Felice D'Onofrio

Metabolic and Cardiovascular Effects of Carvedilol and Atenolol in Non-Insulin-Dependent Diabetes Mellitus and Hypertension: A Randomized, Controlled Trial

Compared with the general population, diabetic patients have an approximately twofold increased risk for hypertension and are more susceptible to the vascular consequences of high blood pressure. Indeed, an estimated 35% to 75% of cardiovascular and renal complications in diabetic patients can be attributed to hypertension [1]. Treatment with -adrenergic antagonists has been shown to be associated with an increased risk for impaired glucose tolerance or diabetes; this has been attributed to the worsening of insulin resistance and the deterioration of lipoprotein metabolism caused by the agents [2]. All this has made physicians reluctant to prescribe -blockers for diabetic patients with hypertension, although cardioselective -blockers have reduced mortality associated with cardiovascular causes in secondary prevention trials [3]. Carvedilol is a multiple-action antihypertensive drug with nonselective -adrenoreceptor and selective -adrenoreceptor blocking activity [4]. Its ratio of 1-blocking potency to 1-blocking potency is 7.6:1 for a 50-mg dose [5]. In addition, carvedilol prevents lipid peroxidation and the depletion of endogenous antioxidants [6]. This may be particularly useful in diabetic patients who may have increased free-radical activity (oxidative stress) [7]. We compared the metabolic and cardiovascular effects of carvedilol with those of atenolol in diabetic patients with hypertension in a randomized, double-blind, controlled trial. Methods Participants Our research protocol was approved by our institutional review board, and informed consent was obtained from patients before participation. Men and women who had noninsulin-dependent diabetes mellitus and had a supine diastolic blood pressure of 90 to 105 mm Hg on at least two occasions at the end of a 4- to 6-week placebo run-in period were eligible to participate. All patients were referred from the outpatient department of our institution and were consecutively chosen. A total of 45 patients met the inclusion criteria and were randomly assigned to treatment. All but 3 patients completed the study. Study Design Our study had a randomized, double-blind design for parallel study groups. Patients who had blood pressure greater than 160/90 mm Hg or who were taking antihypertensive drugs entered a 4- to 6-week run-in period, during which placebo was given to replace the previous antihypertensive drug, if any. Routine hematologic and blood chemistry analyses (hematologic indices, serum sodium and potassium concentrations, liver enzyme levels, urea concentrations, and creatinine concentrations) were done during the initial screening and after the treatment period. Patients were randomly assigned to receive either carvedilol (25 mg once daily) or atenolol (50 mg once daily) in the morning for 24 weeks. After 4 weeks, patients whose diastolic blood pressure while seated was more than 90 mm Hg and had not decreased by at least 10 mm Hg had their dose of study medication doubled for the remaining 20 weeks of the study. A person who was not involved in trial management randomly assigned the patients using random numbers derived from published tables. The list of randomization numbers was used to label the drug boxes, which were given to the participants sequentially. Both patients and caregivers were blinded to treatment, and randomization codes were not broken until all laboratory measurements had been done. Cardiovascular and metabolic variables were checked at the end of the placebo period and at the end of the active treatment period. All participants were instructed to follow a weight-maintaining diet (50% carbohydrates, 30% lipids, 20% protein) for 3 days before the experiments were done. Side effects, concomitant diseases, and blood pressure were assessed by interview and physical examination every fourth week during treatment. Clinical and Laboratory Measurements Patients were asked to refrain from smoking and to fast overnight before each metabolic assessment was done. The euglycemic clamp technique was used to estimate insulin sensitivity in vivo by infusing insulin (1 mU/kg of body weight per minute) and glucose to keep plasma glucose levels at the baseline concentration [8]. At the unchanged plasma glucose concentrations, the amount of glucose required to maintain euglycemia equals whole-body glucose disposal and is expressed in mol/kg per minute (M). The insulin sensitivity index (M/insulin level during the clamp procedure) measures how effectively plasma insulin induces glucose uptake in insulin-sensitive tissues, such as muscle and fat. Substrate oxidation was estimated by indirect calorimetry [9]. On the day after calorimetry, the patients had an oral glucose tolerance test (75 g of glucose). On the third day, they had an insulin tolerance test (0.15 U/kg). Blood pressure was measured with appropriate cuff size three times after patients rested