Lucilla D. Monti

Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass

It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.

Aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment

AIMSnThe study was designed to compare a combined aerobic and resistance training (ART) with an aerobic training (AT) over hemodynamic, glucose metabolism and endothelial factors, adipokines and pro-inflammatory marker release in a population of obese type 2 diabetic patients.nnnMETHODSnForty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings, on the top of a diet regime. Anthropometric, metabolic, hormonal and inflammatory variables were measured at hospitalization and discharge.nnnRESULTSnBoth exercise programs equally improved body weight and fructosamine levels however ART only partially decreased HOMA index compared with AT (ART: -25% vs AT: -54%, p<0.01). Mean blood pressure (AT: -3.6 mmHg vs ART: +0.6 mmHg, p<0.05) and endothelin-1 (ET-1) incremental areas during walking test (AT: -11% vs ART: +30%, p<0.001) decreased after AT while increased after ART. Adiponectin levels increased by 54% after AT while decreased by 13% after ART (p<0.0001) and matrix metalloproteinase-2 (MMP-2), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractan protein-1 (MCP-1) levels significantly decreased in AT while increased in ART group.nnnCONCLUSIONSnCompared with AT, ART similarly enhanced body weight loss but exerted less positive effects on insulin sensitivity and endothelial factors, adipokines and pro-inflammatory marker release.

Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial

Aim: This study assessed the efficacy of long‐term l‐arginine (l‐arg) therapy in preventing or delaying type 2 diabetes mellitus.

L-Arginine enriched biscuits improve endothelial function and glucose metabolism: A pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome

OBJECTIVEnThe aim of this study was to evaluate the effects of a new L-arginine-enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition.nnnMATERIALS/METHODSnThe project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of L-arginine-enriched biscuits that contained 6.6 gL-arginine, 21.9 g carbohydrates, 3.6 g protein, 7.5 g fat and 4.3 g dietary fiber compared with placebo biscuits and 6.6 g powdered L-arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6 g of L-arginine-enriched biscuits or placebo biscuits in a 1600 kcal diet. Each study period lasted 2 weeks with a 2-week washout in between. Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period.nnnRESULTSnIn the first study, the groups that received the L-arginine-enriched biscuits and the powdered L-arginine had similarly increased L-arginine, NOx and cGMP levels and post-ischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the L-arginine-enriched biscuit recipient group displayed increased L-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group.nnnCONCLUSIONSnL-Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS.

Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency.

Patients with growth hormone deficiency (GHD) are known to have reduced life expectancy due to increased cardiovascular and cerebrovascular events. An increase in asymmetric dimethylarginine (ADMA) levels previously found in GHD patients could promote premature atherosclerosis. The aim of this study was to determine whether 6-month growth hormone (GH) replacement therapy was able to decrease ADMA levels and ameliorate endothelial dysfunction. Thirty-one GHD patients were studied before and after 6 months of GH (4 microg/[kg d], daily) replacement therapy. Reduced pretreatment levels of serum insulin-like growth factor (IGF) 1 were normalized during GH treatment (88.2 +/- 62.5 to 191.7 +/- 80.3 ng/mL, P < .0001). After 6 months of GH replacement, plasma cyclic guanosine monophosphate levels significantly increased (2.14 +/- 0.52 to 3.54 +/- 1.2 ng/mL, P < .0001), serum ADMA levels were significantly decreased (0.65 +/- 0.1 vs 0.59 +/- 0.11 mumol/L, P < .05), and arganine (Arg) to ADMA ratio was significantly higher (155 +/- 53 vs 193 +/- 61, P < .01). No changes were observed for plasma nitric oxide end products (nitrite and nitrate) levels after GH treatment (21.9 +/- 14.9 vs 24.1 +/- 19.0 mumol/L, not significant). Basal forearm blood flow remained unchanged, whereas reactive hyperemia increased from 7.30 +/- 5.31 mL/100 mL forearm per minute before GH therapy to 13.18 +/- 7.30 mL/100 mL forearm per minute after 6 months of therapy (P < .001). There was a positive correlation between IGF-1 and cyclic guanosine monophosphate (r = 0.73, P < .0001), IGF-1 and reactive hyperemia (r = 0.63, P < .0001), and IGF-1 and Arg/ADMA ratio (r = 0.44, P < .01). Conversely, a negative correlation was found between IGF-1 and ADMA levels (r = -0.41, P < .02). At the end of the study period, fat-free mass, plasma glucose, and hemoglobin A(1c) levels significantly increased, even if they were still in the reference range, suggesting moderate alteration of glucose metabolism. In conclusion, in GHD patients, GH replacement contributes to decreased, to some extent, cardiovascular risk, reducing ADMA levels and improving Arg/ADMA ratio and endothelial dysfunction.

