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J Vendrell

Publications and source records attributed to J Vendrell.

At least 55 records · Page 3Linked to original sources
PubMed1998

Beta 3-adrenoreceptor gene polymorphism and leptin. Lack of relationship in type 2 diabetic patients.

INTRODUCTION: The beta 3-Adrenergic receptor (beta 3AR) and leptin are molecules involved in the regulation of energy balance. Recently, a mutation in the beta 3AR gene (Trp64Arg) has been reported to be associated with features of insulin resistance, weight gain and early onset of Type 2 Diabetes Mellitus. The aim of this study was to determine the frequency and clinical characteristics of the Trp64Arg mutation in the beta 3AR gene in Type 2 diabetic patients, its relationship with leptin levels, and its role in microangiopathic complications. SUBJECTS AND METHODS: 187 Type 2 diabetic patients and 100 unrelated non-diabetic subjects were studied. There was no difference between the diabetic and nondiabetic subjects in the frequency of the Trp64 and Arg64 alleles (92.5% vs. 92.3% and 7.5% vs. 7.7%, respectively). Type 2 diabetic patients were divided into two groups according to the presence (n = 27) or absence of the mutation (n = 160). RESULTS: Mutation of the beta 3AR gene was not associated with any differences either in the clinical and metabolic parameters or microangiopathic complications. Type 2 diabetic patients carrying the Arg64 allele tended to have a lower diabetes duration, but this was not statistically significant. Plasma leptin levels were not different according to the beta 3AR genotype. CONCLUSIONS: The Trp64Arg mutation is not a major determinant of Type 2 diabetes and its microangiopathic complications. Moreover, this mutation was not clinically relevant in leptin regulation.

Aged↗
PubMed1998

Comparative analysis of the sequences and three-dimensional models of human procarboxypeptidases A1, A2 and B.

A full-length cDNA clone for preprocarboxypeptidase B from human pancreas has been isolated and sequenced. The open reading frame is 1254 bp in length, encoding a protein of 417 amino acids that includes a leader signal peptide of 15 amino acids and a 95-amino acid-long pro-segment. It contains two differences when compared to the sequence reported for pancreas-specific protein, a human serum marker for acute pancreatitis identified as procarboxypeptidase B. The main difference is a previously unreported Cys at position 138, which is needed for the formation of one of the three disulphide bridges. Sequence alignments between human procarboxypeptidases A1, A2 and B and other known forms show that the most conserved region is the enzyme moiety followed by the globular domain of the pro-segment. The maximum variability is found in the connecting region between moieties. The known three-dimensional structures of procarboxypeptidases from bovine and porcine species have been used to model all three human procarboxypeptidases and also to estimatethe interaction energies between the different parts of the molecules, in an attempt to gain insight into the structural features responsible for the differences observed in the functionality of the proenzymes, particularly in their proteolytic activation pathways. Taken together, the results obtained confirm that the main determinant for the rate and mode of activation of procarboxypeptidases is the strength of the interaction between the enzyme and the globular domain of the pro-segment, the connecting segment playing a complementary role.

Amino Acid Sequence↗
PubMed1998

Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance.

