Influence of Lys656Asn polymorphism of the leptin receptor gene on insulin resistance in nondiabetic obese patients Daniel A. de Luis 4 , Manuel Gonzalez Sagrado, Rocio Aller, Olatz Izaola, Rosa Conde Medicine School and Unit of Investigation, Institute of Endocrinology and Nutrition, Hospital Rio Hortega, University of Valladolid, Valladolid, Spain Received 16 August 2006; received in revised form 10 October 2006; accepted 12 October 2006 Abstract Background: Alterations of the normal leptin receptor (LEPR) gene may be involved in the development of obesity. Leptin has been shown to be able to modulate insulin secretion. Different polymorphisms in the LEPR gene have been studied, albeit with unclear results. The polymorphism on codon 656 produces a change in charge, making this change possibly functional. Objective: The objective of this study was to investigate the influence of Lys656Asn polymorphism in the LEPR gene on serum insulin, glucose values, and insulin resistance in the fasted state among obese men and women without diabetes mellitus. Design: Two hundred thirty-three (body mass index, N30 kg/m 2 ) nondiabetic obese patients were analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure determination, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. Statistical analysis was performed for Lys656/Asn656 and Asn656/Asn656 jointly as a mutant allelic group and for Lys656/Lys656 as a wild allelic group. Results: The subjects’ (67 males and 166 females) mean age and mean body mass index were 43.6F16.6 years and 35.3F5.6 kg/m 2 , respectively. One hundred forty-three patients (61.9%) had the genotype Lys656/Lys656 (wild group), whereas 88 (38.1%) had either the genotype Lys656/ Asn656 (n =81; 30.7%) or the genotype Asn656/Asn656 (n=7; 7.4%) (mutant group). Age and sex distribution were similar in both groups. No difference was detected between the mutant and wild allelic groups in anthropometric parameters and dietary intakes. Homeostasis model assessment (HOMA; 2.8F1.7 vs. 5.6F4.8; Pb.05) and insulin (18.1F10.7 vs. 32.1F25 mUI/ml; Pb.05) levels were higher in males with the genotypes Lys656/Asn656 and Asn656/Asn656 than in males with the genotype Lys656/Lys656. Leptin levels were higher in males with a mutant genotype than in males with a wild genotype (39.3F23 vs. 63.5F28 ng/ml; Pb.05). Conclusion: The novel findings of our study are those of the association of the Lys656/Asn656 and Asn656/Asn656 genotypes with higher levels of insulin, HOMA, and leptin in males and the lack of such an association in females. D 2008 Elsevier Inc. All rights reserved. Keywords: Insulin; Lys656Asn LEPR; Obesity 1. Introduction Leptin is a hormone mainly produced by adipose tissue and binds to receptors in the hypothalamus (Friedman & Halas, 1998). The discovery of mutations in the leptin gene and its receptor in rodent models of obesity and in rare cases of morbid obesity indicates that leptin functions as an afferent signal in a negative feedback that regulates energy balancing (Clement, Vaisse, & Lahlou, 1998; Lee, Proenca, & Montez, 1996). However, the roles of leptin and its receptor in the development of obesity in the general population are less clear. The etiology of common obesity is more complex because many genetic, environmental, and metabolic factors might act. It has been suggested that obese patients may be leptin resistant (Considine, Sinha, & Heiman, 1996). One of the explanations could be a decrease in leptin receptor (LEPR) signaling due to a mutant LEPR (Schwartz, Woods, Porte, Seeley, & Baskin, 2000). This has been demonstrated in 1056-8727/08/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2006.10.006 4 Corresponding author. Institute of Endocrinology and Nutrition, Medicine School. Valladolid University, C/Los perales 16, Simancas 47130, Valladolid, Spain. Journal of Diabetes and Its Complications 22 (2008) 199 – 204