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.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Rutanen
Jarno
J
Departments of Medicine, University of Kuopio and Kuopio University Hospital, 70210 Kuopio, Finland.
Pihlajamäki
Jussi
J
Vänttinen
Markku
M
Salmenniemi
Urpu
U
Ruotsalainen
Eija
E
Kuulasmaa
Teemu
T
Kainulainen
Sakari
S
Laakso
Markku
M
D000328:Adult; D032721:Adult Children; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005787:Gene Frequency; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050356:Lipid Metabolism; D008297:Male; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D044104:Receptor, Melanocortin, Type 3