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Francisco J Ortega, José M Moreno-Navarrete, Mónica Sabater, Wifredo Ricart, Gema Frühbeck and José M Fernández-Real


Acute phase mediators promote metabolic changes by modifying circulating hormones. However, there is virtually no data about the link between glucagon and inflammatory parameters in obesity-related chronic low-grade inflammation.

Study design

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


Circulating glucagon concentrations (ELISA), parameters of glucose and lipid metabolism, interleukin 6 (IL6), and complement factor B (CFB) were analyzed in 316 subjects (250 men and 66 women). The effects of weight loss were investigated in an independent cohort of 20 subjects.


Circulating glucagon significantly correlated with glucose (r=0.407, P<0.0001), HbAlc (r=0.426, P<0.0001), fasting triglycerides (r=0.356, P=0.001), and parameters of innate immune response system such as IL6 (r=0.342, P=0.050) and CFB (r=0.404, P=0.002) in obese subjects with altered glucose tolerance, but not in individuals with normal glucose tolerance (NGT). In obese and NGT subjects, glucagon was associated with fasting triglycerides (r=0.475, P=0.003) and CFB (r=0.624, P=0.001). In obese subjects, glucagon (P=0.019) and CFB (P=0.002) independently contributed to 26% of fasting triglyceride variance (P<0.0001) after controlling for the effects of age and fasting serum glucose concentration in multiple lineal regression models. Moreover, concomitant with fat mass, fasting triglycerides, and CFB, weight loss led to significantly decreased circulating glucagon (−23.1%, P=0.004).


According to the current results, acute phase reactants such as IL6 and CFB are associated with fasting glucagon in metabolically compromised subjects. This suggests that glucagon may be behind the association between inflammatory and metabolic parameters in obesity-associated chronic low-grade inflammation.

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.

Free access

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

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.