Recent studies have shown that the tumor necrosis factor (TNF) system is implicated in the insulin resistance of human obesity. Plasma concentrations of the soluble fraction of the TNF receptors 1 and 2 (sTNFR1 and sTNFR2) are thought to reflect the degree of activation of the TNF system. The purpose of this study was to explore whether this activation, as measured by the levels of circulating sTNFR1 and sTNFR2, is associated with insulin resistance. A total of 19 men (mean age 36.2 +/- 1.9; BMI 28.8 +/- 1.2, range 22.2-35.7) and 17 premenopausal women (age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9) were studied. Men showed higher levels of plasma sTNFR1 and sTNFR2 than women. However, obese men showed increased levels of sTNFR2 but similar levels of sTNFR1 in comparison with obese women. In fact, sTNFR2 levels correlated with BMI (r = 0.50, P = 0.002), fat-free mass (FFM) (r = 0.61, P < 0.0001), and waist-to-hip ratio (WHR) (r = 0.39, P = 0.02), but not with fat mass or percent fat mass. sTNFR2 levels correlated with basal glucose levels (r = 0.45, P = 0.007), area under the curve (AUC) for glucose during an oral glucose tolerance test (r = 0.42, P = 0.013), and with the quotient AUC glucose/log AUC insulin (r = 0.41, P = 0.015). sTNFR2 also correlated negatively with insulin sensitivity (S(I)), evaluated using the frequently sampled intravenous glucose tolerance test with minimal model analysis (r = -0.38, P = 0.02). Plasma sTNFR1 levels were not associated with any of these variables. Because WHR influenced both S(I) and sTNFR2 levels, we constructed a multiple linear regression to predict S(I), with WHR and sTNFR2 as independent variables. In this model, both WHR (P = 0.0078) and sTNFR2 levels (P = 0.025) contributed to 47% of the variance in S(I). In parallel with higher FFM, lean and obese men showed a lower S(I) (2.9 +/- 0.9 vs. 5.2 +/- 1.3 min(-1) x mU x l(-1), P = 0.001; and 1.15 +/- 1.1 vs. 1.8 +/- 0.8 min(-1) x mU x l(-1), P = 0.035, respectively) and higher sTNFR2 levels in comparison with lean and obese women, respectively. After controlling for FFM, the correlation between S(I) and sTNFR2 levels disappeared, indicating that FFM was significantly influencing these associations. In summary, plasma sTNFR2 levels, but not sTNFR1, were proportional to BMI, WHR, FFM (a well-known confounder in the evaluation of insulin sensitivity), basal and postload glucose levels, and insulin resistance. These findings support TNF-alpha as a system regulating insulin action in human obesity.

Adult↗
PubMed1997

Characterisation and preliminary X-ray diffraction analysis of human pancreatic procarboxypeptidase A2.

Human procarboxypeptidase A2 has been expressed in a Pichia pastoris heterologous system and purified by hydrophobic interaction and anion exchange chromatographies. The hydrolytic action of carboxypeptidase A2 on peptide substrates with different lengths and residues at the C-terminus was analysed, and a preference towards long substrates with aromatic amino acids in their C-terminal end, particularly tryptophan, was found; with such substrates its activity is similar or higher than that of bovine carboxypeptidase A1. Procarboxypeptidase A2 has been crystallised using a vapour diffusion approach; the crystals obtained belong to the monoclinic system, spacegroup P2(1), and present one procarboxypeptidase A2 molecule per asymmetric unit. The crystals diffract beyond 1.8 A resolution and are suitable for detailed X-ray analysis.

Animals↗
PubMed1997

The three-dimensional structure of human procarboxypeptidase A2. Deciphering the basis of the inhibition, activation and intrinsic activity of the zymogen.

The three-dimensional structure of human procarboxypeptidase A2 has been determined using X-ray crystallography at 1.8 A resolution. This is the first detailed structural report of a human pancreatic carboxypeptidase and of its zymogen. Human procarboxypeptidase A2 is formed by a pro-segment of 96 residues, which inhibits the enzyme, and a carboxypeptidase moiety of 305 residues. The pro-enzyme maintains the general fold when compared with other non-human counterparts. The globular part of the pro-segment docks into the enzyme moiety and shields the S2-S4 substrate binding sites, promoting inhibition. Interestingly, important differences are found in the pro-segment which allow the identification of the structural determinants of the diverse activation behaviours of procarboxypeptidases A1, B and A2, particularly of the latter. The benzylsuccinic inhibitor is able to diffuse into the active site of procarboxypeptidase A2 in the crystals. The structure of the zymogen-inhibitor complex has been solved at 2.2 A resolution. The inhibitor enters the active site through a channel formed at the interface between the pro-segment and the enzyme regions and interacts with important elements of the active site. The derived structural features explain the intrinsic activity of A1/A2 pro-enzymes for small substrates.

Binding Sites↗
PubMed1997

The TNF-beta gene Nco I polymorphism is not associated with hypertriglyceridemia or insulin resistance in lean and obese subjects.

