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The vasodilation induced by systemic insulin infusion is mediated by nitric oxide and is impaired both in obese subjects and patients with essential hypertension. Whether this vascular defect explains the metabolic resistance to insulin action is uncertain. In 8 overweight male patients with essential hypertension, we used the double forearm (ie, infused versus control) technique, combined with the euglycemic hyperinsulinemic clamp, to test whether sustained vasodilation (induced by intra-arterial sodium nitroprusside infusion) improves insulin-mediated glucose uptake. During the clamp, whole-body glucose disposal rose to 24.4+/-2.9 micromol x min(-1) x kg(-1). Forearm blood flow in the control forearm was stable (3.1+/-0.4 versus 2.9+/-0.3 mL x min[-1] x dL[-1]), while in the infused forearm it increased from 3.4+/-0.5 to 10.6+/-1.3 mL x min(-1) x dL(-1) in response to sodium nitroprusside. During insulin administration, tissue glucose extraction rose from 2+/-1% to 21+/-4% (P<.001) in the control forearm and from 2+/-1% to 8+/-3% in the infused forearm (P<.02 versus baseline for both); the calculated net glucose uptake reached similar plateaus in the two forearms (3.5+/-0.7 versus 3.7+/-0.6 micromol x min(-1) x kg(-1), control versus infused, P=.6). We conclude that in overweight male patients with essential hypertension, increasing forearm perfusion with sodium nitroprusside does not attenuate the insulin resistance of forearm tissues.

Objective: Insulin resistance is a potential target for pharmacologic intervention in non-insulin-dependent diabetes. Troglitazone is being evaluated as an insulin enhancer in insulin resistant states., Research Design and Methods: We randomized 40 patients with non-insulin-dependent diabetes to diet plus placebo (n = 15) or diet plus troglitazone (n = 25; 200 mg/day) treatment for 8 weeks. Fasting endogenous glucose production (EGP, by the stable isotope technique) and whole-body insulin sensitivity (by the insulin suppression test) were measured at baseline and on days 3, 7, 14, 28, and 56 of treatment., Results: By day 56, fasting plasma glucose had risen from 12.0 +/- 0.9 to 12.8 +/- 1.2 mmol/L in the placebo group and had fallen from 12.4 +/- 0.6 to 11.3 +/- 0.6 mmol/L in the troglitazone group (p = 0.03). This was the result of small improvements in whole-body insulin sensitivity (steady-state plasma glucose during the insulin suppression test: from 11.09 +/- 1.1 to 10.3 +/- 0.8 mmol/L versus 13.8 +/- 1.0 to 10.0 +/- 0.9 mmol/L, placebo versus troglitazone; p = 0.01) and EGP (from 103% +/- 3% versus 96% +/- 2% of baseline, placebo versus troglitazone; p = 0.09). The time course of insulin action showed an early (first week of treatment) decrease in EGP in the troglitazone group that was maintained throughout, whereas steady-state plasma glucose levels began to diverge toward the end of treatment. The effects of insulin on plasma free fatty acid and potassium concentrations were not different between placebo and troglitazone. The cardiovascular risk profile (heart rate; serum triglycerides; total, low-density lipoprotein, and high-density lipoprotein cholesterol; proinsulin; uric acid; plasminogen activator inhibitor-1 antigen and activity; 24-hour blood pressure monitoring and urinary albumin excretion) was unaltered by troglitazone treatment., Conclusions: Troglitazone as monotherapy for typical non-insulin-dependent diabetes had a modest anti-hyperglycemic effect and, at the dose used in this study, had no effect on cardiovascular risk factors.

Objectives: To test whether cardiological syndrome X is an insulin-resistant state. SETTING, DESIGN AND SUBJECTS: The coronary care unit of a referral centre for angina pectoris in Pisa, Italy. A case-control study, involving 10 patients with unequivocal (angiographycally proven) cardiological syndrome X, but normal glucose tolerance, blood pressure and lipid levels, and 13 matched healthy subjects., Main Outcome Measures: Insulin sensitivity and pattern of substrate oxidation (assessed by the euglycaemic insulin clamp technique in combination with indirect calorimetry)., Results: Fasting plasma glucose and insulin levels were 5.05 +/- 0.11 versus 4.88 +/- 0.11 mmol l-1 and 68 +/- 10 versus 56 +/- 6 pmol l-1, respectively (controls versus patients, ns). During the insulin clamp, glucose disposal rate was nearly identical in patients and controls (25.9 +/- 1.8 and 27.2 +/- 1.8 mumol kg-1 min-1, respectively. P = 0.88). Non-oxidative glucose disposal accounted for similar proportions of total glucose uptake (59 versus 53%, patients versus controls, ns). Resting energy expenditure (13.7 +/- 0.6 versus 13.8 +/- 0.8 cal kg-1 min-1, ns) and insulin-induced thermogenesis were similar in the two groups. Fasting plasma NEFA concentrations (0.64 +/- 0.09 and 0.64 +/- 0.06 mmol l-1, patients and controls, ns) fell in a similar time-course and to virtually identical nadirs (0.13 +/- 0.02 and 0.14 +/- 0.02 mmol l-1) after insulin infusion. Fasting plasma potassium was similar in patients and controls (3.99 +/- 0.10 and 4.16 +/- 0.04 mmol l-1, ns), and insulin induced equivalent hypokalaemia (-14 versus -19%)., Conclusions: None of the in vivo actions of insulin were impaired in patients with 'pure' syndrome X when compared to matched controls. Therefore, we conclude that cardiological syndrome X is not an insulin resistant state per se, and that any decrease in insulin sensitivity found in this condition is likely to be secondary.

