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1.  Prognostic Effect of Circulating Adiponectin in a Randomized 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women at Risk for Breast Cancer 
Journal of Clinical Oncology  2011;30(2):151-157.
Purpose
Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer.
Patients and Methods
We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period.
Results
At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels.
Conclusion
Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.
doi:10.1200/JCO.2011.35.2237
PMCID: PMC3255561  PMID: 22162577
2.  The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls 
BMC Gastroenterology  2012;12:111.
Background
Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls.
Methods
To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery.
Results
Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features.
Conclusions
The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.
doi:10.1186/1471-230X-12-111
PMCID: PMC3444917  PMID: 22898488
Adiponectin; Adiponutrin; Chronic hepatitis C; Fibrosis; Gender; Genetics; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Pnpla3; Steatosis
3.  Adipokines and Sexual Hormones Associated with the Components of the Metabolic Syndrome in Pharmacologically Untreated Subjects: Data from the Brisighella Heart Study 
We evaluated the association of the sex hormone pattern and the serum level of the main adipokines to metabolic syndrome (MS) and its components in 199 pharmacologically untreated subjects. Men and women included in the age-class subgroups were matched for body mass index, waist circumference, blood pressure, heart rate, fasting plasma glucose, and plasma lipids. Men without MS had significantly lower leptin/adiponectin ratio than men with MS. Women without MS had lower leptin and leptin/adiponectin ratio than women with MS but had significantly higher adiponectin, estrone, and dehydroepiandrosterone levels. In men, the leptin/adiponectin ratio is the main factor associated to MS diagnosis (OR: 3.36, 95% CI 1.40–8.08), while in women adiponectin alone appears to be a protective factor (OR: 0.87, 95% CI 0.79–0.95). In conclusion, in a sample of pharmacologically untreated subjects, leptin/adiponectin ratio seems to be the factor more strongly associated to MS and its components.
doi:10.1155/2011/724816
PMCID: PMC3216320  PMID: 22114592
4.  Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer 
Cancer research  2008;68(22):9512-9518.
The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Since fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low-dose on features linked to insulin resistance in premenopausal women at-risk for breast cancer.
We randomized 235 women to low-dose tamoxifen (5 mg/daily), or fenretinide (200 mg/daily), or their combination or placebo for two years. We employed the homeostasis model assessment (HOMA; fasting insulin*glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA ≥2.8 to <2.8.
There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index ≥25 kg/m2) had a 7-fold greater probability to normalize HOMA after two years of fenretinide treatment (OR=7.0; 95%CI: 1.2-40.5), with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times as compared to subjects not taking tamoxifen (OR=0.15; 95%CI: 0.03-0.88). In this group only 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P=0.07).
Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.
doi:10.1158/0008-5472.CAN-08-0553
PMCID: PMC2599903  PMID: 19010927
risk biomarkers; insulin resistance; breast cancer prevention; HOMA
5.  Impaired Expression of Insulin-Like Growth Factor-1 System in Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients 
Muscle & Nerve  2012;45(2):200-208.
Introduction
Adult muscle fibers are a source of growth factors, including insulin-like growth factor-1 (IGF-1). These factors influence neuronal survival, axonal growth, and maintenance of synaptic connections.
Methods
We investigated the components of the IGF system in skeletal muscle samples obtained from 17 sporadic amyotrophic lateral sclerosis patients (sALS) and 29 control subjects (17 with normal muscle and 12 with denervated muscle unrelated to ALS).
Results
The muscle expression of IGF-1 and IGF-binding proteins 3, 4, and 5 (IGF-BP3, -4, and -5, respectively), assessed by immunohistochemistry, was differently decreased in sALS compared with both control groups; conversely, IGF-1 receptor β subunit (IGF-1Rβ) was significantly increased. Western blot analysis confirmed the severe reduction of IGF-1, IGF-BP3, and -BP5 with the increment of IGF-1Rβ in sALS.
Conclusion
In this study we describe the abnormal expression of the IGF-1 system in skeletal muscle of sALS patients that could participate in motor neuron degeneration and should be taken into account when developing treatments with IGF-1. Muscle Nerve, 2012
doi:10.1002/mus.22288
PMCID: PMC3306791  PMID: 22246875
amyotrophic lateral sclerosis; IGF-1; IGF-BPs; IGF-1 receptor; skeletal muscle

Results 1-5 (5)