G. Buzzigoli

Insulin Resistance in Essential Hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.

Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects

Raised levels of free fatty acids (FFA) compete with glucose for utilization by insulin-sensitive tissues, and, therefore, they may induce insulin resistance in the normal subject. The influence of experimental elevations in FFA levels on glucose metabolism in native insulin-resistant states is not known. We studied seven women with moderate obesity (63% above their ideal body weight) but normal glucose tolerance with the use of the insulin clamp technique with or without an infusion of Intralipid + heparin. Upon raising plasma insulin levels to approximately 60 microU/mL while maintaining euglycemia, whole body glucose utilization (3H-3-glucose) rose similarly without (from 66 +/- 7 to 113 +/- 11 mg/min m2, P less than .02) or with (from 70 +/- 7 to 137 +/- 19 mg/min m2, P less than .02) concomitant lipid infusion. In contrast, endogenous glucose production was considerably (73%) suppressed (from 66 +/- 7 to 15 +/- 8 mg/min m2, P less than .001) during the clamp without lipid, but declined only marginally (from 70 +/- 7 to 48 +/- 7 mg/min m2, NS) with lipid administration. The difference between the control and the lipid study was highly significant (P less than .02), and amounted to an average of 3.8 g of relative glucose overproduction during the second hour of the clamp. Blood levels of lactate rose by 34 +/- 15% (.1 greater than P greater than .05) in the control study but only by 17 +/- 10% (NS) during lipid infusion. Blood pyruvate concentrations fell in both sets of experiments (by approximately 45% at the end of the study) with similar time courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary hemodynamics and myocardial metabolism in patients with syndrome X: Response to pacing stress

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.

Operation of Randle's Cycle in Patients With NIDDM

It has been suggested that the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) may be caused by substrate competition between glucose and free fatty acids (FFAs) (Randles cycle). We measured substrate oxidation and energy metabolism in 10 nonobese untreated NIDDM patients with fasting glucose levels of 7–8 mM with indirect calorimetry in the basal state and during an isoglycemic-hyperinsulinemic (∼100 mU/L) clamp without (control) and with a concomitant infusion (∼0.35 mmol/min) of Intralipid, a triglyceride emulsion. In the control study, fasting rates of total glucose turnover ([3−3H]glucose) and glucose and lipid oxidation (9.4 ± 1.4, 7.3 ± 1.3, and 3.0 ± 0.4 μmol · kg−1 · min−1, respectively) were comparable with those of nondiabetic individuals. After insulin administration, lipid oxidation was normally suppressed (to 1.3 ± 0.3 μ · kg−1 · min−1 P < 0.01), as were the circulating levels of FFA, glycerol, and β-hydroxybutyrate, whereas glucose oxidation doubled (14.1 ± 1.8 μmol; · kg−1 · min−1 P <0.01). Because glycemia was clamped at 7.5 mM, endogenous glucose production (EGP) was completely suppressed, and total glucose disposal was stimulated (to 25.7 ± 5.2 μmol · kg−1 · min−1 P < 0.01 vs. baseline), but glucose clearance (3.6 ± 0.8 ml · kg−1 · min−1) was 30% reduced compared with normal. With concomitant lipid infusion, FFA, glycerol, and β-hydroxybutyrate all rose during the clamp; correspondingly, lipid oxidation was maintained at fasting rates (3.6 ± 0.2 μmol · kg−1 · min−1 P < 0.01 vs. control). As a consequence, the insulin-induced increase in glucose oxidation was abolished (7.9 ±1.3 μmol · kg−1 · min−1 P < 0.01 vs. control), and total glucose disposal was inhibited (21.8 ± 4.6 μmol · kg−1 · min−1 P < 0.05 vs. control) by an amount almost equal to the decrement in glucose oxidation. Lipid infusion did not detectably interfere with insulin-induced suppression of EGP. Energy expenditure failed to increase during the control insulin clamp but was significantly stimulated (∼10%, P < 0.01) by concomitant lipid administration (diet-induced thermogenesis). We conclude that in mildly hyperglycemic, nonobese NIDDM patients, excessive fatty substrate oxidation is unlikely to be responsible for the insulin resistance; increased lipid provision, however, enhances lipid oxidation and energy expenditure and inhibits glucose oxidation and total disposal. Thus, in this type of diabetes, Randles cycle does not appear to be spontaneously overactive but can be induced acutely, with metabolic and energetic consequences similar to those observed in nondiabetic subjects.

