Anna D'Amore

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.

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.

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.

Evidence for a relationship between free radicals and insulin action in the elderly

In forty healthy subjects with normal glucose tolerance divided by age into four groups (group A, subjects with mean age < 25 years [n = 10]; group B, subjects with mean age < 40 years [n = 9]; group C, subjects with mean age < 60 years [n = 11]; group D, subjects with mean age > 75 years [n = 10]) and were matched for body mass index (BMI), lean body mass (LBM), mean arterial blood pressure, and sedentary life style, we determined the plasma O2- production, reduced to oxidized glutathione level ratio (GSH/GSSG), and plasma membrane microviscosity. Euglycemic hyperinsulinemic (1 mU/kg.min-1 for 120 minutes) glucose clamp with simultaneous D-3-H glucose infusion and indirect calorimetry allowed determination of glucose turnover parameters and substrate oxidation. In the oldest group of subjects, a significant increase in plasma O2-production and membrane microviscosity associated with a significative reduction in glucose disappearance rate (Rd), total body glucose disposal (TBGD), and nonoxidative glucose metabolism was found. In group D subjects (n = 10), all of these changes were correlated with one another. In a multiple regression analysis of the pooled data from all study subjects (n = 40), only plasma O2- production levels displayed a statistically significant relation with TBGD and nonoxidative glucose metabolism. In conclusion, in aged patients a significant relationship between free radical production and insulin action seems to exist.

Left ventricular hypertrophy is associated with a stronger impairment of non-oxidative glucose metabolism in hypertensive patients

Abstract. Hypertensive patients with left ventricular hypertrophy (LVH) have a higher degree of hyper‐insulinaemia than hypertensive patients without LVH. Obese patients with LVH have also been demonstrated to have a very low glucose disappearance rate after an intravenous glucose bolus. No studies have investigated the difference in insulin action and substrate oxidation in hypertensive patients with and without LVH. For this reason 36 subjects were enrolled for our study: (1) healthy control subjects (n=10); (2) hypertensive patients without LVH (n= 12); and (3) hypertensive patients with LVH (n= 14). All subjects underwent an oral glucose tolerance test (OGTT, 75 g of glucose) and a euglycaemic hyperinsulinaemic glucose clamp (insulin infusion rate, 71 pmol(kgmin)‐1 for 120min). In this latter test indirect calorimetry allowed substrate oxidation determination. Echocardiographic methods allowed LVH assessment. Hypertensive patients with LVH had the lowest insulin‐mediated nonoxidative glucose metabolism compared to hypertensive patients without LVH (P<0.01) and to healthy subjects (P< 0.001). In the whole group of hypertensive patients (n= 26), partial correlations showed left ventricular mass index (LVMI) associated with fasting plasma insulin levels (r= 0.44 P<0.005), insulin‐mediated whole body glucose disposal (r= ‐0.41 P<0.01) and nonoxidative glucose metabolism (r= ‐0.33 P<0.04) independently of age, body weight, systolic blood pressure and plasma catechola‐mines levels. In conclusion, our data provide evidence that LVH in hypertensive patients is associated with a worsening in nonoxidative glucose metabolism.

Low-Dose Iloprost Infusion Improves Insulin Action in Aged Healthy Subjects and NIDDM Patients

OBJECTIVE To investigate the effect of iloprost infusion on insulin action. RESEARCH DESIGN AND METHODS Thirteen healthy subjects and 13 non-insulin-dependent diabetes mellitus (NIDDM) patients matched for age (68.2 ± 0.5 vs. 67.9 ± 0.5 years, NS), gender ratio (7 men:6 women vs. 6 men:7 women), body weight, body fat distribution, arterial blood pressure, and plasma triglycéride levels (1.89 ± 0.09 vs. 1.87 ± 0.08 mmol/l, NS) were studied. In eight healthy subjects and eight NIDDM patients, we studied insulin action by euglycemic glucose clamp (insulin infusion rate 2 mU · kg−1 · min−1) along with saline and iloprost delivery (0.7 ng · kg−1 · min−1). In the other five subjects of each group, forearm blood flow and insulin-mediated glucose uptake during saline and iloprost infusion (0.7 ng · kg−1 · min1) were investigated. RESULTS Iloprost infusion improved insulin-stimulated whole-body glucose uptake and oxidative and nonoxidative glucose metabolism in both study groups. Forearm blood flow under basal conditions and with insulin infusion (2 mU · kg−1 · min−1) did not show any significant difference from that during saline and iloprost infusion (0.7 ng · kg−1 · min−1) in healthy subjects and diabetic patients. CONCLUSIONS Iloprost infusion improves insulin action in healthy subjects and NIDDM patients.

Different contribution of substrates oxidation to insulin resistance in malnourished elderly patients with cancer.

Background. The relative contribution of malnutrition and cancer to insulin resistance in elderly patients is still poorly understood.

Effects of physiological plasma insulin levels on glucose turnover parameters in familial hypercholesterolemia

Eight young, non-obese patients with primary familial hypercholesterolemia (FH) and 8 healthy subjects matched for age, body mass index, lean body mass, plasma triglyceride and HDL-levels and arterial blood pressure were selected from a lipid clinic. Patients with FH had higher plasma LDL-cholesterol (8.3 +/- 0.5 vs. 4.1 +/- 0.2 mmol/l, P < 0.001) than controls but similar plasma triglyceride (1.15 +/- 0.04 vs. 1.10 +/- 0.02 mmol/l P = NS) levels. Both study groups were submitted to a euglycaemic hyperinsulinemic glucose clamp combined with simultaneous infusion of [3H]glucose to measure insulin action on whole-body glucose uptake and on hepatic glucose production. Two insulin infusion rates (0.15 mU/kg per min from 0 to 120 min and 0.30 mU/kg per min from 121 to 240 min) were used resulting in similar plasma insulin levels in both groups studied. Our results demonstrate that both whole-body glucose uptake and hepatic glucose output are similar in the fasting state as well as during insulin administration in both groups of subjects. We conclude that, in the absence of other causes of insulin resistance, isolated hypercholesterolemia is associated with normal sensitivity to insulin in both liver and peripheral tissues.