Role of Endothelial Dysfunction and Insulin Resistance in Angina Pectoris and Normal Coronary Angiogram

Angina pectoris and a normal coronary angiogram or cardiac syndrome X is a heterogeneous syndrome that probably encompasses different pathophysiological entities. Patients affected by cardiac syndrome X are often women presenting with severe, invalidating chest pain. However, there is a significant discrepancy among the severity of symptoms, the lack of hemodynamic evidence of myocardial ischemia and the relatively benign long-term prognosis. The vascular endothelium has numerous important functions, including the regulation of vascular tone, blood flow and permeability, secreting both vasorelaxing and vasoconstricting factors. It has been found that both endothelium and non-endothelium-mediated coronary blood flow are impaired in patients with cardiac syndrome X. Interestingly, it has been shown that impaired nitric oxide-dependent vasodilation could increase coronary microvessel tone and produce spasm. It has also been reported that circulating endothelin-1 levels are elevated with a direct relationship between endothelin-1 levels and impaired coronary flow reserve in these patients. In addition, patients with high endothelin-1 levels showed a time onset of chest pain during exercise significantly lower compared to patients with low endothelin-1 concentrations. Moreover, the nitric oxide/endothelin-1 ratio was found decreased in patients with cardiac syndrome X and endothelin-1 levels were also positively correlated with fasting asymmetric dimethylarginine levels. All in all, these data suggest a role of endothelial dysfunction as a cause of regional myocardial and peripheral blood flow abnormalities. Further studies are necessary to characterize the prevailing mechanisms determining alterations in nitric oxide/endothelin-1 pathway in these patients, in order to find new therapies able to improve both quality of life and prognosis.ZusammenfassungAngina pectoris und ein normales Koronarangiogramm, auch kardiales Syndrom X genannt, umfasst unterschiedlichste pathophysiologische Entitäten. Syndrom-X-Patienten sind häufig Frauen mit schweren, auch die Lebensqualität beeinträchtigenden Symptomen bei Fehlen hämodynamisch nachweisbarer myokardialer Ischämien und relativ guter Langzeitprognose. Das vaskuläre Endothel hat viele wichtige Funktionen. Es regelt den vaskulären Tonus, den Blutfluss und die Permeabilität der Gefäßwand und sezerniert vasorelaxierende und vasokonstringierende Faktoren. Bei Patienten mit Syndrom X ist sowohl die endothelabhängige als auch die nicht endothelabhängige Vasomotion gestört. Interessant ist, dass die Stickstoffmonoxid-(NO-)abhängige Vasodilatation gestört ist und einen erhöhten Tonus der Mikrogefäße hervorrufen kann. Auch koronare Spasmen wurden beobachtet. Das zirkuläre Endothelin-1 ist erhöht und könnte für die eingeschränkte koronare Flussreserve bei diesen Patienten verantwortlich sein. Zusätzlich zeigen Patienten mit hohem Endothelinspiegel einen früher einsetzenden thorakalen Schmerz unter Belastung als Patienten mit niedrigem Endothelinspiegel. Das Verhältnis von NO zu Endothelin-1 ist bei Syndrom-X-Patienten niedrig. Der Endothelin-1-Spiegel korreliert positiv mit dem Nüchternspiegel des asymmetrischen Dimethylarginins. Diese Daten lassen vermuten, dass die endotheliale Dysfunktion eine Ursache für regionale myokardiale und periphere Flussanomalien ist. Weitere Studien sind notwendig, um den Mechanismus zu charakterisieren, der zur Veränderung der NO- und Endothelin-1-Metabolismen bei diesen Patienten führt, um neue therapeutische Ansätze zu finden und die Lebensqualität sowie Prognose der Patienten zu verbessern.

Fasting hyperinsulinemia associates with increased sub-clinical inflammation in first-degree relatives normal glucose tolerant women independently of the metabolic syndrome

To evaluate the influence of gender on the relationship between inflammation and hyperinsulinemia in first‐degree relatives of type 2 diabetic patients independently of metabolic syndrome.

Basal insulin therapy is associated with beneficial effects on postoperative infective complications, independently from circulating glucose levels in patients admitted for cardiac surgery

Highlights • The effect of insulin per se on infective complications during cardiac surgery was evaluated.• Eight hundred twelve patients were included.• Insulin therapy decreased infections independently from glycemic levels.• Basal + premeal insulin therapy is well tolerated without severe hypoglycemia cases.

Decreased diabetes risk over 9 year after 18-month oral l-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of l-arginine study)

PurposeThis study aimed to determine whether l-arginine supplementation lasting for 18xa0months maintained long-lasting effects on diabetes incidence, insulin secretion and sensitivity, oxidative stress, and endothelial function during 108xa0months among subjects at high risk of developing type 2 diabetes.MethodsOne hundred and forty-four middle-aged subjects with impaired glucose tolerance and metabolic syndrome were randomized in 2006 to an l-arginine supplementation (6.4xa0g orally/day) or placebo therapy lasting 18xa0months. This period was followed by a 90-month follow-up. The primary outcome was a diagnosis of diabetes during the 108xa0month study period. Secondary outcomes included changes in insulin secretion (proinsulin/c-peptide ratio), insulin sensitivity (IGI/HOMA-IR), oxidative stress (AOPPs), and vascular function. After the 18xa0month participation, subjects that were still free of diabetes and willing to continue their participation (104 subjects) were further followed until diabetes diagnosis, with a time span of about 9xa0years from baseline.ResultsAlthough results derived from the 18xa0month of the intervention study demonstrated no differences in the probability of becoming diabetics, at the end of the study, the cumulative incidence of diabetes was of 40.6% in the l-arginine group and of 57.4% in the placebo group. The adjusted HR for diabetes (l-arginine vs. placebo) was 0.66; 95% CI 0.48, 0.91; pxa0<xa00.02). Proinsulin/c-peptide ratio (pxa0<xa00.001), IGI/HOMA-IR (pxa0<xa00.01), and AOPP (pxa0<xa00.05) levels were ameliorated in l-arginine compared to placebo.ConclusionsThese results may suggest that the administration of l-arginine could delay the development of T2DM for a long period. This effect could be mediated, in some extent, by l-arginine-induced reduction in oxidative stress.