Daniela Manzella

Oxidative Stress and Advancing Age: Results in Healthy Centenarians

OBJECTIVE: Our study aims at investigating the degree of oxidative stress in centenarians

Age-related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians.

It is widely known that advancing age is associated with impaired glucose handling. A unifying hypothesis explaining the relationship between aging and insulin resistance might encompass four main pathways, namely: (a) anthropometric changes (relative and absolute increase in body fat combined with a decline in fat free mass) which could be the anatomic substrate for explaining the reduction in active metabolic tissue; (b) environmental causes, mainly diet style and physical activity; (c) neuro‐hormonal variations [decline in plasma dehydroepandrosterone sulphate (DHEAS) and IGF‐1]; and finally (d) the rise in oxidative stress. Indeed previous studies have also investigated the occurrence and the degree of insulin resistance in healthy centenarians. Such data demonstrated that age‐related insulin resistance is not an obligatory finding in the elderly and that healthy centenarians have a preserved insulin action compared to aged subjects. Why insulin action is preserved in centenarians is still not known. Nevertheless, a possible approach to the question is to outline the centenarians anthropometric, endocrine and metabolic characteristics in order to design a clinical picture of such metabolic ‘successful aging’. According to the remodeling theory of age, the preserved insulin action in centenarians might be the net result of the continuous adaptation of the body to the deleterious changes that occur over time. Nevertheless, only future longitudinal studies specifically designed to investigate the relationship between extreme old age and degree of insulin sensitivity will provide a conclusive answer with regard to the pathophysiology of adaptive metabolic changes occurring in the elderly. Copyright

Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients

We investigated the possible role of losartan on insulin-mediated glucose uptake, substrate oxidation and blood flow in insulin-resistant hypertensive patients. Sixteen newly diagnosed patients with mild-to-moderate hypertension were studied. The study design was a single-blind, randomised, placebo-controlled trial. After a 1 week run-in period, each patient was randomly assigned to placebo (nu2009=u20097) and losartan (nu2009=u20099). Both treatment periods lasted 4 weeks. At baseline, and at the end of the placebo and losartan treatment periods, euglycaemic hyperinsulinaemic glucose clamp and indirect calorimetry were performed. Before and along each glucose clamp, blood flow was also determined in the femoral artery by image-directed duplex ultrasonography combining B-mode imaging and pulse Doppler beams. Losartan vs placebo lowered systolic blood pressure by 163 ± 3.5 and 147 ± 4.1 mmu2009Hg (Pu2009<u20090.001), and diastolic blood pressure by 95 ± 3.2 and 85 ± 3.2 mmu2009hg (Pu2009<u20090.001). losartan enhanced glucose metabolic clearance rate by 5.1 ± 0.3 and 6.3 ± 0.4 mg/kg × min (Pu2009<u20090.05), and whole body glucose disposal (wbgd) by 29.2 ± 0.5 and 38.1 ± 0.4 μ mol/kg free fatty mass (FFM) × min (Pu2009<u20090.01) but did not affect heart rate. insulin-mediated change in blood flow was greater after losartan than placebo administration (111 ± 4 vs 84 ± 3%, Pu2009<u20090.01). per cent change in insulin-mediated stimulation of blood flow and wbgd were also correlated (ru2009=u20090.76, Pu2009<u20090.01). analysis of substrate oxidation revealed that losartan adminstration improved insulin action and non-oxidative glucose metabolism (nogm) (30.8 ± 2.2 vs 22.8 ± 2.8u2009μmol/kg FFM × min, Pu2009<u20090.05). in conclusion losartan improves insulin-mediated glucose uptake through an increase in nogm and blood flow in hypertensive patients.

Association of Fasting Plasma Free Fatty Acid Concentration and Frequency of Ventricular Premature Complexes in Nonischemic Non-Insulin-Dependent Diabetic Patients

We investigated the association between free fatty acid (FFA) concentration and ventricular premature complexes (VPCs) in nonischemic patients with non-insulin-dependent diabetes mellitus using 3 approaches: cross-sectional analysis (n = 142), intervention including induction of elevated FFA levels with Intralipid heparin (n = 15), and reduction in FFA levels with Acipimox (n = 34) and a longitudinal follow-up study (n = 59). Patients at the third tertile of fasting plasma FFA concentration had the strongest increase in VPCs. Independently of age, sex, body mass index (BMI), waist/hip ratio, left ventricular mass index, glycated hemoglobin, fasting plasma insulin and triglyceride concentration, and daily physical activity, FFA concentration and VPCs were significantly correlated (r = 0.21 p <0.01). At multiple logistic regression analysis independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, glycated hemoglobin, fasting plasma insulin, triglycerides and potassium concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity, plasma FFA concentration was a significant determinant of VPCs (odds ratio 1.2, 95% confidence interval 1.0 to 2.3). Intralipid infusion (10% in 24 hours) (n = 15) and acipimox administration (250 mg, 4 times/day) (n = 34) increased, and decreased fasting plasma FFA concentration, respectively. In those studies, change in VPCs paralleled the effects on plasma FFA. In the longitudinal study (n = 59), plasma FFA concentration predicted the development of VPCs (RR 1.4 95% confidence interval 1.0 to 1.9) independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, fasting plasma triglyceride concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity. In conclusion, in nonischemic patients with non-insulin-dependent diabetes mellitus, plasma FFA concentration is associated with the frequency of ventricular premature complexes.