Interindividual differences in TNF-alpha monocyte responses can be accounted for by genetic polymorphisms at the TNF-beta locus defined by the Nco I restriction enzyme. Higher triglyceride levels in non-insulin-dependent diabetic patients homozygous at the 10.5-kb fragment of the TNF-beta gene have been described. The aim of this study was to investigate whether the Ncol polymorphism of the TNF-beta gene influences the relationship between insulin resistance and triglyceride levels. Thirty-eight healthy volunteers were divided into two groups according to the absence [homozygous for class 1 allele (1/1), n=16] or presence of the class 2 allele [n=22; 19 heterozygous (1/2), and 3 homozygous (2/2)]. Both groups were comparable in sex, age, BMI, waist/hip ratio, fat mass and percentage of body fat as measured by bioelectric impedance, skinfold measurements, and blood pressure (all p>0.05). There were no differences in serum cholesterol (total, or HDL and VLDL fractions) or in total or VLDL triglycerides between the groups (all p>0.05). The insulin sensitivity index (Minimal Model method) was comparable for the two groups. In summary, the 10.5-kb homozygous genotype of the TNF-beta locus does not contribute to differences in triglyceride levels or insulin sensitivity among nondiabetic subjects.

Adult↗
PubMed1997

Crystal structure of an oligomer of proteolytic zymogens: detailed conformational analysis of the bovine ternary complex and implications for their activation.

The pancreas of ruminants secretes a 100 kDa non-covalent ternary complex of the zymogen of a metalloexopeptidase, carboxypeptidase A, and the proforms of two serine endopeptidases, chymotrypsin C and proteinase E. The crystal structure of the bovine complex has been solved and refined to an R-factor of 0.192 using synchrotron radiation X-ray data to 2.35 A resolution. In this heterotrimeric complex, the 403 residue procarboxypeptidase A takes a central position, with chymotrypsinogen C and proproteinase E attached to different surface sites of it. The procarboxypeptidase A subunit is composed of the active enzyme part and the 94 residue prodomain, similar to the monomeric porcine homologous form. The 251 residue subunit chymotrypsinogen structure, the first solved of an anionic (acidic pI) chymotrypsinogen, exhibits characteristics of both chymotrypsinogen A and elastases, with a potential specificity pocket of intermediate size (to accommodate apolar medium-sized residues) although not properly folded, as in bovine chymotrypsinogen A; this pocket displays a "zymogen triad" characteristic for zymogens of the chymotrypsinogen family, consisting of three non-catalytic residues (one serine, one histidine, and one aspartate) arranged in a fashion similar to the catalytic residues in the active enzymes. Following the traits of this family, the N terminus is clamped to the main molecular body by a disulphide bond, but the close six residue activation segment is completely disordered. The third zymogen, the 253 residue proproteinase E, bears close conformational resemblance to active porcine pancreatic elastase; its specificity pocket is buried, displaying the second "zymogen triad". Its five N-terminal residues are disordered, although the close activation site is fixed to the molecular surface. The structure of this native zymogen displays large conformational differences when compared with the recently solved crystal structure of bovine subunit III, an N-terminally truncated, non-activatable, proproteinase E variant lacking the first 13 residues of the native proenzyme. Most of the prosegment of procarboxypeptidase A and its activation sites are buried in the centre of the oligomer, whilst the activation sites of chymotrypsinogen C and proproteinase E are surface-located and not involved in intra or inter-trimer contacts. This organization confers a functional role to the oligomeric structure, establishing a sequential proteolytic activation for the different zymogens of the complex. The large surface and number of residues involved in the contacts among subunits, as well as the variety of non-bonded interactions, account for the high stability of the native ternary complex.

Animals↗
PubMed1997

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 gene's 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.

Aged↗
PubMed1997

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

Tumor necrosis factor-alpha (TNF-alpha), 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-alpha 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-alpha 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-alpha promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-alpha 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 mU/l, 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) x mU(-1) x l(-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-alphaNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.

Adult↗
PubMed1996

[Apolipoprotein AI-CIII, B, and CII gene polymorphisms in patients with non-insulin dependent diabetes mellitus. Association with hyperlipemia].

