Association of chemokines IP-10/CXCL10 and I-TAC/CXCL11 with insulin resistance and enhance leukocyte endothelial arrest in obesity.

BACKGROUND AND AIMS: Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. METHODS AND RESULTS: We have studied 45 obese patients (mean age 44 ± 6 years, body mass index 45 ± 9 kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p < 0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3. CONCLUSIONS: The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.

Postprandial triglyceridaemia is modulated by insulin resistance but not by grade of obesity in abdominal and morbid obese subjects.

BACKGROUND: Obesity is associated with high cardiovascular risk. Postprandial lipidaemia has been associated with cardiovascular disease risk. Our aim was to identify whether anthropometric parameters, insulin resistance (IR) and/or fasting plasma triglycerides may determine postprandial changes in lipoprotein concentrations in abdominal and morbid obese subjects. METHODS: We have studied 20 non-diabetic, normolipidaemic subjects with abdominal obesity, 20 morbid obese subjects and 20 healthy individuals, that have similar age and gender. In all of them a standardised oral fat load test (OFLT) with unsaturated fat was performed. RESULTS: During the OFLT, the postprandial triglycerides response was significantly higher in subjects with abdominal obesity compared with morbid obese subjects (4 hours triglycerides pick value and AUC of triglycerides). Both obese groups showed significantly higher postprandial triglycerides response compared with healthy subjects. Dividing the obesity group according to the presence of IR, we found that IR was an important factor related with postprandial lipaemia but not BMI or waist circumference. In addition, postprandial glycaemia and insulinaemia significantly decreased in all studied subjects, being the highest decrease in morbid obese subjects and in subjects with IR. Postprandial triglyceridaemia significantly correlated with IR parameters and not with anthropometric parameters in AO and MO subjects. CONCLUSION: In subjects with AO and MO, postprandial triglycerides values are higher than healthy individuals and independently predicted by fasting IR parameters. Furthermore, unsaturated fat improved IR state.

Altered Semmes-Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects.

BACKGROUND: Different lines of evidence suggest that oxidative stress (OS) is implicated in the pathogenesis of diabetic neuropathy. The Semmes-Weinstein monofilament (SWM) test is an efficient tool for evaluating diabetic polyneuropathy and diabetic foot. In this study, we analyzed the association between OS markers and altered SWM test results in type 2 diabetes (T2DM) patients. METHODS: Seventy T2DM patients were studied and 34 showed altered SWM results. The clinical and biochemical parameters were determined using standardized methods. Levels of oxidized glutathione (GSSG) and malondialdehyde (MDA) were measured in circulating mononuclear cells using high-performance liquid chromatography. RESULTS: We found that T2DM patients with altered SWM test results had significantly higher GSSG (3.53 ± 0.31 vs. 3.31 ± 0.35 mmol/ml, p < 0.05) and MDA (1.88 ± 0.16 vs. 1.75 ± 0.19 nmol/ml, p < 0.01) values compared to diabetic patients with normal SWM test outcomes. Moreover, altered SWM test results were independently related to age, glycosylated hemoglobin, and GSSG levels, but there was no association between OS markers and altered neuropathy sensitivity score (NSS) values. CONCLUSIONS: Alteration of the glutathione system and MDA values in T2DM patients are associated with loss of proprioceptive (pressure) sensitivity, but not with symptomatic polyneuropathy (as evaluated by NSS). This finding may be important for understanding how OS affects distal symmetric polyneuropathy in diabetic patients.

Effect of personality on blood glucose control in patients with type 1 diabetes.

