This Article Full Text Full Text (PDF) A correction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rutanen, J. Articles by Laakso, M. Search for Related Content PubMed PubMed Citation Articles by Rutanen, J. Articles by Laakso, M. Related Collections Diabetes and Insulin Metabolism

Single Nucleotide Polymorphisms of the Melanocortin-3 Receptor Gene Are Associated with Substrate Oxidation and First-Phase Insulin Secretion in Offspring of Type 2 Diabetic Subjects

Departments of Medicine (J.R., J.P., M.V., U.S., E.R., T.K., M.L.) and Clinical Radiology (S.K.), University of Kuopio and Kuopio University Hospital, 70210 Kuopio, Finland

Context: The melanocortin-3 receptor (MC3R) is a part of the melanocortin system that regulates appetite and energy metabolism. The Lys/Thr6 and Ile/Val81 polymorphisms of the MC3R gene have been previously associated with high insulin levels and obesity in children.

Objective: The objective was to determine whether single nucleotide polymorphisms (SNPs) of MC3R are associated with glucose, lipid, and energy metabolism.

Design, Setting, and Participants: We screened the Lys/Thr6 and Ile/Val81 mutations and six noncoding SNPs of MC3R in a cross-sectional study of 216 middle-aged nondiabetic Finnish subjects who were offspring of type 2 diabetic patients.

Main Outcome Measures: Insulin secretion was evaluated by an iv glucose tolerance test, and insulin sensitivity and energy metabolism by the hyperinsulinemic euglycemic clamp and indirect calorimetry.

Results: Carriers of the Thr6 and Val81 alleles had significantly lower rates of lipid oxidation [0.85 ± 0.38 vs. 1.00 ± 0.43 mg/kg of lean body mass (LBM)/min; P = 0.022, adjusted for sex, body mass index, age, and family relationship] and higher rates of glucose oxidation in the fasting state (11.28 ± 4.64 vs. 9.71 ± 4.53 µmol/kg of LBM/min; P = 0.031) than subjects with the Lys/Lys6 and Ile/Ile81 genotypes. They had lower rates of lipid oxidation during the hyperinsulinemic clamp (0.32 ± 0.41 vs. 0.44 ± 0.34 mg/kg of LBM/min; P = 0.021) and higher insulin levels in an iv glucose tolerance test (insulin under the curve during the first 10 min, 3220 ± 1765 vs. 2454 ± 1538 pmol/liter·min; P = 0.025) compared to subjects with the common genotypes.

Conclusions: Our results suggest that SNPs of MC3R may regulate substrate oxidation and first-phase insulin secretion.