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Biomedical subjects

Angelo Avogaro

Publications and source records attributed to Angelo Avogaro.

49 records · Page 3Linked to original sources
PubMed2004

Insulin generates free radicals by an NAD(P)H, phosphatidylinositol 3'-kinase-dependent mechanism in human skin fibroblasts ex vivo.

Oxidative stress may be involved in the development of vascular complications associated with diabetes; however, the molecular mechanism responsible for increased production of free radicals in diabetes remains uncertain. Therefore, we examined whether acute hyperinsulinemia increases the production of free radicals and whether this condition affects proliferative extracellular signal-regulated kinase (ERK-1 and -2) signaling in human fibroblasts in vitro. Insulin treatment significantly increased intracellular superoxide anion (O(2)(-)) production, an effect completely abolished by Tiron, a cell-permeable superoxide dismutase (SOD) mimetic and by polyethylene glycol (PEG)-SOD, but not by PEG catalase. Furthermore, insulin-induced O(2)(-) production was attenuated by the NAD(P)H inhibitor apocynin, but not by rotenone or oxypurinol. Inhibition of the phosphatidylinositol 3'-kinase (PI 3'-kinase) pathway with LY294002 blocked insulin-stimulated O(2)(-) production, suggesting a direct involvement of PI 3'-kinase in the activation of NAD(P)H oxidase. The insulin-induced free radical production led to membranous translocation of p47phox and markedly enhanced ERK-1 and -2 activation in human fibroblasts. In conclusion, these findings provided direct evidence that elevated insulin levels generate O(2)(-) by an NAD(P)H-dependent mechanism that involves the activation of PI 3'-kinase and stimulates ERK-1- and ERK-2-dependent pathways. This effect of insulin may contribute to the pathogenesis and progression of cardiovascular disease in the insulin resistance syndrome.

Biological Transport↗
PubMed2004

Acute alcohol consumption improves insulin action without affecting insulin secretion in type 2 diabetic subjects.

OBJECTIVE: Long-term exposure to alcohol is associated with an improvement in insulin sensitivity. At this time, however, there is no definitive proof that alcohol per se has an effect on the insulin sensitivity index (S(i)) in type 2 diabetes patients. The aim of the present study was to assess the role of acute moderate alcohol intake on insulin sensitivity and insulin secretion in comparable subjects with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Frequently sampled intravenous glucose tolerance tests (FSIGTs) were performed twice on eight healthy and eight type 2 diabetic volunteers. Forty grams of alcohol (vodka 40% wt/vol) or tap water were sipped from time -60 min to the end of the FSIGT. RESULTS: Lactate area under the curve (AUC) was higher in both groups during the alcohol study than in the control study. Free fatty acid (FFA) AUC was higher in type 2 diabetic subjects than in control subjects; alcohol slightly reduced FFA by 17% in control subjects (34 +/- 4 mmol. min(-1). l(-1); P = 0.1) but significantly decreased FFA by 23% in type 2 diabetic subjects (54 +/- 10; P = 0.007). Beta-cell response was markedly reduced in type 2 diabetic subjects regardless of the type of study. Alcohol significantly increased S(i) in both groups. CONCLUSIONS: Acute alcohol consumption improves insulin action without affecting beta-cell secretion. This effect may be partly due to the inhibitory effect of alcohol on lipolysis. Alcohol intake increases insulin sensitivity and may partly explain both the J-shaped relationship between the prevalence of diabetes and the amount of alcohol consumption and the decreased mortality for myocardial infarction.

Aged↗
PubMed2003

Elevated non-esterified fatty acids impair nitric oxide independent vasodilation, in humans: evidence for a role of inwardly rectifying potassium channels.

UNLABELLED: To evaluate the role of elevation of non-esterified fatty acids on forearm nitric oxide (NO) dependent and independent relaxation, four studies were performed in the forearms of 14 normals: (1). endothelium-dependent and -independent vasodilations were assessed during acetylcholine (Ach) and sodium nitroprusside (SNP) infusions; (2). flow-mediated vasodilation (FMD) was assessed; (3) .bradykinin (BK) was infused during NO and prostaglandin inhibition (NO clamp); (4). blood flow (FBF) was measured during Ouabain, a Na(+)/K(+) ATPase, and BaCl(2), rectifying potassium channel (K(IR)) blockers, respectively. All studies were performed before and after 120 min. Intralipid+heparin (high-NEFA) infusion. Ach-mediated FBF increase was lower at high-NEFA (332+/-34 vs. 436+/-44% at 45 microg l forearm(-1) min(-1); % of ratio infused: control arm P<0.05), while SNP response was similar. FMD did not differ before and during high-NEFA, which induced a blunted response of FBF during BK with or without NO clamp. Ouabain and BaCl(2)-mediated FBF inhibition was lower (P<0.01) at high-NEFA. During ouabain alone FBF decreased slightly. IN CONCLUSION: High-NEFA exerts a negative role on both NO-dependent and independent vasodilations. The decrease in FBF, mediated by K(IR) inhibition, is blunted by high-NEFA: these substrates interfere with hemodynamic/metabolism coupling, possibly through the inhibition of these channels.

