Influence of Lys656Asn polymorphism of the leptin receptor gene on insulin resistance in nondiabetic obese patients

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, >30 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 43.6+/-16.6 years and 35.3+/-5.6 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; 2.8+/-1.7 vs. 5.6+/-4.8; P<.05) and insulin (18.1+/-10.7 vs. 32.1+/-25 mUI/ml; P<.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 (39.3+/-23 vs. 63.5+/-28 ng/ml; P<.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.