Context: The melanocortin-3 receptor (MC3R) is a part of the melanocortin system that regulates appetite and energy metabolism. The Thr/Thr 6 and Val/Val81 [corrected] 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 Lys 6 and Ile 81 [corrected] 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 micromol/kg of LBM/min; P = 0.031) than subjects with the Thr/Thr 6 and Val/Val 81 [corrected] 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.