for 5 minutes in the supine position. Plasma glucose, insulin, glucagon, and epinephrine levels were measured as described elsewhere [10]; hemoglobin A1c (HbA1c) was measured by column chromatography (Bio-Rad, Milan, Italy); and cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were determined enzymatically [9]. Left ventricular mass normalized by surface area was measured by echocardiography [9]. Serum levels of lipid peroxides were measured as reaction products of malondialdehyde with thiobarbituric acid (thiobarbituric-acid-reactive substances) according to the method of Waravdekar and Sadlaw [11], with slight modifications. Normal lipid peroxide values for our laboratory are 0.34 to 0.86 mol/L. Statistical Analysis All values in the tables are presented as the mean SD unless otherwise noted; 95% CIs are provided where appropriate. The areas under the glucose and insulin curves were calculated by trapezoidal rule [12]. Change was calculated as the value obtained at the end of intervention minus the value obtained at the beginning of intervention. A preliminary analysis of variance was used to assess the significance within and between groups. One-sample t-tests were used to compare values obtained before and after carvedilol or atenolol therapy, and two-sample t-tests were used for between-group comparisons. Results Three patients (two in the atenolol group and one in the carvedilol group) were unavailable for follow-up; they refused to complete the study and did not specify a reason. These patients dropped out early (between weeks 4 and 8) after randomization; analysis of the study results did not differ when the analysis was done according to actual treatment or according to intention to treat (we used the latter method). Compliance, determined by tablet count, was 94.5% in the carvedilol group and 95% in the atenolol group. The baseline characteristics of the 45 patients who completed the study are shown in Table 1. The two groups were similar at baseline. Body mass index did not change in either group after treatment. Approximately one third of patients in each group (32% in the carvedilol group and 35% in the atenolol group) required upward dose titration at week 4 because of inadequate response. At the end of treatment, 91% of patients receiving carvedilol and 85% of those receiving atenolol had a diastolic blood pressure while seated of less than 90 mm Hg or had their diastolic blood pressure decreased by more than 10 mm Hg (P > 0.2 for comparison). Average systolic and diastolic blood pressure and left ventricular mass decreased in both groups, but the differences between the groups were small (P > 0.2) (Table 2). The decrease in heart rate was greater in patients receiving atenolol than in those receiving carvedilol (P < 0.005). The decrease in mean triglyceride level was 0.56 mmol/L greater (P < 0.001) and the increase in high-density lipoprotein cholesterol level was 0.13 mmol/L greater (P < 0.001) with carvedilol than with atenolol. Table 1. Baseline Characteristics of the Study Patients Table 2. Effects of 24-Week Intervention with Carvedilol or Atenolol in 45 Patients with Non-Insulin-Dependent Diabetes Mellitus and Hypertension* Mean fasting plasma glucose and insulin levels decreased during carvedilol treatment and increased during atenolol treatment (Table 2). The HbA1c level decreased by 1.4% in the carvedilol group and increased by 4% in the atenolol group (P < 0.001 for the difference). Mean total glucose disposal and insulin sensitivity index increased during carvedilol treatment and decreased during atenolol treatment (P 0.01 for the difference). Serum levels of thiobarbituric-acid-reactive substances decreased by 0.25 mol/L in the carvedilol group and did not change in the atenolol group (P < 0.001 for the difference). The decreases in plasma glucose and insulin responses to the oral glucose load were 61 mmol/L 180 minutes greater (CI, 101 to 21 mmol/L 180 minutes; P = 0.035) and 6.2 nmol/L 180 minutes greater (CI, 9.8 to 2.6 nmol/L 180 minutes; P = 0.03), respectively, with carvedilol than with atenolol (data not shown). The plasma glucose level nadir occurred 60 minutes after the insulin bolus was administered and was not affected by either drug (P = 0.09) (data not shown). Glucagon and epinephrine responses to hypoglycemia were similar before and after treatment with both drugs (P > 0.08) (data not shown). Discussion Our results show that both carvedilol and atenolol effectively decrease blood pressure and ventricular mass in patients with diabetes and hypertension. They also show that the drug doses administered in this study are equivalent with regard to their ability to decrease blood pressure in these patients, who are particularly at risk for cardiovascular disease. The similarities between the two drugs end with their cardiovascular effects, however; their metabolic effects are different and, to a large extent, divergent. Fasting plasma glucose and insulin levels decreased during carvedilol treatment and increased during atenolol treatment. Th