BACKGROUND: Dislipidaemia is an usual feature in patients affected by non insulin dependent diabetes mellitus. Several studies show that this disease could be genetically determined. The aim of this study was to ascertain whether any of the genetic polymorphism remaining in three apolipoprotein loci (apolipoprotein AI-CIII, B100 and CII) is related with the presence of dislipidaemia in non insulin dependent diabetes mellitus patients. PATIENTS AND METHODS: 53 non insulin dependent diabetes mellitus patients with less than 5 years evolution and treated only with diet, were included. 86 healthy persons were included as the control group. The lipidic parameters analyzed were: cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein AI, B and lipoprotein (a). The following polymorphic variants were analyzed: RFLP-Sacl of the apolipoprotein AI-CIII-AIV cluster, RFLP-Xbal of the apolipoprotein B100 region and the RFLP-Taql of the apolipoprotein E-CI-CII cluster. RESULTS: There were no genetic nor allelic differences in the distribution of the genes, between controls and diabetic patients. Regarding the apolipoprotein CII gen, the diabetic patients with the T2T2 genotype had higher triglyceride levels (p < 0.01) compared with the remaining genotypes and compared with the control group having the same genotype (p < 0.01) matched for sex, age and body mass index. There was no difference in the metabolic parameters' distribution related to the genotypic distribution of the apolipoproteins AI-CIII and B100 genes. CONCLUSIONS: The apolipoprotein CII can be related with the presence of hypertriglyceridaemia in non insulin dependent diabetes mellitus patients.

Adult↗
PubMed1996

Calculation and number processing: neuropsychological assessment and daily life difficulties.

One hundred unselected brain-damaged outpatients received a standardized battery of numerical tests (EC301) and, independently, a questionnaire on numerical activities in daily life (ADL). Comparisons between the two types of measurement were drawn from the scorings for different functional components of the calculation and number processing system. Results indicated high ranking correlations between the two instruments. The EC301 battery generally proved more powerful than the questionnaire in detecting the presence of mild-to-discrete impairments, but some aspects of numerical difficulties in nonaphasic patients were scored higher on the ADL questionnaire.

Activities of Daily Living↗
PubMed1996

CD4 masking during human immunodeficiency virus type 1 infection, quantified on peripheral blood lymphocytes, is a potential marker of disease progression.

In human immunodeficiency virus type 1 (HIV-1)-infected adults, the proportion of gp120-free CD4 molecules on the surface of T lymphocytes was measured by double-epitope EIA and expressed as a CD epitope concentration ratio. In 51% of these patients (n=81), CD4 T cells showed a significant decrease (up to 100%) in the accessibility of the CD4 epitope in the D1 domain remained accessible. Of interest, a significant increase in the CD4 gp120 binding site concentration, without a change in T cell counts, was observed within 10 days after initiation of zidovudine treatment. Furthermore, CD4 masking by gp120 was associated with a poor clinical patient status. The assessment of the CD4 epitope concentration ratio is proposed as a surrogate marker of disease progression in HIV-1-infected patients.

Adult↗
PubMed1995

Crystallization and preliminary X-ray analysis of the ternary complex of procarboxypeptidase A from bovine pancreas.

The ternary complex of procarboxypeptidase A, chymotrypsinogen C and proproteinase E from bovine pancreas has been crystallized using the sitting drop vapour diffusion method. The success in obtaining crystals has been found to be critically dependent on the prevention of autolysis of the complex. In preliminary stages, crystals twinned by merohedry were obtained from a solution containing MgCl2 and polyethylenglycol 400 as precipitating agent. Later on, untwinned ones could be grown employing CaCl2 instead of MgCl2. These latter crystals belong to the rhombohedral system and to the spacegroup R3 with cell dimensions a = b = 188.5 A and c = 82.5 A. Consideration of the possible values of Vm accounts for the presence of one ternary complex molecule-oligomere per asymmetric unit. The crystals diffract beyond 2.6 A resolution and are suitable for X-ray analysis.

Animals↗
PubMed1995

The sequence and conformation of human pancreatic procarboxypeptidase A2. cDNA cloning, sequence analysis, and three-dimensional model.