Effects of different insulin infusion rates on heart rate variability in lean and obese subjects.

The low-frequency to high-frequency ratio (LF/HF ratio) is an index of cardiac sympathovagal balance. We hypothesized that insulin might also stimulate the LF/HF ratio. Thus, 15 lean and 15 obese subjects were studied. Each subject underwent sequential hyperinsulinemic clamps (insulin infusion rate 0.50, 1, and 2 mU/kg x min) while the heart rate was recorded by the Holter technique continuously. Indirect calorimetry allowed determination of the respiratory quotient (Rq) and substrate oxidation. The leg blood flow (LBF), leg vascular resistance (LVR), and plasma norepinephrine concentration were also measured. In seven lean subjects, hyperinsulinemic clamps were repeated along with propranolol infusion (0.1 mg x kg(-1) as an intravenous bolus dose followed by continuous intravenous infusion of 0.5 mg x kg(-1) x min(-1) throughout the study). Lean subjects had better insulin action than obese subjects. Insulin infusion was associated with an increase of the deltaLF/HF ratio in both lean (P < .001 for time-dependent changes) and obese (P < .02 for time-dependent changes) subjects; however, the extent of insulin-mediated stimulation of the LF/HF ratio was greater in lean versus obese subjects. Insulin infusion did not significantly affect HF values in both groups. Independently of gender, body fat, changes in the plasma norepinephrine concentration, LBF, and LVR, the deltaLF/HF ratio at the end of the fastest insulin infusion (0.8 +/- 0.2 v 0.3 +/- 0.2, P < .04) was still greater in lean versus obese subjects. The deltaLF/HF ratio was also more stimulated during insulin versus insulin + propranolol infusion in lean subjects. In conclusion, insulin stimulates the LF/HF ratio in both lean and obese subjects and thus produces a shift in the cardiac autonomic nervous system activity toward sympathetic predominance.

Hyperinsulinemia is associated with ventricular premature complexes

The study investigated a possible association between fasting plasma insulin (FPI) levels and ventricular premature complexes (VPCs). One hundred eighty-six subjects without coronary artery disease (CAD), diabetes, hypertension, and left ventricular hypertrophy were recruited. All subjects underwent 24-hour electrocardiographic monitoring and oral glucose tolerance testing. The subjects were slightly overweight, normotensive, and nondiabetic. Subjects at the third tertile of FPI concentrations were the oldest and heaviest, with prevalent upper-body fat distribution, and had enhanced fasting plasma triglyceride and potassium concentrations, lower fasting plasma high-density lipoprotein (HDL) cholesterol concentration, and a greater number of VPCs versus subjects at the first and second tertiles. Independently of age, sex, body mass index (BMI), and waist to hip ratio (WHR), VPCs were correlated with FPI concentration (r = .19, P < .01). Multiple logistic regression analyses in which the presence or absence of VPCs was the dependent variable demonstrated that FPI concentrations were associated with VPCs independently of age, sex, BMI, WHR, daily physical activity (DPA), left ventricular mass index (LVMI), plasma low-density lipoprotein (LDL)/HDL cholesterol ratio, and triglyceride concentration (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0 to 1.6). After addition to the model of fasting plasma free fatty acids ([FFA] OR, 0.7; 95% CI, 0.6 to 1.3) or potassium (OR, 0.7; 95% CI, 0.6 to 1.1) concentrations, the association between FPI concentrations and VPCs is no longer significant. In conclusion, FPI concentrations are associated with VPCs in nondiabetic, normotensive, nonischemic subjects.

Oxidative Stress and Advancing Age

Free radicals are highly reactive atoms or molecules that have one or more unpaired electrons in their atomic structure. Oxidative damage inflicted by reactive oxygen species is also referred to as “oxidative stress” (1). The susceptibility of a given organ or system to the oxidative stress is function of the balance between pro-oxidant factors and those scavenging them (1). The nonenzymatic, free radicals mediated oxidation of biological molecules, membranes and tissue is associated with a variety of pathological events such as cancer, aging and, diabetes mellitus (1). In this latter disease, oxidative stress seems mainly due to both an increased production of plasma free radical concentrations and a sharp reduction of antioxidant defenses (1).

Should we recommend the therapeutical use of vitamin E in diabetic patients

The therapeutic application of vitamin E was initially restricted to thrombocytopenic purpura and later extended to coronary artery diseases and peripheral vascular arteriosclerosis due to the potency of its effects. Several recent studies have pointed out that vitamin E supplementation is useful for reducing low-density lipoprotein oxidation and thus might be protective towards coronary heart disease. Such data has been confirmed in many in vitro data, while in vivo results of reports from epidemiological studies are much more controversial. More consistent is the evidence showing vitamin E to improve endothelial function especially in diabetic patients. Finally, chronic vitamin E has been demonstrated to improve the metabolic control in diabetic patients. Whether chronic vitamin E administration at pharmacological doses and for long time, is safe is still debated. A sure response to such a query will open the possibility for recommending vitamin E as a therapeutic agent in diabetic patients.