MAGNESIUM AND GLUCOSE HOMEOSTASIS

SummaryMagnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects.

Metformin Improves Glucose, Lipid Metabolism, and Reduces Blood Pressure in Hypertensive, Obese Women

OBJECTIVE To determine the effects of metformin on blood pressure, left ventricular mass, and some metabolic and endocrine parameters in nondiabetic, obese, hypertensive women. RESEARCH DESIGN AND METHODS Twelve obese, nondiabetic, hypertensive women received 850 mg metformin 2 times/day for 12 wk and placebo for another 12 wk, according to a double-blind, cross-over, randomized design. All patients were hospitalized 4 times, i.e., before randomization and after each treatment (metformin or placebo), to conduct metabolic and cardiovascular investigations (oral glucose tolerance test, euglycemic clamp associated with indirect calorimetry, and echocardiography). RESULTS Fasting glucose, HbA1c, fasting and glucose-stimulated insulin, blood pressure and left ventricular mass, cholesterol, triglycerides, and fibrinogen decreased significantly after metformin treatment, whereas high-density lipoprotein cholesterol increased. The improvement in glucose metabolism resulted from increased sensitivity to insulin. CONCLUSIONS These findings suggest that metformin treatment in obese, nondiabetic, hypertensive women produces a more favorable cardiovascular risk profile.

Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

SummaryOur study investigates short- and long-term effects of infusion of non-esterified fatty acids (NEFA) on insulin secretion in healthy subjects. Twelve healthy individuals underwent a 24-h Intralipid (10% triglyceride emulsion) infusion at a rate of 0.4 ml/min with a simultaneous infusion of heparin (a bolus of 200 U followed by 0.2 U/min per kg body weight). After an overnight fast (baseline), at 6 and at 24 h of Intralipid infusion and 24 h after Intralipid discontinuation (recovery test), all subjects underwent an intravenous glucose tolerance test (iv-GTT) (25 g of glucose/min). Intralipid infusion caused a threefold rise in plasma NEFA concentrations with no difference between the 6- and the 24-h concentrations. Compared to baseline acute insulin response (AIR) (AIR=63±8 mU/l), short-term (6-h) Intralipid infusion was associated with a significant increase in AIR (86±12 mU/l p<0.01); in contrast, long-term (24-h) Intralipid delivery was associated with inhibition of AIR (31±5 mU/l) compared to baseline (p<0.001) and to the 6-h (p<0.03) triglyceride emulsion infusion. Intralipid infusion was associated with a progressive and significant decline in respiratory quotient (RQ). A positive correlation between changes in fasting plasma NEFA concentrations and AIR at the 6-h infusion (r=0.89 p<0.001) was found. In contrast, at the end of the Intralipid infusion period, changes in plasma NEFA concentrations and AIR were negatively correlated (r=−0.87 p<0.001). The recovery test showed that fasting plasma NEFA concentrations, RQ and AIR had returned to baseline values. In the control study (n=8) 0.9% NaCl infusion did not mimick the effect of Intralipid. In conclusion, our study demonstrates that short- and long-term exposures of beta cells to high plasma NEFA concentrations have opposite effects on glucose-induced insulin secretion.