A full-length cDNA clone coding for human pancreatic preprocarboxypeptidase A2 has been isolated from a lambda gt 11 human pancreatic library. Expression clones were identified by specific interaction with antisera raised against the native protein. The open reading frame of the polynucleotide sequence is 1254 base pairs in length and encodes a protein of 417 amino acids. This cDNA includes a short leader signal peptide of 16 amino acids and a 94-amino acid-long activation segment. The amino acid sequence shows 89% identity to that of rat procarboxypeptidase A2, the only A2 form sequenced so far, and 64% identity to that of human procarboxypeptidase A1. The newly determined sequence was modeled to the three-dimensional crystal structures of both bovine carboxypeptidase A and porcine procarboxypeptidase A1 by a novel distance geometry approach. Biases in the modeling were avoided by relying exclusively on automatic procedures and by using random structures as starting points. Information taken from the known homologous structures refers only to the backbone since no explicit data describing the conformation of side chains were transferred. Ten structures of human carboxypeptidase A2 were determined on the basis of each of the two known crystal structures. The root-mean-square distance for the backbone atoms between the 10 structures and their mean for 237 selected residues is 0.7 A when starting from the bovine protein and 0.8 A for 251 selected residues when starting from the porcine protein. The 94 residue-long activation segment was also determined in the modeling based on the porcine zymogen; its structure is well defined but not its orientation with respect to the enzyme moiety. The model obtained for human procarboxypeptidase A2 is discussed with respect to the specificity and activation of the enzyme.

Amino Acid Sequence↗
PubMed1995

The activation pathway of procarboxypeptidase B from porcine pancreas: participation of the active enzyme in the proteolytic processing.

The activation process of porcine pancreatic procarboxypeptidase B (pro-CPB) has been studied in detail by a number of complementary methodologies, and a description of the molecular events that lead to the generation of active carboxypeptidase B (CPB) has been deduced. The generated CPB participates in the degradation of its own activation segment by excising C-terminal residues from fragments produced by tryptic proteolysis. The trimming action of CPB is, however, not essential for the release of a fully functional enzyme, in contrast to what was previously reported for porcine procarboxypeptidase A (pro-CPA). In the model presented here, the activation process is solely dependent on the first tryptic cleavage, at the limit between the activation segment and the enzyme region, and the former piece loses all of its inhibitory capacity once severed from the proenzyme. The use of heterologous inhibitors of CPB activity during the study of the tryptic activation process of pro-CPB has been required for the capture of short-lived, otherwise nondetectable, intermediates. This has allowed a complete description of the process and shown that the first proteolytic action of trypsin can also take place on a second target bond. Structural considerations that take into account the three-dimensional structures of the A and B forms of the proenzymes lead us to propose that the differences in conformation at the region that connects the globular activation domain to the enzyme are the main responsible elements for the differences observed in the activation processes of both proenzymes.

Amino Acid Sequence↗
PubMed1995

Medullary thyroid carcinoma mimicking an autonomous functioning nodule.

A 42-year-old woman with a medullary thyroid carcinoma (MTC) inside of an autonomously functioning thyroid nodule is reported. The patient was initially diagnosed of a hyperfunctioning autonomous thyroid adenoma but the histopathological and immunohistochemistry study were diagnostic for a MTC. This is the first case of a medullary thyroid carcinoma associated with thyroid hyperfunction which was presented as a hot nodule in the scintigraphy. We propose a systematic performance of a fine needle biopsy in all thyroid nodules because of the possibility of carcinoma associated to functioning nodules could be present.

Adult↗
PubMed1995

A tumor necrosis factor-beta polymorphism associated with hypertriglyceridemia in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent (type II) diabetes mellitus is associated with significant abnormalities of lipoprotein metabolism. Control of glycemia rarely completely corrects the alterations in lipid metabolism, suggesting a participation of environmental and genetic factors. The observation that tumor necrosis factor (TNF) can modulate triglyceride metabolism offers a new genetic candidate to be analyzed. Samples of DNA from 91 control subjects and 61 diet-treated type II diabetic patients were analyzed to determine the lipid profile and a possible association with TNF genetic polymorphisms. For TNF restriction fragment length polymorphisms, we used the Nco I restriction enzyme and a TNF-alpha probe obtaining two allelic bands at 10.5 and 5.5 kb. We found a significant association (P < .01) of the 10.5-kb homozygous genotype in type II diabetic subjects with high triglyceride levels. Furthermore, these patients showed significant differences in triglycerides as compared with matched control subjects with the same genotype (P < .001). This study provides support for considering the TNF locus as a susceptibility genetic region in the hypertriglyceridemia of type II diabetes.

Adult↗