Anti-Human INSR monoclonal antibody

Objective Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response. We performed a large-scale candidate-gene study to identify genetic risk factors predictive of topiramate-induced weight loss. Methods We collected DNA samples from patients who had previously participated in clinical trials to assess the efficacy of topiramate for the treatment of obesity. A custom chip containing single nucleotide polymorphisms from similar to 480 candidate genes was utilized to genotype a discovery cohort of 445 obese patients from a clinical study. Variants predictive of topiramate-induced weight loss were identified and further tested in an independent replication cohort of drug-naive, obese patients with type 2 diabetes (N=139). Results We identified a haplotype in INSR that may contribute to differential topiramate-induced weight loss. Carriers and noncarriers of an INSR haplotype lost 9.1 and 7.0% of body weight, respectively (P=6.5x10(-6), P-adj=0.001). This finding was replicated, with carriers and noncarriers losing 9.5 and 7.3% of body weight, respectively (P-Bonf=0.02), in the independent replication cohort. We also identified an SNP in HNF1A that may be associated with topiramate response and an SNP in GRIA3 that may be associated with nonpharmacologic treatment response. Conclusion According to our preliminary findings, genetic variation in the INSR and HNF1A genes may differentially affect weight loss in obese individuals treated with topiramate and genes related to insulin action are implicated in modulating topiramate response. However, these findings need to be further replicated in additional larger samples.

Background and objectives: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease characterized by accumulation of triglycerides in hepatocytes without alcohol consumption. Considering the key role of insulin resistance in NAFLD, we investigated whether insulin (INS) and insulin receptor (INSR) gene variants were associated with NAFLD risk. Materials and methods: This study was conducted as a case-control study and 230 subjects, including 128 controls and 102 cases with biopsy-proven NAFLD, were enrolled and genotyped using PCR-RFLP method. Results: We observed no significant difference in genotype or allele frequencies between the cases with NAFLD and controls for INS gene rs689 variant either before or after adjustment for confounding factors including age, BMI, sex, smoking status, systolic blood pressure, and diastolic blood pressure. However, the INSR rs1799817 "TT" genotype compared with the "CC" genotype and "CC+CT" genotypes appears to be a marker of decreased NAFLD susceptibility (P=0.029; OR=0.14, 95% CI=0.03-0.82 and P=0.048; OR=0.20, 95% CI=0.04-0.98, respectively). Conclusions: To our knowledge, our findings suggested for the first time that the INSR rs1799817 "TT" genotype compared with the "CC" genotype and "CC+CT" genotypes had 86% and 80% decreased risks for NAFLD, respectively. Nevertheless, further studies are needed to confirm these findings. (C) 2016 Elsevier B.V. All rights reserved.