Improved Insulin Response and Action by Chronic Magnesium Administration in Aged NIDDM Subjects

In eight aged non-insulin-dependent diabetes mellitus (NIDDM) subjects, insulin response and action were studied before and after chronic magnesium supplementation (2 g/day) to diet. Chronic magnesium supplementation to diet versus placebo produced 7) a significant increase in plasma (0.83 ± 0.05 vs. 0.78 ± 0.06 mM, P < .05) and erythrocyte (2.03 ± 0.06 vs. 1.88 ± 0.09 mM, P < .01) magnesium levels, 2) an increase in acute insulin response (AIR) (4.0 ± 0.6 vs. - 1 .6 ± 0.6 mU/L, P < .05) to glucose pulse, and 3) an increase in glucose infusion rate (GIR) (3.6 ± 0.6 vs. 2.9 ± 0.5 mg kg∼1 min−1 P < .025) calculated in the last 60 min of a euglycemic-hyperinsulinemic (100U m2 · min−1 during 180 min) glucose clamp. Net increase in AIR, glucose disappearance rate after glucose pulse, and GIR were significantly and positively correlated to the net increase in erythrocyte magnesium content calculated after chronic magnesium supplementation to diet. In conclusion, our data suggest that NIDDM subjects may benefit from therapeutic chronic administration of magnesium salts.

Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients

OBJECTIVE To investigate the potential metabolic benefits deriving from daily vitamin E administration in type II diabetic patients. RESEARCH DESIGN AND METHODS Twenty-five type II diabetic patients were invited to randomly take placebo or vitamin E (d-α-tocopherol; 900 mg/day) along a similar 3-mo period in a double-blind, crossover procedure. A wash-out period of 30 days separated the two treatment periods. At the end of each treatment period blood samples were drawn for plasma metabolites determination, and an intravenous glucose tolerance test (25 g of glucose as bolus in 3 min) was performed. During this study oral hypoglycemic agents were not discontinued or changed in their dosage. RESULTS Chronic vitamin E administration reduced plasma glucose (8.3 ± 0.3 vs. 7.5 ± 0.2 mM, P > 0.05), triglycerides (2.27 ± 0.08 vs. 1.67 ± 0.09 mM, P < 0.02), free fatty acids (786 ± 116 vs. 483 ± 64 mM), total cholesterol (6.74 ± 0.09 vs. 5.50 ± 0.10 mM, P < 0.05), low-density lipoprotein cholesterol (4.73 ± 0.11 vs. 3.67 ± 0.07 mM, P < 0.04), and apoprotein B (1.7 ± 0.3 vs. 1.0 ± 0.1 g/L) levels but did not affect β-cell response to glucose. HbA1 levels (7.8 ± 0.3 vs. 7.1 ± 0.5%, P < 0.05) were also significantly lowered after chronic vitamin E administration. CONCLUSIONS Daily vitamin E supplements seem to produce a minimal but significant improvement in the metabolic control in type II diabetic patients. More studies are necessary before conclusions can be drawn about the safety of vitamin E during long-term administration.

Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure

Congestive heart failure is a condition associated with increased plasma norepinephrine levels. Moreover, norepinephrine has been recently demonstrated to affect glucose homeostasis by decreasing insulin sensitivity. In the present study, eight patients suffering from chronic congestive heart failure and 10 healthy age- and body mass index-matched subjected were submitted to both an oral glucose tolerance test (OGTT; 75 g) and a euglycemic hyperinsulinemic glucose clamp. During the 360 minutes of the glucose clamp, insulin was infused at three different rates (25, 50, and 100 mU/kg/h), while D-3H glucose infusion allowed determination of glucose turnover. In basal conditions, patients versus controls had similar plasma glucose (5.2 +/- 0.1 v 4.9 +/- 0.2 mmol/L,P = NS), but higher plasma insulin (125.7 +/- 9.2 v 35.7 +/- 3.3 pmol/L,P less than .01), norepinephrine (5.39 +/- 0.13 v 1.47 +/- 0.22 nmol/L,P less than .001), and free fatty acid (FFA) (927 +/- 79 v 792 +/- 88 mumol/L,P less than .05) levels. In patients, basal plasma norepinephrine correlated with FFA levels (r = .65, P less than .025). After loading glucose, plasma glucose and insulin levels were still significantly higher in patients than controls. Euglycemic hyperinsulinemic glucose clamp produced a lower insulin-mediated inhibition of endogenous (hepatic) glucose production (HGP) and a greater increase in both glucose disappearance rate (Rd) and glucose metabolic clearance rate (gMCR) in patients than in controls during the first two insulin infusion rates (25 and 50 mU/kg/h). By contrast, these differences disappeared during the highest insulin infusion rate (100 mU/kg/h). Insulin-mediated decrease in plasma FFA levels was also lower in patients than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Total-body and myocardial substrate oxidation in congestive heart failure

