Cristóbal Richart

The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels.

Tumor necrosis factor-α (TNF-α), acting as a modulator of gene expression in adipocytes, is implicated in the development of insulin resistance and obesity. The aim of this study was to investigate whether the Nco I polymorphism of the TNF-a gene influences the relationship among insulin resistance, percent body fat, and serum leptin levels. A sample of 38 subjects (19 men, mean age 36.2 ± 1.9 years, BMI 28.8 ± 1.2 kg/m2, range 22.2–35.7; and 19 women, age 34.9 ± 1.4 years, BMI 28.1 ± 0.8 kg/m2, range 19–37.9) was divided into two groups on the basis of the Nco I genotype. Twenty-three subjects were (+/+) homozygotes for the presence of the Nco I restriction site that is associated with a guanine at position −308 of the TNF-a promoter. Of the other subjects, 12 were (+/−) heterozygotes and 3 (−/−) homozygotes for the absence of the restriction site, resulting from a guanine-to-adenine substitution at position −308 of the TNF-a promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-a than the wild-type allele TNF-1 in vitro. TNF-1 (+/+) and TNF-2 (+/− and −/−) groups of subjects were comparable in sex, age, BMI, waist-to-hip ratio, and several skinfold measurements. Basal serum insulin was greater (14.2 ± 2 vs. 9.2 ± 0.9 mlM, P = 0.041) in the TNF-2 group in the presence of comparable serum glucose concentration. The integrated area under the curve of serum insulin concentrations, measured in response to a 75-g oral glucose challenge, and the percent body fat, measured by bioelectric impedance, were significantly increased in TNF-2 subjects (226.8 ± 33 vs. 139.4 ± 17.8 mU/l, P = 0.032; 33.6 ± 2.8 vs. 24.9 ± 2%, P = 0.01). TNF-2 subjects also showed a decreased insulin sensitivity index, as determined by the frequently sampled intravenous glucose tolerance test with minimal model analysis (1.9 ± 0.4 vs. 3.05 ± 0.3 min−1 · mU−1 · 1−1 P = 0.03). These differences were more marked among women. Paralleling the known relationship between insulin and leptin levels, serum leptin concentration was clearly increased in the TNF-2 group (19.6 ± 3.4 vs. 11.1 ± 1.5 ng/ml, P = 0.03). Therefore, (+/−) heterozygotes and (−/−) homozygotes may be more susceptible to developing insulin resistance and increased percent body fat. Results of the present study suggest that TNF-αNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.

The interleukin-6 (−174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians

Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position −174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians — a population with high rates of insulin resistance and T2DM — and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (−174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P=0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P=0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P=0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians.

New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women

BackgroundVaspin and omentin are recently described molecules that belong to the adipokine family and seem to be related to metabolic risk factors. The objectives of this study were twofold: to evaluate vaspin and omentin circulating levels and mRNA expression in subcutaneous and visceral adipose tissues in non-diabetic morbidly obese women; and to assess the relationship of vaspin and omentin with anthropometric and metabolic parameters, and other adipo/cytokines.DesignWe analysed vaspin and omentin circulating levels in 71 women of European descent (40 morbidly obese [BMI ≥ 40 kg/m2] and 31 lean [BMI ≤ 25]). We assessed vaspin and omentin gene expression in paired samples of visceral and subcutaneous abdominal adipose tissue from 46 women: 40 morbidly obese and 6 lean. We determined serum vaspin and plasma omentin levels with an Enzyme-Linked Immunosorbent Assay and adipose tissue mRNA expression by real time RT-PCR.ResultsSerum vaspin levels in the morbidly obese were not significantly different from those in controls. They correlated inversely with levels of lipocalin 2 and interleukin 6. Vaspin mRNA expression was significantly higher in the morbidly obese, in both subcutaneous and visceral adipose tissue.Plasma omentin levels were significantly lower in the morbidly obese and they correlated inversely with glucidic metabolism parameters. Omentin circulating levels, then, correlated inversely with the metabolic syndrome (MS). Omentin expression in visceral adipose tissue was significantly lower in morbidly obese women than in controls.ConclusionsThe present study indicates that vaspin may have a compensatory role in the underlying inflammation of obesity. Decreased omentin circulating levels have a close association with MS in morbidly obese women.