Acetylcholine↗
PubMed2003

Monocyte NADPH oxidase subunit p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress.

Oxidative stress is associated with diabetes mellitus: a role of vascular NADPH oxidase as a source of superoxide has been demonstrated. We determined whether in type 2 diabetes mononuclear cells, NADPH oxidase and the inducible hemeoxygenase (HO-1) gene expressions are activated. In monocytes from 25 outpatients with type 2 diabetes, p22(phox) gene expression was higher (0.71 +/- 0.09 p22(phox)/beta-actin gene expression ratio) than that observed in 19 controls (0.56 +/- 0.09, P < 0.001). Similarly, HO-1 gene expression was significantly higher in diabetic patients (0.77 +/- 0.12 HO-1/beta-actin gene expression ratio) than in controls (0.41 +/- 0.14, P < 0.001). The p22(phox) and HO-1 gene expressions were also determined during (plasma glucose 363 +/- 40 mg/dl) and after (125 +/- 11 mg/dl) metabolic decompensation in 10 type 2 diabetic patients. The correction of the metabolic milieu was associated with a 19% +/- 3% (P < 0.01) and 30% +/- 3% (P < 0.01) decrease in the p22(phox) and HO-1 gene expressions, respectively. In a multivariate analysis, age was independently associated to p22(phox) gene expression in circulating monocytes in type 2 diabetics [13% (adjusted R(2)), P < 0.05]. Decompensated type 2 diabetes is associated with increased p22(phox) and HO-1 gene expressions in circulating monocytes; the metabolic normalization reduces but does not normalize this activation. These findings suggest that these cells, which play a crucial role in the earliest events of atherosclerotic lesion, are subjected to an increased oxidative stress.

Actins↗
PubMed2003

L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach.

Defective endothelium is a key event in the development of atherosclerosis in diabetes: alteration of the L-arginine-nitric oxide (NO) pathway has been suggested. We propose a modeling approach of the L-arginine-NO pathway in vivo in both control and type 2 diabetic subjects based on the intravenous bolus injection of L-[(15)N]arginine and subsequent noncompartmental and compartmental model analysis of L-[(15)N] arginine in plasma and [(15)N]nitrate in the urine. No differences in arginine kinetics were observed between normal subjects and diabetic patients. [(15)N]nitrates were detectable up to 48 h from the L-(15)[N]arginine administration; no differences were found in the tracer-to-tracee ratio in each urine collection. However, the NO synthesis in plasma from arginine was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental analysis, by Mann-Whitney test) in diabetic patients than in control subjects when expressed both in absolute terms (50% decrease) and as percentage of NO turnover (30% decrease). This new modeling approach of L-arginine-NO pathway provides a detailed picture of arginine kinetics and nitrate metabolism. From our data, it appears that noncomplicated type 2 diabetic patients have a decreased conversion of arginine to NO.

Arginine↗
PubMed2003

[Diabetes and multimetabolic syndrome].

The metabolic syndrome is associated with increased morbility and mortality for cardiovascular disease. This syndrome is determined not only by metabolic alterations such as hyperglycemia, and hyperlipidemia but also by a chronic proinflammatory state. Another culprit in the formation and progression of vascular disease is the so-called endothelial dysfunction which is linked to insulin resistance itself. The common denominator of the metabolic syndrome is insulin resistance. The most convincing evidence for the existence of a syndrome comes from the cluster analysis which outlines four main factors: the "metabolic factor", the "pressor factor", the "lipid factor", and the "obesity factor". It is clear that the presence of the metabolic syndrome appears to identify a substantial additional cardiovascular risk above the individual risk factors. The studies available in the literature have pointed out the beneficial effects, in terms of cardiovascular mortality, of the treatment with inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins): this risk reduction has been observed despite the fact that high triglyceride and low HDL cholesterol levels, but not hypercholesterolemia, are the main features of the dyslipidemia observed in patients with this syndrome. Yet, despite a normal LDL cholesterol level, patients with this syndrome are at high risk for future cardiovascular events: for this reason treatment with statins is mandatory.

Diabetes Mellitus↗
PubMed2002

The fatty acid composition of plasma phospholipids and the insulin sensitivity in elderly diabetic patients. The Pro.V.A. study.

