Myocardial muscle is considered to be a target tissue for insulin action, but direct measurements of insulin's effects on cardiac hemodynamics and intermediary metabolism in humans are scarce. We combined great cardiac vein (GCV)/arterial catheterization with the euglycemic insulin clamp technique and thermodilution in six healthy middle-aged (53 +/- 2 yr) volunteers. In the fasting state, the myocardium extracted free fatty acid (FFA), lactate, pyruvate, glycerol, and beta-hydroxybutyrate (6.4 +/- 0.8, 6.2 +/- 1.0, 0.58 +/- 0.12, 0.44 +/- 0.15, and 11 +/- 2 mumol/min, respectively) and consumed 0.26 +/- 0.02 mmol/min oxygen. As fasting plasma insulin (73 +/- 6 pmol/l) was raised and clamped at 503 +/- 16 pmol/l for 100 min while maintaining euglycemia (approximately 5 mmol/l), arterial levels of lactate and pyruvate rose (by 121 and 159%, respectively), whereas FFA, glycerol, and beta-hydroxybutyrate fell (by 69, 48, and 85%, respectively, all P < 0.001). Correspondingly, net myocardial uptake of glucose, lactate, and pyruvate increased to 18.9 +/- 3.5, 32.0 +/- 2.3, and 2.7 +/- 0.5 mumol/min, respectively, whereas net extraction of circulating FFA, glycerol, and beta-hydroxybutyrate was abolished (all P < 0.001). The stimulation of lactate and pyruvate uptake was the result of both increased arterial supply and enhanced myocardial extraction ratio (from 19 +/- 3 to 51 +/- 6% for lactate, from 26 +/- 5 to 44 +/- 5% for pyruvate, P < 0.001 for both). This shift from fat to carbohydrate fuel usage occurred in the absence of changes in oxygen consumption, heart rate, GCV blood flow, aortic pressures, coronary vascular resistance, and left ventricular end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

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 ...

Insulin promotes potassium uptake into skeletal muscle by stimulating the activity of the Na+-K+ pump. To test whether insulin-induced glucose and potassium uptake are linked processes in vivo, we used the perfused forearm technique in healthy volunteers. Local hyperinsulinemia (125 +/- 11 microU/ml for 100 min) induced a net uptake of glucose and potassium (4.79 +/- 0.61 and 0.76 +/- 0.22 mumol.min-1.100 ml-1 of forearm volume, respectively). When an intra-arterial ouabain infusion (0.72 microgram.min-1.100 ml-1, producing local levels of approximately 0.5 mM) was superimposed on the insulin infusion, potassium uptake was blocked (0.026 +/- 0.190 ml.min-1.100 ml-1, P less than 0.02), and glucose uptake was decreased (to 3.31 +/- 0.34 mumol.min-1.100 ml-1, P less than 0.03). The latter change was explained by a 30% fall in forearm blood flow (from 2.95 +/- 0.10 to 2.01 +/- 0.18 ml.min-1.100 ml-1, P less than 0.001). To separate out the effect of blood flow, in another series of studies forearm blood flow was clamped by co-infusing propranolol and phentolamine (7 and 8 micrograms.min-1.100 ml-1, respectively). Under these conditions of fixed flow (7.0 +/- 0.8 ml.min-1.100 ml-1), ouabain still abolished the stimulatory effect of insulin on potassium uptake but had only a small (and statistically insignificant) effect on forearm glucose extraction (from 20 +/- 2 to 16 +/- 2%, P = N>). We conclude that in human forearm muscle ouabain inhibits Na+-K+ exchange and depresses insulin-induced glucose uptake via an adrenergic-mediated limitation of blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown that essential hypertension is frequently associated with insulin resistance. The tissues responsible for this metabolic alteration have not been denned. We tested the hypothesis that skeletal muscle is the site of insulin resistance of essential hypertension with the use of the perfused forearm technique. Eight hypertensive (age 42 ±3 years, body mass index 27±1 kg/m 2 , intra-arterial mean blood pressure 126±4 mm Hg) and seven normotensive (age 48±3 years, body mass index 26±1 kg/m 2 , mean blood pressure 95±4 mm Hg) male volunteers were studied. After glucose ingestion (40 g/m 2), normal glucose tolerance in the patients was maintained at the expense of a heightened plasma insulin response, suggesting the presence of insulin resistance. During graded, local (intra-arterial) hyperinsulinemia encompassing the physiological range (12-120 milliunits/1), glucose uptake by forearm tissues was significantly (/»<0.03) reduced in the hypertensive subjects as compared with the controls at each of five insulin steps, by 43% on the average. In addition, forearm lactate and pyruvate release were significantly less stimulated in the hypertensive than in the normotensive group (p<0.01 for both), presumably as a consequence of the decreased glucose influx. Forearm exchange of oxygen, carbon dioxide, lipid substrates (free fatty acids, glycerol, and /3-hydroxybutyrate), and potassium were similar in the hypertensive and normotensive groups in the basal state. Insulin had no effect on oxygen consumption, carbon dioxide production, and respiratory quotient in either study group, whereas it stimulated free fatty acids, glycerol, and potassium uptake to the same extent in the hypertensive and normotensive groups. We conclude that the insulin resistance of untreated essential hypertension is present in skeletal muscle, is not secondary to increased fatty substrate use (normal respiratory quotient), and is selective for glucose metabolism. Because forearm substrate oxidation is unaltered, the defect in glucose disposal must predominantly involve glucose conversion into glycogen. {Hypertension 1991;17:170-178)