A polymorphism in the promoter of the tumor necrosis factor-α gene (-308) is associated with coronary heart disease in type 2 diabetic patients

BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine in the inflammation process of atherosclerosis. Through its effects on lipid metabolism, insulin resistance and endothelial function, it might be involved in coronary heart disease (CHD). A biallelic polymorphism within the promoter of TNF-alpha locus at the position -308 has been reported to be associated with TNF production. We have studied the association of this polymorphism with CHD in a Mediterranean non-diabetic and type 2 diabetic population. METHODS Three hundred and forty one CHD patients (106 with type 2 diabetes), 207 healthy matched control subjects and 135 type 2 diabetic patients without CHD were evaluated. A single nucleotide polymorphism at the promoter TNF-alpha (-308) was analyzed by RFLP-PCR. RESULTS TNF-alpha (-308) genotype and allele frequencies for A carriers were higher in CHD patients than those observed in the control group (32.3 vs. 23.2%, P=0.03; and 18.8 vs. 12.1%, P=0.0047; respectively) independently of other risk factors. Genotypic analysis revealed that CHD patients with type 2 DM displayed a greater prevalence of the -308 TNF-alpha A allele (40.6%) than controls (23.2%) or CHD patients without type 2 DM (28.5%) (P=0.0056). The odds ratio for CHD in type 2 diabetic patients in presence of -308 TNF-alpha A allele was 2.86 (CI 95%: 1.55-5.32). This difference was observed mainly in diabetic women for the A allele carriers (OR: 4.29; CI 95%: 1.6-11.76). CONCLUSIONS These results suggest that -308 TNF-alpha gene polymorphism may contribute to CHD risk in patients with type 2 diabetes and it could constitute an useful predictive marker for CHD in type 2 diabetic women.

Distribution and determinants of adiponectin, resistin and ghrelin in a randomly selected healthy population

Objective  Adiponectin, resistin, ghrelin and the IGF‐I system seem to play an important role in the regulation of body composition throughout life, but the mechanisms are not well understood. The aim of our study was to analyse the distribution among sexes and all decades of the adult life of adiponectin, resistin and ghrelin and their relationship with anthropometric, body composition parameters and the IGF‐I system.

FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women.

OBJECTIVE The adipocyte/macrophage fatty acid-binding protein 4 (FABP4) has been described as a biomarker for adiposity and metabolic syndrome (MS). The aims of this study were to assess the relationship between FABP4 and inflammatory cytokines related to obesity, and to evaluate FABP4 mRNA expression in visceral and subcutaneous adipose tissue in non-diabetic morbidly obese women versus healthy lean women. METHODS We analyzed circulating levels of FABP4 in 81 Spanish women: 38 lean (body mass index (BMI)<25 kg/m(2)) and 43 morbidly obese (BMI>40 kg/m(2)). We took 30 follow-up blood samples at 6 and 12 months after bariatric surgery. We assessed FABP4 gene expression in samples of subcutaneous abdominal and visceral adipose tissue. Adipose tissue mRNA expression was determined by real-time RT-PCR. RESULTS In morbidly obese women, plasma FABP4 levels were significantly higher than in non-obese patients. These levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin levels. Post-operative FABP4 levels decreased by a maximum of 30% after 12 months. We also found an inverse association between FABP4 and adiponectin levels, and positive correlations between FABP4 and circulating leptin, tumor necrosis factor (TNF) receptors, C-reactive protein (CRP) and interleukin 6 levels. Linear regression analysis revealed that FABP4 was more closely related to HOMA2-IR than adiponectin, CRP, TNF-RI, or leptin. Furthermore, high circulating FABP4 levels were associated with the presence of MS. FABP4 mRNA expression in visceral adipose tissue was related to its circulating levels in morbidly obese women. CONCLUSIONS Our results indicate that serum FABP4 is associated with inflammatory factors related to obesity and MS in non-diabetic morbidly obese women.

Left ventricular mass and diastolic function in normotensive young adults with autosomal dominant polycystic kidney disease.

