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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.