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  • Author: Abel López-Bermejo x
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Ken K Ong, Francis de Zegher, Abel López-Bermejo, David B Dunger and Lourdes Ibáñez

Abstract

Objective

Addition of androgen receptor (AR) blockade (flutamide) to insulin-sensitising therapy (metformin) may confer synergistic benefits in girls with hyperinsulinaemic androgen excess. We hypothesised that girls with shorter AR gene CAG repeat alleles, and thus greater receptor sensitivity, might benefit more from the addition of low-dose flutamide.

Design

Open randomised crossover study.

Methods

In this study, 32 post-menarcheal girls (mean age 12.1 years) with a history of low birth weight and precocious pubarche were subgrouped by CAG genotype (‘short’: CAG mean length ≤20, n=14; ‘long’: CAG >20, n=18). Within each subgroup, girls were 1:1 randomised to metformin alone (850 mg/day) or in combination with flutamide (62.5 mg/day) for 12 months. To allow comparisons with no treatment, long-CAG girls randomised to flutamide–metformin, and short-CAG girls randomised to metformin alone were observed for 12 months before treatment. Body composition by absorptiometry, fasting lipid profiles and levels of insulin, glucose and androgens were measured during the first 12 months on each treatment.

Results

In all girls, 12 months flutamide–metformin lowered body fat and improved lipid profiles when compared with no treatment. Compared with metformin alone, flutamide–metformin achieved greater reductions in the percentage of body fat and abdominal fat mass in the short-CAG subgroup (P=0.001 to P<0.0001). In contrast, in the long-CAG subgroup, flutamide–metformin produced no further improvements when compared with metformin alone.

Conclusions

In young post-menarcheal girls with preclinical androgen excess, low-dose flutamide–metformin improved body composition and key endocrine–metabolic abnormalities. However, only those girls with genetic markers of greater AR sensitivity may benefit from the addition of flutamide above metformin alone.

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.

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.