OBJECTIVE: The diagnosis of type 1 diabetes mellitus (DM1) has a major impact on young people and their families. Psychosocial factors, patient motivation, participation and acceptance of the disease are essential to achieve good blood glucose control. Our aims were to analyse personality traits and how they are related to blood glucose control in patients with DM1. METHODS: Sixty-two patients with DM1 over 18 years of age, with at least one-year disease duration and absence of advanced chronic complications were studied. Clinical, biological and personality parameters were measured. The Millon Index of Personality Styles was administered for personality assessment. RESULTS: Significant correlations between different personality variables and glycated haemoglobin (HbA1c) values were found. Individuals with poor blood glucose control had significantly higher scores on the Feeling-guided (53.6±25.7 vs 36.2±26.8, p=0.021), Innovation-seeking (36.7±24.1 vs 21.9±21.4, p=0.025), Dissenting (41.1±24.4 vs 15.6±16.6, p=0.001), Submissive (41.5±25.1 vs 28.3±14.7, p=0.038) and Dissatisfied (37.5±27.5 vs 19.5±20.2, p=0.015) scales. This psychological profile is characterised by greater focus on emotions and personal values (feeling-guided), the tendency to reject conventional ideas (innovation-seeking), an aversion to complying with norms and a preference for autonomy (unconventional/dissenting), labile self-confidence (submissive/yielding) and expressed disagreement with others (dissatisfied/complaining). Factor analysis based on the main components of the variance yielded four factors. Factor characterised as related to rebelliousness or independent judgement and action was correlated with poor blood glucose control (r=0.402, p<0.05). CONCLUSION: The rebellious or non-conformist personality type is closely associated with poor blood glucose control in patients with DM1.

[Plasma homocysteine, Lp(a), and oxidative stress markers in peripheral macroangiopathy in patients with type 2 diabetes mellitus]. / Homocisteína plasmática, Lp(a) y marcadores de estrés oxidativo en la vasculopatía periférica del paciente con diabetes tipo 2.

AIM: To study new risk factors for peripheral macroangiopathy (PM) in patients with diabetes, as oxidative stress (OS) and its interaction with classical risk factors: age, Lp(a), plasma homocysteine values and HbA1c. SUBJECTS AND METHODS: We studied 204 type2 diabetic (T2DM) patients, consecutive selected form a reference hospital and a secondary hospital form our Community (2009-2010). Design was a case (ABI<0.89) control (ABI0.9-1.2) study. PM was defined using ankle brachial index (ABI). Thirty nine T2DM subjects presented ABI>1.2 and were excluded. Clinical and biological parameters were determined using standard methods. RESULTS: Comparing clinical and biological parameters obtained in both studied groups (T2DM+ABI<0.9 vs T2DM+ABI0.9-1.2), we found statistical significant differences in age, evolution time of diabetes, Lp(a) and plasma homocysteine values. No differences were found in OS parameters: reduced glutathione, oxidized glutathione and maloldialdehide between studied groups. Plasma homocysteine values were an independent risk factor for the presence of PM and were related to evolution time of diabetes and reduced glutathione. CONCLUSIONS: We have confirmed that Lp(a) and independently plasma homocysteine values were related to PM in T2DM subjects. No association with PM and OS markers (GSH, GSSG and MDA) were found in T2DM with more than 10years of evolution time of their disease and high prevalence of chronic complications.

Unsaturated Oral Fat Load Test Improves Glycemia, Insulinemia and Oxidative Stress Status in Nondiabetic Subjects with Abdominal Obesity.

AIMS: To evaluate the changes in glycemia, insulinemia, and oxidative stress markers during an oral fat load test in nondiabetic subjects with abdominal obesity and to analyze the association between postprandial oxidative stress markers and postprandial glucose and insulin responses. METHODS: We included 20 subjects with abdominal obesity (waist circumference > 102 cm for men and > 88 cm for women) and 20 healthy lean controls (waist circumference < 102 cm for men and < 88 cm for women). After 12 hours of fasting we performed a standardized fat load test (0-8 hours) with supracal® (50 g/m2). We determined metabolic parameters, oxidized and reduced glutathione, and malondialdehyde. RESULTS: In both groups, insulin, HOMA, oxidized/reduced glutathione ratio, and malondialdehyde significantly decreased in the postprandial state after the OFLT. All these parameters were significantly higher in the abdominal obesity group at baseline and during all the postprandial points, but the reduction from the baseline levels was significantly higher in the abdominal obesity group. CONCLUSION: Unsaturated fat improves insulin resistance and oxidative stress status. It is possible that a consumption of unsaturated fat could be beneficial even in subjects with abdominal obesity in postprandial state.

Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients.

Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine plasma levels in the hypothyroid group were similar to those of the control group; whereas in hyperthyroidism, these values were significantly increased. However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NO(x) production. When all subjects were analyzed together, free T(4) levels were directly correlated with ADMA and inversely correlated with NO(x).

Ca2+-activated K+ channels mediate relaxation of forearm veins in chronic renal failure.

BACKGROUND: In arteries, agonists such as acetylcholine release an endothelium-derived hyperpolarizing factor (EDHF) that is neither nitric oxide nor prostacyclin. OBJECTIVES: To examine the responses to acetylcholine in segments of forearm veins from patients with chronic renal failure who either had never received dialysis or had undergone long-term dialysis, and to determine the contribution of nitric oxide and EDHF to endothelium-dependent relaxation in veins from patients with chronic renal failure. METHODS: Isometric tension was recorded in rings of forearm vein from 34 non-dialysed patients, 27 dialysed patients and 14 multiorgan donors (controls). RESULTS: Relaxation in response to acetylcholine was reduced in veins of non-dialysed and dialysed patients. The inhibitors of nitric oxide synthase NG-monomethyl-l-arginine (l-NMMA) and NG,NG-dimethyl-l-arginine (ADMA) reduced by 50% the maximum relaxation in response to acetylcholine in veins from controls and non-dialysed patients; the remaining relaxation was inhibited by 20 mmol/l KCl or by the K+ channel blockers tetraethylammonium chloride, iberiotoxin, charybdotoxin and the combination of barium plus ouabain, but not by apamin or glibenclamide. Relaxation in veins from dialysed patients was inhibited by K+ channel blockade but not by l-NMMA or ADMA. CONCLUSIONS: The results demonstrate that the endothelium-dependent relaxation in forearm veins from controls and non-dialysed patients is mediated by release of nitric oxide and EDHF. In contrast, the relaxation in veins from dialysed patients is mediated mainly by EDHF. EDHF-induced relaxation involves activation of large-conductance Ca2+-activated K+ channels.

Influence of nitric oxide on neurogenic contraction and relaxation of the human gastroepiploic artery.

BACKGROUND: The objective of this study was to characterize the neurogenic contraction and relaxation of the human gastroepiploic artery and to determine whether the responses are mediated by nitric oxide (NO) from neural or endothelial origin. METHODS: Rings of human gastroepiploic artery were obtained from 18 patients (12 men, 6 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the contractile and relaxant responses to electrical field stimulation. RESULTS: In arteries under resting conditions, electrical field stimulation (2 to 8 Hz) caused frequency-dependent contractions that were of greater magnitude in arteries denuded of endothelium and blocked by tetrodotoxin (10(-6) mol/L). The inhibitor of NO synthesis N(G)-monomethyl-L-arginine (L-NMMA, 10(-4) mol/L) increased contractile responses only in arteries with endothelium. In preparations contracted with norepinephrine in the presence of guanethidine (10(-6) mol/L) and atropine (10(-6) mol/L), electrical stimulation induced frequency-dependent relaxations. This neurogenic relaxation was prevented by L-NMMA (10(-4) mol/L) and tetrodotoxin (10(-6) mol/L), but was unaffected by removal of the endothelium. CONCLUSIONS: The results provide functional evidence that NO is released by autonomic nerves of the human gastroepiploic artery. We hypothesize that the release of NO from both endothelial and neurogenic origin may modulate resistance of the human gastroepiploic artery. Dysfunction in any of these sources of NO should be considered in some form of vasospasm.