In Vivo Effect of Insulin on Intracellular Calcium Concentrations: Relation to Insulin Resistance

Elevated intracellular calcium concentrations ([Ca2+]i) have been described in essential hypertension and other insulin-resistant states. Our aim was to explore the relationship between insulin resistance and abnormal Ca2+ metabolism. In 50 nondiabetic subjects, half of whom had untreated essential hypertension, we simultaneously measured the in vivo effect of insulin on glucose metabolism (by the insulin clamp technique) and on platelet [Ca2+]i (by the Fura-2 method). In each subject, [Ca2+]i measurements (both in Ca(2+)-free medium and, sequentially, following in vitro Ca2+ loading) were obtained in the fasting state and after 2 hours of euglycemic hyperinsulinemia. In the fasting state, no association was found between any measure of [Ca2+]i and gender, age, body mass index (BMI), blood pressure, or insulin sensitivity. In contrast, following in vivo insulin, platelet [Ca2+]i increased significantly (from 23 +/- 1 to 28 +/- 1 nmol/L in Ca(2+)-free medium, P < .01) in the whole group, and an insulin-induced increase in [Ca2+]i was associated with insulin resistance (r = .35, P = .01) but not with hypertension (r = .2, P = .17) and with impaired glucose storage (as determined by indirect calorimetry, r = .39, P = .01) but not with glucose oxidation. Thus, the 12 most insulin-resistant subjects were characterized by a cluster of abnormalities (mild overweight, higher blood pressure and prevalence of hypertension, higher serum triglycerides and insulin response to oral glucose, and reduced glucose storage) that included an insulin-induced increase in [Ca2+]i (9 +/- 2 nmol/L, P < .001 v basal). We conclude that insulin resistance, rather than hypertension, is associated with an abnormal in vivo effect of insulin on platelet [Ca2+]i.

Effects of acute hypercarnitinemia during increased fatty substrate oxidation in man

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)

Insulin sensitivity in familial hypercholesterolemia

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dilazep on coronary and systemic hemodynamics in humans

The cardiovascular effects of dilazep, a new antianginal drug, were investigated in 18 patients, who underwent cardiac catheterization and coronary angiography for the evaluation of chest pain. Dilazep, 0.2 mg/kg, was injected intravenously over 1 to 2 minutes. The changes induced by dilazep in coronary tone were assessed by quantitative angiography in four patients, changes in systemic and coronary hemodynamics and blood gases in eight patients, and changes in systemic and pulmonary hemodynamics and blood gases in six. In 6 of the 18 patients the effects on hemoglobin-O2 oxygen binding were also investigated. Following dilazep administration, we observed a marked reduction of coronary resistance (six patients) (0.5 vs 1.0 mm Hg X min X ml-1, p less than 0.01) and of aortic-coronary sinus oxygen difference (seven patients) (4.6 vs 12.3 vol%, p less than 0.01), and a 23% increase in coronary diameter (four patients) (p less than 0.001). Total systemic resistance was also reduced by dilazep (six patients). Conversely, only minimal or insignificant changes were observed in heart rate (14 patients), aortic pressure (14 patients), total pulmonary resistance (six patients), myocardial oxygen consumption (six patients), double product (14 patients), blood gases (seven patients), and hemoglobin-oxygen affinity (six patients). We conclude that dilazep exerts a powerful dilating action on coronary vasculature without appreciable increase of myocardial oxygen consumption and cardiac work simultaneously with a reduction of peripheral resistance.