BACKGROUND AND AIMS: The prevalence of diabetes is increasing worldwide indicating that life-style habits are important determinants for this disease. The aim of this study was to examine the effects of dietary fats on insulin sensitivity in diabetic patients. METHODS: In a randomly selected sample of population aged 65 and older, plasma phospholipid fatty acid composition was determined by gaschromatography. The plasma phospholipid fatty acid composition is a reliable marker of the type of fats present in the diet. Insulin resistance was estimated with the Homeostasis Model Assessment (HOMA). RESULTS: Body weight, height, body mass index (BMI), waist circumference, serum cholesterol as well as fasting insulin, and the HOMA index were lower in the older groups. With increasing age, there was an increase in the monounsaturated fatty acid content and a decrease in the polyunsaturated and n-6 polyunsaturated fatty acids. In the linear regression analysis, saturated fatty acids were significantly related to waist circumference, fasting glucose, fasting insulin, and HOMA. Significant relations were also obserued between HOMA and BMI, triglycerides, waist circumference, and age. Triglycerides and HDL cholesterol were strongly interrelated as well as BMI and waist circumference. In the multiple regression analysis including age, BMI, waist circumference, triglycerides, HDL cholesterol, and saturated fatty acids, the HOMA index was predicted significantly only by age, BMI, and triglycerides. This model explained 28% of the HOMA variance. CONCLUSIONS: In elderly diabetic patients insulin sensitivity is modulated by age, BMI, and triglycerides, but the type of dietary fats is not independently associated with insulin sensitivity.

Age Factors↗
PubMed2002

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach.

The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S(G)(2*)), insulin sensitivity (S(I)(2*)), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 microg/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 +/- 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant (P < 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 +/- 7 min in the basal state and at 55 +/- 13 min in the Epi state (P < 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress.

Adult↗
PubMed2002

Glucose tolerance during moderate alcohol intake: insights on insulin action from glucose/lactate dynamics.

Moderate alcohol (ETOH) intake has been associated with a significant reduction in risk for infarction among general populations. In this study, we assessed the effects of low-dose ETOH (40 g over 3-h period as vodka) on the interaction between glucose (G), insulin, and lactate (L) during the insulin-modified frequently sampled i.v. glucose tolerance test (FSIGT) (0.3 U/kg body weight between 20-25 min) in eight normal volunteers. In the control (C) study, water was administered. An insulin-independent two-compartment model was used to describe G and L kinetics. Insulin sensitivity (S(I)) was significantly higher in the ETOH study than in the C study (2.49 +/- 0.52 vs. 0.92 +/- 0.20 10(-4) min(-1)microU(-1)ml, C vs. ETOH; P = 0.0391). No significant differences were observed in G effectiveness (0.029 +/- 0.004 vs. 0.033 +/- 0.004 min(-1)). Blood L levels were higher during FSIGT when ETOH was administered [area under the curve (AUC), 201 plus minus 16 vs. 123 +/- 23 mmol/liter in 240 min; P = 0.0001]. The dynamic analysis of blood L concentrations showed that ETOH also significantly decreased L clearance (0.0016 +/- 0.0011 vs. 0.0029 +/- 0.0002 min(-1); P = 0.0156), whereas no difference was observed for the fractional conversion of the rate of G disappearance to L (0.0033 +/- 0.0012 vs. 0.0031 +/- 0.0005 min(-1)). ETOH decreased baseline plasma FFA concentration; AUC of FFA was markedly reduced with ETOH (65 +/- 14 vs. 109 plus minus 17 mmol/liter in 240 min; P = 0.0063) and inversely correlated with S(I) (r = 0.693; P = 0.0029). The amount of C-peptide in 240 min as well as the amounts before and after insulin administration were not different between the two tests. We concluded that G and L kinetics derived from FSIGT shows that moderate ETOH intake: 1) improves insulin action; 2) decreases L clearance; and 3) does not affect beta cell function. Because ETOH at moderate doses has a marked antilipolytic action, it might improve insulin action by improving substrate competition. The present findings suggest that moderate alcohol consumption in the diet should not be discouraged.

Adult↗
PubMed2002

Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes.