Microalbuminuria in patients with essential hypertension is a marker of incipient glomerular dysfunction and clusters with lipid and hemodynamic abnormalities. Recent evidence has shown that hypertensive patients with microalbuminuria have a hyperinsulinemic response to oral glucose, suggesting the presence of insulin resistance. To directly test this possibility we studied insulin action in two accurately matched groups (n = 10 each) of hypertensive patients with or without microalbuminuria (14 +/- 2 versus 52 +/- 7 mg/24 h-1, mean of three 24-hour collections). In response to glucose ingestion microalbuminuric patients showed slight hyperglycemia (area under the curve, 928 +/- 43 versus 784 +/-19 nmol/L-1/2h-1, P < .02) and a marked hyperinsulinemia (26.8 +/- 3.3 versus 49.8 +/- 3.7 nmol/L-1/2h-1, P < 0.01). Basal arterial blood pressure, heart rate, and forearm blood flow were similar in the two groups and did not change significantly during a 2-hour euglycemic insulin clamp. Insulin-stimulated wholebody glucose uptake was 25% lower in microalbuminuric patients (33.5 +/- 2.5 versus 25.2 +/- 2.1 mumol/min-1/kg-1, P < .02). This difference was entirely due to a 40% reduction in glycogen synthesis (12.9 +/- 1.8 versus 21.3 +/- 3.2 mumol/min-1/kg-1, P < .05) as glucose oxidation was similarly stimulated in the two groups. In contrast there was no difference in the ability of insulin to suppress hepatic glucose production (by approximately 100% at the end of the clamp), to decrease fractional sodium and potassium excretions (by 35%), to lower circulating free fatty acids (by 80%), and to reduce plasma potassium concentrations (by 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Insulin simultaneously causes hypokalaemia and antinatriuresis, and it has been suggested that the two effects are tightly coupled. Whether these actions are preserved in patients with essential hypertension is not known. 2. Eight hypertensive patients and eight normotensive control subjects were studied before and after the ingestion of 75 g of glucose. Despite similar glycaemic profiles, the patients showed a hyperinsulinaemic response incremental area 49 +/- 8 versus 27 +/- 6 nmol l-1 3 h, P < 0.04) but a blunted hypokalaemic response (-7 +/- 1 versus -16 +/- 1%, P < 0.001). Both absolute and fractional urinary excretion of sodium and potassium were significantly decreased during glucose-induced hyperinsulinaemia in hypertensive patients as well as in normotensive subjects (P < 0.05 for all changes). 3. To test whether hypokalaemia is required for insulin-induced antinatriuresis, each hypertensive patient received another oral glucose load during which enough potassium chloride was given to clamp the plasma potassium concentration at baseline. Under these conditions, significant insulin-induced antinatriuresis still occurred. In addition, whereas the glycaemic profile was superimposable, the response of the plasma insulin concentration was significantly greater with than without maintenance of the plasma potassium concentration (total area 79 +/- 14 versus 63 +/- 8 nmol l-1 3 h, P < 0.04). 4. We conclude that (a) insulin causes antinatriuresis, antikaliuresis and hypokalaemia under physiological conditions; (b) in hyperinsulinaemic (insulin-resistant) patients with essential hypertension, the antinatriuretic action of insulin is quantitatively preserved; and (c) clamping plasma potassium levels prevents insulin-induced antikaliuresis but not antinatriuresis, and potentiates the insulin secretory response to glucose.

