whether sustained vasodilation with adenosine could overcome the muscle insulin resistance present in mildly overweight patients with essential hypertension. Using the forearm technique, we measured the response to a 40-min local intraarterial infusion of adenosine given under fasting conditions (n = 6) or superimposed on a euglycemic insulin clamp (n = 8). In the fasting state, adenosine-induced vasodilation (forearm blood flow from 2.6+0.6 to 6.0±+1.2 ml min-'dl-', P < 0.001) was associated with a 45% rise in muscle oxygen consumption (5.9+1.0 vs 8.6+1.7 amol min'-dl-', P < 0.05), and a doubling of forearm glucose uptake (0.47+0.15 to 1.01+0.28 ,Amol min'-dl'-, P < 0.05). The latter effect remained significant also when expressed as a ratio to concomitant oxygen balance (0.08±0.03 vs 0.13+0.04 jAmol tumol'-, P < 0.05), whereas for all other metabolites (lactate, pyruvate, FFA, glycerol, citrate, and 13-hydroxybutyrate) this ratio remained unchanged.During euglycemic hyperinsulinemia, whole-body glucose disposal was stimulated (to 19+3 jmol min-'kg-'), but forearm blood flow did not increase significantly above baseline (2.9+0.2 vs 3.1+0.2 ml min'-dl'`, P = NS). Forearm oxygen balance increased (by 30%, P < 0.05) and forearm glucose uptake rose fourfold (from 0.5 to 2.3 Amol min-'dl-', P < 0.05). Superimposing an adenosine infusion into one forearm resulted in a 100% increase in blood flow (from 2.9+0.2 to 6.1+0.9 ml min-'dl-', P < 0.001); there was, however, no further stimulation of oxygen or glucose uptake compared with the control forearm. During the clamp, the ratio of glucose to oxygen uptake was similar in the control and in the infused forearms (0.27±0.11 and 0.23+0.09, respectively), and was not altered by adenosine (0.31±0.9 and 0.29+0.10). We conclude that in insulin-rel5-76sistant patients with hypertension, adenosine-induced vasodilation recruits oxidative muscle tissues and exerts a modest, direct metabolic effect to promote muscle glucose uptake in the fasting state. Despite these effects, however, adenosine does not overcome muscle insulin resistance. (J. Clin. Invest. 1994. 94:1570-1576 (3)(4)(5). The role of blood flow, and, consequently, of the supply of glucose and insulin to target tissues in the physiologic modulation of in vivo glucose metabolism has been recently reevaluated. Evidence has been provided that systemic insulin infusion with maintenance of euglycemia is associated with peripheral vasodilation (6). When regional data have been extrapolated to the whole body, the insulin-induced increase in blood flow has been estimated to explain up to 50% of the total amount of glucose taken by skeletal muscle (7). Furthermore, typical states of insulin resistance, such as obesity and diabetes mellitus, have been reported to manifest both cellular (i.e., reduced arterio-venous gradient) and vascular (i.e., blunted vasodilation) resistance to insulin action (7,8). Thus, the ...