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: 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 non-coding SNPs of MC3R in a cross-sectional study of 216 middle-aged non-diabetic Finnish subjects who were offspring of type 2 diabetic patients.

Main Outcome Measures: Insulin secretion was evaluated by an intravenous glucose tolerance test (IVGTT) 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/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 IVGTT (insulin under the curve during the first 10 minutes, 3220 ± 1765 vs. 2454 ± 1538, pmol/Lxmin, 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.