To test whether carnitine availability is rate-limiting for fat oxidation under conditions of augmented oxidative use of fatty substrates, two series of studies were performed. In study no. 1, L-carnitine (1 g + 0.5 g/h intravenously [i.v.]) or saline was given to eight volunteers during a 4-hour infusion of a 10% triglyceride emulsion, thereby increasing plasma free-carnitine levels from 38 +/- 4 to 415 +/- 55 mumol/L. Fat infusion increased plasma triglyceride levels (80%) and lipid oxidation (30%), and decreased (28%) carbohydrate oxidation (as measured by indirect calorimetry); hypercarnitinemia had no influence on these responses. In study no. 2 in 12 healthy subjects a bolus of L-carnitine (3 g) or saline was administered 40 minutes before aerobic exercise (bicycling for 40 minutes at 60 W), followed by 2 minutes of anaerobic exercise (250 W) and 50 minutes of recovery. Oxygen consumption (VO2), increased to 18.3 +/- 0.7 mL.min-1 x kg-1 during aerobic exercise, reached a maximum of 46.0 +/- 0.8 mL.min-1 x kg-1 during the anaerobic bout, and returned to baseline within a few minutes, with no difference between control and carnitine. At virtually identical mean energy expenditure rates (196 +/- 7 v 197 +/- 7 J.min-1 x kg-1, saline v carnitine), after carnitine administration the entire exercise protocol was sustained by a lower mean carbohydrate oxidation rate (42.1 +/- 3.6 v 36.5 +/- 2.3 mumol.min-1 x kg-1, P < .03) and a higher mean lipid oxidation rate (6.7 +/- 1.0 v 8.3 +/- 0.7 mumol.min-1 x kg-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary hemodynamics, myocardial metabolism and left ventricular function at rest and after incremental atrial pacing were evaluated in 12 patients with stress-induced angina and ST segment depression, angiographically normal coronary arteries and no evidence of spasm, generally labeled as syndrome X, and in 10 normal subjects. At baseline study, great cardiac vein flow was comparable in patients and control subjects. During pacing, an equivalent rate-pressure product was reached in the two groups, but the slope of the relation between rate-pressure product and great cardiac vein flow was significantly less steep in patients than in normal subjects (0.0027 vs. 0.0054 ml/mm Hg.beat, p less than 0.001). Nevertheless, the left ventricular ejection fraction was comparable in both groups at rest (66 +/- 6% vs. 71 +/- 7%, p = NS) and during pacing (71 +/- 7% vs. 66 +/- 5%, p = NS). At baseline study, myocardial glucose extraction was more efficient in patients with syndrome X (p less than 0.05), but net myocardial exchange of pyruvate and alanine was, respectively, smaller and greater than in control subjects. Lactate was extracted to a similar extent in the two groups and in no instance was net lactate release observed during pacing or recovery. During pacing and recovery, patients with syndrome X showed net pyruvate release, unlike the control subjects in whom net pyruvate exchange was positive. In addition, patients with syndrome X continued to show net myocardial extraction of alanine during spacing and recovery, whereas normal subjects produced alanine throughout the study. Myocardial carbohydrate oxidation increased significantly during maximal pacing in normal subjects but not in patients, in whom it always remained below (p less than 0.01) the concurrent rate of myocardial uptake of carbohydrate equivalents (glucose, lactate, pyruvate, alanine). Myocardial energy expenditure was significantly lower in patients than in control subjects at maximal rate-pressure product levels (p less than 0.01). The metabolic pattern in patients with syndrome X therefore is not consistent with classic ischemia, although differences in the net exchange of circulating substrates (glucose, pyruvate, alanine) can be demonstrated. Thus, in patients with syndrome X, the symptoms, electrocardiographic signs and impairment in the increase in great cardiac vein flow during pacing coexist with preserved global and regional left ventricular function and myocardial energy efficiency.

We evaluated low density lipoprotein (LDL) electrophoretic mobility (EM) as an index of nonenzymatic glycosylation in 88 insulin-dependent diabetic patients. Among well-controlled diabetics, 36% had increased EM and among poorly controlled patients, 63% had increased EM. This incidence difference was found to be statistically significant by the X2 test. EM can be used as a sufficiently reliable index of LDL nonenzymatic glycosylation.

Since insulin modulates key enzymes of lipid metabolism, different biological activities of biosynthetic human insulin (BHI) and conventional insulins might induce different plasma lipid and apolipoprotein patterns in diabetic patients chronically treated with the former or the latter insulin preparation. In this study we have evaluated the effects of 3 months of therapy with BHI on plasma lipid and apolipoprotein concentrations in a group of type I diabetics previously treated with insulin of animal origin and the results have been compared with those from diabetics maintained on conventional insulin therapy. In the latter, no change occurred in the clinical and metabolic parameters. Patients transferred to BHI showed lower HDL-cholesterol and HDL3-cholesterol levels at 30 days from the beginning of BHI treatment, and both parameters returned to, and were maintained the basal values at subsequent controls. Total cholesterol, HDL2-cholesterol, triglycerides, apolipoproteins AI, AII and B remained substantially constant throughout the study. Glycometabolic control, which was evaluated by fasting plasma glucose and glycosylated hemoglobin, exhibited a transient, moderate deterioration at the 30-day control, and returned to basal level in the following weeks. No major change was noted as far as daily insulin dosage and relative body weight were concerned. Thus, long-term BHI treatment of type I diabetics does not cause any major change in plasma lipid and apolipoprotein patterns in comparison with animal insulin therapy, so that the validity of using BHI in the treatment of type I diabetes is confirmed.

In order to evaluate if in insulin-dependent diabetes lipid and apolipoprotein levels are differently affected by metabolic control in men and women, we measured the concentrations of fasting plasma glucose, mean plasma glucose, glycosylated hemoglobin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and apolipoproteins A and B in 94 sex matched patients. Diabetic men and women were strictly comparable as far as age, relative body weight and metabolic control were concerned. In women, total and LDL cholesterol, triglycerides and apolipoprotein A correlated positively with HbA1 but not with fasting and mean plasma glucose. In men, no correlation between metabolic control and lipid and apolipoprotein levels was found. We conclude that, in diabetic women, the degree of metabolic control may affect the concentrations of plasma lipids, thus explaining, at least in part, the increased risk for coronary atherosclerosis in these patients.