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Menzaghi C.,Research Unit of Diabetes and Endocrine Disease | De Cosmo S.,Unit of Endocrinology | Copetti M.,Unit of Biostatistics | Salvemini L.,Research Unit of Diabetes and Endocrine Disease | And 6 more authors.
Diabetologia | Year: 2011

Aims/hypothesis: Insulin resistance is associated with reduced serum adiponectin and increased albuminuria levels. Thus, one would anticipate an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin in patients with elevated albuminuria. These findings may have been confounded by the presence of diseases and related treatments known to affect circulating adiponectin and albuminuria. We therefore studied the relationship between circulating adiponectin and albuminuria in the absence of such confounders. Methods: To this purpose, the relationship between adiponectin isoforms and albumin:creatinine ratio (ACR) was investigated in a family-based sample of 634 non-diabetic untreated white individuals with normal kidney function. We also investigated whether the two variables share a common genetic background and addressed the specific role of the gene encoding adiponectin on that background by genotyping several ADIPOQ single nucleotide polymorphisms (SNPs). Results: ACR was directly associated with high molecular weight (HMW) adiponectin isoform (p=0.024). The two variables shared some genetic correlation (ρg=0.38, p=0.04). ADIPOQ promoter SNP rs17300539 was associated with HMW adiponectin (p=4.8×10-5) and ACR (p=0.0027). The genetic correlation between HMW adiponectin and ACR was no longer significant when SNP rs17300539 was added to the model, thus reinforcing the role of this SNP in determining both traits. Conclusions/interpretation: Our study shows a positive, independent correlation between HWM adiponectin and ACR. ADIPOQ variability is associated with HMW adiponectin and ACR, and explains some of the common genetic background shared by these traits, thus suggesting that ADIPOQ and HMW adiponectin modulate albuminuria levels. © 2011 Springer-Verlag. Source

Menzaghi C.,Research Unit of Diabetes and Endocrine Disease | Salvemini L.,Research Unit of Diabetes and Endocrine Disease | Fini G.,Research Unit of Diabetes and Endocrine Disease | Thompson R.,Joslin Diabetes Center | And 11 more authors.
PLoS ONE | Year: 2012

Background: High serum resistin levels have been associated with kidney dysfunction. Most of these studies have been carried out in individuals with severe kidney impairment, diabetes, cardiovascular disease and related treatments. Thus, the observed association might have been influenced by these confounders. Our aim was to study the relationship between serum resistin, urinary albumin/creatinine ratio (ACR) and glomerular filtration rate (GFR) in a family-based sample, the Gargano Family Study (GFS) of 635 non diabetic, untreated Whites. Methods: A linear mixed effects model and bivariate analyses were used to evaluate the phenotypic and genetic relations between serum resistin and both ACR and eGFR. All analyses were adjusted for sex, age, age squared, BMI, systolic blood pressure, smoking habits and physical exercise. Results: After adjustments, resistin levels were slightly positively associated with ACR (β±SE = 0.049±0.023, p = 0.035) and inversely related to eGFR (β±SE = -1.43±0.61, p = 0.018) levels. These associations remained significant when either eGFR or ACR were, reciprocally, added as covariates. A genetic correlation (ρg = -0.31±0.12; adjusted p = 0.013) was observed between resistin and eGFR (but not ACR) levels. Conclusion: Serum resistin levels are independently associated with ACR and eGFR in untreated non-diabetic individuals. Serum resistin and eGFR share also some common genetic background. Our data strongly suggest that resistin plays a role in modulating kidney function. © 2012 Menzaghi et al. Source

Formoso G.,University of Chieti Pescara | Di Tomo P.,University of Chieti Pescara | Andreozzi F.,University of Catanzaro | Succurro E.,University of Catanzaro | And 8 more authors.
Cardiovascular Research | Year: 2011

Aims TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intimamedia thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis.Methods and results In 430 Caucasians of European ancestry, carotid IMT was increased in QR (n 116) and RR (n 15) when compared with QQ (n 299) subjects (P 0.009), thus replicating similar data recently obtained among Asians. In human umbilical vein endothelial cells (HUVECs) naturally carrying the QQ genotype, 24 h insulin stimulation increased monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, and mitogen-activated protein kinase (MAPK) kinase (MEK)MAPK activation. Conversely, QR- and RR-HUVECs had increased unstimulated monocyte adhesion, VCAM-1 and ICAM-1 expression, and MEKMAPK activation which did not increase further upon insulin stimulation. In addition, QQ-, QR-, and RR-HUVECs showed similar basal Akt phosphorylation and nitric oxide synthase activity which, however, were significantly increased by insulin only in QQ cells. Conclusion The TRIB3 R4 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. This abnormality may favour vasoreactivity, intimamedia thickening, and plaque formation and may, therefore, underlie the deleterious role exerted by the variant on the susceptibility to atherosclerosis. © 2010 The Author. Source

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