Congestive heart failure is a condition associated with increased plasma norepinephrine levels, which have been demonstrated to impair glucose handling. In the present study, 10 patients suffering from congestive heart failure and 10 healthy age- and body mass index-matched subjects were submitted to a hyperinsulinemic (insulin infusion rate, 0.5 mU/kg.min-1) glucose clamp, while simultaneous D-3H-glucose infusion and indirect calorimetry allowed for determination of glucose turnover parameters and substrate oxidation, respectively. On a separate day, basal local (myocardial) indirect calorimetry was also performed. Our data demonstrate that in congestive heart failure, fasting myocardial glucose oxidation (Gox) was inhibited with a simultaneous increase in lipid oxidation (Lox). In our patients, a significant decrease in total-body insulin-stimulated glucose metabolism (31.0 +/- 0.5 v 20.3 +/- 0.4 mumol/kg.min-1, P < .01) and nonoxidative glucose metabolism (18.9 +/- 1.1 v 11.0 +/- 0.5 mumol/kg.min-1, P < .05) was also found. Such latter changes were also associated with a simultaneous overdrive of Lox (0.4 +/- 0.2 v 1.9 +/- 0.2 mumol/kg.min-1, P < .02) that was correlated with an enhanced availability of plasma free fatty acids (FFAs).

Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (type II) diabetic patients

Ten healthy subjects and 30 non-insulin-dependent (type II) diabetic patients matched for age, gender ratio, body mass index, lean body mass (LBM), waist to hip ratio, and arterial blood pressure volunteered for the study. In all subjects, fasting plasma free radical (O2-) levels and basal membrane lipid fluidity (MLF) and protein mobility (MPM) were determined. The whole group of subjects underwent a euglycemic hyperinsulinemic glucose clamp with simultaneous indirect calorimetry for substrate oxidation determination. Diabetic patients versus controls displayed higher fasting plasma glucose (8.3 +/- 0.4 v 5.1 +/- 0.4 mmol/L, P +/- .001), O2- (0.48 +/- 0.02 v 0.16 +/- 0.02 mumol/L x min), and hemoglobin A1c ([HbA1C] 7.9% +/- 0.4% v 5.7% +/- 0.3%, P < .03) levels and a stronger reduction in basal MLF (0.243 +/- 0.006 v 0.318 +/- 0.009, P < .003) and basal MPM (0.348 +/- 0.003 v 0.518 +/- 0.010, P < .002). Whole-body glucose disposal (WBGD) and oxidative and nonoxidative glucose metabolism were also significantly lower in diabetics than in controls. In diabetic patients (n = 30), plasma O2- levels correlated with basal MLF (r = -.59, P < .005), basal MPM (r = -.84, P < .001), fasting plasma insulin level (r = .51, P < .004), WBGD (r = -.53, P < .002), and nonoxidative (r = -.45, P < .01) glucose metabolism. In conclusion, our results demonstrate that a relationship between plasma O2- levels and insulin action occurs in non-insulin-dependent diabetics.

Effect of metformin on food intake in obese subjects

It has been hypothesized that metformin inhibits food intake, but in humans such effect needs to be demonstrated. Our study aims at investigating the effect of metformin administration on food intake in obese, non‐diabetic, normotensive patients.