In patients with diabetes and coronary artery disease, the potential negative role of sulfonylurea drugs is under intensive investigation. We assessed the effects of treatment with glibenclamide or insulin on the extension of left ventricular myocardial dysfunction induced by acute ischemia. Nineteen consecutive patients with type 2 diabetes and coronary artery disease entered the study. Each patient was randomly assigned to either insulin or glibenclamide therapy. Treatment was crossed over after 12 weeks and maintained for another 12 weeks. At the end of each treatment, left ventricular myocardial function at rest and during dipyridamole infusion was studied by two-dimensional echocardiography under the same conditions of metabolic control. Glibenclamide or insulin treatment did not influence the rest values of left ventricular dimensions, left ventricular ejection fraction (LVEF), or wall motion score index (WMSI). Dipyridamole infusion, in patients receiving glibenclamide treatment, decreased LVEF (43 +/- 7 vs. 37 +/- 12%, P < 0.005) and increased WMSI (1.4 +/- 0.28 vs. 1.98 +/- 0.24, P < 0.001) compared with baseline values; during insulin treatment, LVEF (46 +/- 8 vs. 45 +/- 11%, NS) and WMSI (1.4 +/- 0.29 vs. 1.6 +/- 0.4, NS) did not change significantly. Peak stress LVEF was higher (45 +/- 11 vs. 37 +/- 12%, P < 0.001) and WMSI lower (1.6 +/- 0.4 vs. 1.98 +/- 0.24, P < 0.001) in patients receiving insulin. The results indicate that in patients with type 2 diabetes and coronary artery disease, ischemic myocardial dysfunction induced by dipyridamole infusion is less severe during treatment with insulin than with glibenclamide. Restitution of a preconditioning mechanism in insulin-treated patients may be the potential beneficial mechanism.

Cardiomyopathies↗
PubMedDate not supplied

Continuous glucose monitoring in conditions other than diabetes.

BACKGROUND: The development of new systems for continuous glucose monitoring has recently increased the interest for their potential applications among physicians involved in diabetes care. One of the most common applications of such devices is the identification of hypoglycaemic events in insulin-treated diabetic patients (particularly during the night) and the evaluation of the full daily glucose excursions. METHODS: Among commercially available glucose sensors, the Glucoday system has been utilized for practical clinical application in the last two years. One of the most important features of this device is the accuracy in monitoring interstitial glucose values, specifically in the hypoglycaemic range. This feature is clinically relevant when applied in the clinical setting of patients with type 1 diabetes mellitus. The ability to monitor glucose continuously could be indeed a useful tool for the study of hypoglycaemic conditions other than diabetes. RESULTS: In patients with hyperinsulinaemic hypoglycaemia, recurrent episodes of asymptomatic hypoglycaemia are common, and in patients with glycogen storage diseases, avoidance of recurrent and prolonged hypoglycaemic episodes usually require frequent determinations by mean of home blood glucose monitoring. CONCLUSIONS: Experimental preliminary evidences suggest that this new technology could be applied in the clinical setting to help the physician to identify mainly nocturnal hypoglycaemic events, otherwise not revealed by traditional self blood-glucose monitoring, even in those patients who are not treated by conventional insulin therapy.

Adult↗
PubMedDate not supplied

Oral amino acids in elderly subjects: effect on myocardial function and walking capacity.

BACKGROUND: With advancing age the risk of developing serious nutritional deficiencies increases, and disturbances to the actions of insulin and insulin-like growth factor, coupled with reduced protein/amino acid (AA) intake, impair protein synthesis in muscles. OBJECTIVE: To assess the effects of administering oral AAs on walking capacity and perceived walking impairment, isometric muscular strength, and myocardial function at rest and during isometric exercise. METHODS: One hundred elderly subjects (aged >65 years) with reduced physical activity were randomized to receive an oral AA mixture (12 g/day) or placebo for 3 months. At baseline and after 3 months of therapy we assessed physical capacity with the 6-min walk test, and perceived physical impairment with the walking impairment questionnaire (WIQ); we assessed maximal isometric muscular strength of the right hand with a handgrip dynamometer, and left ventricular ejection fraction (LVEF) using quantitative two-dimensional echocardiography at rest and during acute overload. RESULTS: Three months of AA treatment resulted in significant increases in 6-min walk distance (268.8 +/- 34.9 vs. 212 +/- 40 m, p < 0.001), WIQ scores (distance: 68.3 +/- 12 vs. 53 +/- 14.8%, p < 0.001; speed: 72.2 +/- 14.4 vs. 52.8 +/- 12%, p < 0.001; stairs: 98.2 +/- 24 vs. 72.4 +/- 22%, p < 0.001), and in maximal muscular isometric strength (20.2 +/- 2 vs. 14 +/- 2.8 kg, p < 0.001). Moreover, peak stress LVEF was higher during AA administration when compared to placebo administration (67 +/- 7 vs. 56 +/- 9%, p < 0.01). Left ventricular response to exercise normalized during AA administration in 24 out of 32 (75%) patients with abnormal LV response at baseline, whereas it remained unchanged in the placebo group. CONCLUSION: An oral AA supply such as that used in this study improves ambulatory capacity, maximal isometric muscle strength and myocardial ability to match an acute overload in elderly subjects without affecting the main metabolic parameters. These functional gains may translate into increased perceived walking capacity.

Administration, Oral↗