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  • Author: José Manuel Fernández-Real x
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Ana Megia, Joan Vendrell, Cristina Gutierrez, Modest Sabaté, Montse Broch, José-Manuel Fernández-Real and Inmaculada Simón


Resistin is expressed and secreted by the placenta during pregnancy. Increased serum resistin levels have been found in the second half of normal pregnancy, but its role in the pathogenesis of the insulin resistance of pregnancy is undetermined.


The objective of the study was to assess the relationship between circulating resistin levels and insulin sensitivity in gestational diabetes mellitus (GDM).

Design and setting

A case (n=23)–control (n=35) study was performed at the obstetrics and endocrinology clinic of a university hospital.


In total, 58 Caucasian women with a singleton pregnancy who had been referred for a 100 g oral glucose tolerance test were enrolled between the weeks 26 and 30, and 22 women with GDM were also evaluated after pregnancy.

Main outcome measures

Serum resistin and insulin sensitivity in GDM during and after pregnancy. The relationship of resistin to metabolic abnormalities was evaluated.


Resistin levels were lower in GDM women than in pregnant women with normal glucose tolerance (NGT) (4.32±1.56 vs 9.30±1.32 ng/ml, P<0.001), and experienced a further decrease after parturition (4.24±1.56 vs 3.11±1.63 ng/ml, P=0.003). The association between low serum resistin levels and the diagnosis of GDM was independent of the degree of insulin sensitivity.


Lower resistin levels were observed in GDM than in NGT women and decreased after parturition, suggesting a role for resistin in the development of this disease. But we have failed to find an independent relationship between resistin levels and insulin sensitivity during pregnancy.

Free access

Gemma Villuendas, José I Botella-Carretero, Abel López-Bermejo, Carme Gubern, Wifredo Ricart, José Manuel Fernández-Real, José L San Millán and Héctor F Escobar-Morreale

Objective: The IGF-II receptor gene (IGFIIR) is located at chromosome 6q26, a region that harbors a genetic marker linked to insulin-resistant traits in Mexican–Americans. In the present study conducted in Spaniards, we tested a common polymorphism in IGFIIR for association with type 2 diabetes and insulin-resistant traits.

Design: Case–control association study.

Methods: One hundred and forty-five type 2 diabetic patients and 217 non-diabetic controls were genotyped for the ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR. Phenotyping included anthropometrics and a metabolic profile, including serum lipid levels and surrogate indexes of insulin resistance whenever possible.

Results: Diabetic patients were more frequently homozygous for the wild type 144 bp allele of IGFIIR compared with controls (diabetic patients 77.2%, controls 51.6%, P<0.001) suggesting a potential protective role against type 2 diabetes for the IGFIIR 140 bp variant. Carrying 140 bp alleles was associated with an odds ratio of having diabetes of 0.290 (95% confidence interval 0.109–0.770), and controls homozygous for the wild type 144 bp allele presented with lower insulin and triglyceride levels, which are proxies for insulin resistance.

Conclusions: The ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR is associated with type 2 diabetes and influences surrogate markers of insulin resistance in non-diabetic subjects.

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María del Mar Grasa, José Gulfo, Núria Camps, Rosa Alcalá, Laura Monserrat, José María Moreno-Navarrete, Francisco José Ortega, Montserrat Esteve, Xavier Remesar, José Antonio Fernández-López, José Manuel Fernández-Real and Marià Alemany


Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.


Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m2).


SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones.


Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.


The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity.

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Francisco J Ortega, Mónica Sabater, José M Moreno-Navarrete, Neus Pueyo, Patricia Botas, Elias Delgado, Wifredo Ricart, Gema Frühbeck and José Manuel Fernández-Real


Increased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance.


We performed both cross-sectional and longitudinal (diet-induced weight loss) studies.


Circulating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (S I, Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19).


Circulating calprotectin was significantly increased in IGT–T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin with S I was independent of BMI and age. In fact, S I together with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR.


These findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity.

Free access

José Manuel Fernández-Real, Marek Straczkowski, Begoña Lainez, Matilde R Chacón, Irina Kowalska, Abel López-Bermejo, Antonio García-España, Agnieszka Nikolajuk, Ida Kinalska and Wifredo Ricart

Objective: Serum concentrations of soluble tumor necrosis factor-α (TNF-α) receptor 2 (sTNFR2) are associated with insulin resistance. In a recent study, we provided evidence for the existence of a biologically active form of sTNFR2 produced by alternative splicing (DS-TNFR2). We aimed to evaluate whether this circulating DS-TNFR2 is associated with insulin action in humans.

Design and methods: Real time PCR (light cycler technology) evaluated DS-TNFR2 expression in monocytes. DS-TNFR2 was measured using a monoclonal antibody against an epitope present in TNFR2 (first 14 residues of the juxtamembrane region) but predicted to be absent in soluble proteolytic cleavage-produced TNFR2. Insulin sensitivity was measured using euglycemic hyperinsulinemic clamp (n = 76) and homeostatic model of assessment (HOMA) value in a replication study of 223 subjects.

Results: Real time PCR confirmed gene expression of DS-TNFR2 in monocytes from healthy subjects. A significant and positive association was found between serum DS-TNFR2 concentration and insulin sensitivity (P = 0.032, n = 76). This association was most significant in subjects with normal glucose tolerance (r = 0.44, P = 0.002). The subjects in whom DS-TNFR2 was detectable were more insulin sensitive than those with undetectable DS-TNFR2 (42.12±22.08 vs 31.71± 16.95 μmol × kg−1 × min−1, P = 0.039). DS-TNFR2 was inversely associated with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, fasting serum glucose, serum triglycerides and serum uric acid concentration and with the HOMA value (P = 0.03) in the replication study. Circulating DS-TNFR2 declined with increased number of components of the metabolic syndrome.

Conclusion: Native sTNFR2 and DS-TNFR2 show opposite associations with insulin action. DS-TNFR2 might play a role as a counterpart of the proinflammatory environment associated with insulin resistance.