Left ventricular hypertrophy is often found very early in the course of autosomal dominant polycystic kidney disease (ADPKD). Diastolic dysfunction has been shown in hypertensive adult patients with ADPKD with increased left ventricular mass (LVM), but there are no data about diastolic function in the young ADPKD population without hypertension and with normal renal function. To evaluate very early alterations in cardiac structure and diastolic function in young normotensive patients with ADPKD, color Doppler echocardiography was performed in 46 young normotensive patients with ADPKD and 35 healthy subjects. LVM, transmitral pulsed Doppler flow (diastolic function), and valvular abnormalities were studied. Patients with ADPKD showed higher LVM indices (LVMIs) than controls (89.7+/-17.3 v 68.5+/-17.2 g/m2; P < 0.0001). Peak early diastolic velocity (E wave) deceleration time and isovolumic relaxation time were significantly prolonged in patients with ADPKD compared with controls (E wave deceleration time, 182.5+/-51.3 v 149.4+/-34 msec; P=0.002; isovolumic relaxation time, 97.7+/-17.5 v 79+/-15 msec; P=0.0001). No differences were found in valvular abnormalities in the two groups. In conclusion, young normotensive patients with ADPKD showed increased LVMIs and Doppler abnormalities consistent with early diastolic dysfunction.

Angiotensin I—converting enzyme and angiotensinogen gene polymorphisms in non—insulin-dependent diabetes mellitus. Lack of relationship with diabetic nephropathy and retinopathy in a caucasian mediterranean population

Genotypic abnormalities of the renin-angiotensin system have been suggested as a risk factor for the development of microangiopathic complications in diabetic patients. We studied the relationship of either an insertion-deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and the M235T and T174M variant polymorphisms of the angiotensinogen (AGT) gene in non-insulin-dependent diabetes mellitus (NIDDM) patients and its relationship with cardiovascular complications. A total of 193 NIDDM patients (89 men and 104 women aged 59.2 +/- 10.0 years; diabetes duration, 13.2 +/- 6.2 years) and 90 control subjects (42 men and 48 women aged 45.4 +/- 12.6 years) were recruited for the association study. Distribution of the genotype or allelic frequencies for all the studied polymorphisms did not differ significantly between controls and NIDDM patients. ACE and AGT genes did not display any difference in clinical or metabolic parameters according to each genes genotype for either the control or the NIDDM group. For evaluation of nephropathy and retinopathy, NIDDM patients were matched with subjects not having microangiopathic complications. Thus, a total of 60 patients had diabetic nephropathy and were compared with 100 patients with normoalbuminuria. Sixty-eight NIDDM patients had diabetic retinopathy, and 92 patients presented no signs of retinopathy. There were no differences in genotypic or allelic distribution between NIDDM patients for either the presence or absence of retinopathy or nephropathy. We conclude that the ACE and AGT polymorphisms do not contribute to the genetic susceptibility to diabetic nephropathy and retinopathy in a caucasian Mediterranean population.

ALCOHOL DEHYDROGENASE OF HUMAN AND RAT BLOOD VESSELS : ROLE IN ETHANOL METABOLISM

© 1997 Federation of European Biochemical Societies.

Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine.

A 65-year-old man with chronic lymphocytic leukemia (CLL) diagnosed 11 years ago and treated with standard dose of fludarabine developed a rapidly fatal progressive neurological syndrome. Differential diagnoses included brain infiltration by CLL as opposed to progressive multifocal leukoencephalopathy (PML). A magnetic resonance imaging (MRI) scan showed a hyperintense T2-weighted signal in the left frontal region. Cerebro-spinal fluid polymerase chain reaction (PCR) was positive for virus JC (JCV). These findings were compatible with the diagnosis of PML. Fludarabine has been used to treat acute leukemias, CLL and follicular lymphomas. Its toxicity includes myelosuppression, immunosuppression and sporadic life-threatening neurotoxicity, although standard doses of it are considered safe. Late-onset fatal cerebral dysfunction caused by JCV after standard-dose fludarabine has been described previously. The widespread and increasing use of fludarabine makes it interesting to define the potential of standard doses of fludarabine for causing severe neurological side-effects such as PML.