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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 3 1112-1117
Copyright © 2007 by The Endocrine Society

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

Jarno Rutanen, Jussi Pihlajamäki, Markku Vänttinen, Urpu Salmenniemi, Eija Ruotsalainen, Teemu Kuulasmaa, Sakari Kainulainen and Markku Laakso

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


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE MELANOCORTIN-3 (MC3R) and -4 (MC4R) receptors belong to the family of melanocortin receptors that are part of the melanocortin system. The MC3R gene is expressed widely in the central nervous system (CNS) and also in peripheral tissues (1), whereas MC4R is expressed mainly in the CNS. The melanocortin system receives information about nutritional status through many peripheral humoral mediators, e.g. leptin and gastric peptides (2). This information is mediated by neuroendocrine hormones that have an anorexigenic effect on appetite (3) and increase energy expenditure (4, 5). Blocking this system leads to severe obesity in animals (6) and humans (7).

The Ile/Asn 183 substitution of MC3R has been associated with severe obesity (8). The Lys/Thr 6 and the Ile/Val 81 substitutions of MC3R, which are in tight linkage disequilibrium (LD), have been shown to associate with pediatric onset of obesity and high insulin levels (9, 10). These two variations are likely to be inactivating mutations because they impair the function of MC3R in vitro by binding approximately 60% less {alpha}-MSH analog than wild-type receptors (9).

Because animal studies suggest that MC3R affects peripheral energy metabolism (11) and because we have shown earlier that single nucleotide polymorphisms (SNPs) in MC4R regulate energy expenditure in humans (5), we investigated the effects of eight common SNPs of MC3R on metabolic parameters in 216 middle-aged, nondiabetic Finns who were offspring of type 2 diabetic subjects. We also screened for the rare Ile/Asn 183 substitution. Insulin sensitivity and the rates of energy expenditure and substrate oxidation were determined by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry. Abdominal fat distribution was evaluated by computed tomography (CT), and insulin secretion capacity by an iv glucose tolerance test (IVGTT).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The collection of subjects and the study protocol have been previously published (12). In brief, the subjects were selected from an ongoing study and included healthy nondiabetic offspring of patients with type 2 diabetes. The diabetic patients (probands) were randomly selected among type 2 diabetic subjects living in the region of the Kuopio University Hospital. Spouses of the probands had to have a normal glucose tolerance in an oral glucose tolerance test. A total of 216 offspring (one to three from each family) were studied. The study protocol was approved by the Ethics Committee of the University of Kuopio. All study subjects gave an informed consent. Clinical characteristics of study subjects are given in Table 1Go.


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  		TABLE 1. Clinical and laboratory characteristics of 216 study subjects

 
Measurements and metabolic studies

On the first day, blood pressure (BP) was measured with a mercury sphygmomanometer in a sitting position after a 5-min rest. Height and weight were measured to the nearest 0.5 cm and 0.1 kg, respectively. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. Waist (at the midpoint between the lateral iliac crest and lowest rib) was measured to the nearest 0.5 cm. Fasting blood samples were drawn after 12 h fasting, followed by an oral glucose tolerance test (75 g of glucose). Subjects with normal glucose tolerance (n = 182), isolated impaired fasting glucose (n = 4), or impaired glucose tolerance (n = 30) (13) were included in further studies. On the second day after the 12-h fast, an IVGTT and the hyperinsulinemic euglycemic clamp including indirect calorimetry were performed as previously described in detail (12). In the hyperinsulinemic clamp, the mean amount of glucose infused during the last hour was used to calculate the rates of whole body glucose uptake (WBGU). Furthermore, a CT scan was performed to evaluate the amount of abdominal and sc fat as previously described (12).

Laboratory determinations

Blood glucose was measured by the glucose oxidase method (Glucose and Lactate Analyzer 2300 Stat Plus, Yellow Springs Instrument Co., Inc., Yellow Springs, OH), and plasma insulin and C-peptide by RIA (Phadeseph Insulin RIA 100, Pharmacia Diagnostics AB, Uppsala, Sweden; and 125J RIA kit, Incstar Co., Stillwater, MN, respectively). Cholesterol and triglyceride levels from the whole serum and from lipoprotein fractions were assayed by automated enzymatic methods (Roche Diagnostics, Mannheim, Germany) (14). Serum free fatty acids (FFAs) were determined by an enzymatic method from Wako Chemicals GmbH (Neuss, Germany). Nonprotein urinary nitrogen was measured by automated Kjeldahl method.

DNA analysis

We screened five promoter [rs4627642 (A/T), rs6024730 (G/A), rs16979603 (T/C), rs6014649 (G/A), and rs6127698 (G/T)], two coding region [rs3746619 (Lys/Thr 6) and rs3827103 (Ile/Val 81)], and one 3' flanking region [rs2870730 (G/C)] polymorphisms, and the Ile/Asn 183 mutation of MC3R using the TaqMan Allelic Discrimination Assays (Applied Biosystems, Foster City, CA). Genotyping reaction was amplified on a GeneAmp PCR system 2700 (95 C for 10 min, followed by 40 cycles of 95 C for 15 sec and 60 C for 1 min), and fluorescence was detected on an ABI Prism 7000 Sequence Detection System (Applied Biosystems). The primer and probe sequences are available from the authors by request. Selection of the SNPs was based on the genotype data from Utah residents with ancestry from northern and western Europe available from the HapMap (public release 20, January 24, 2006) project web site (http://www.hapmap.org) (15). Tagger software available at http://www.broad.mit.edu/mpg/tagger/ (16) was used to select SNPs and to evaluate whether selected SNPs covered adequately the region of the MC3R locus (5.5 kb upstream, 1.1 kb region of MC3R, and 5.5 kb downstream). The SNPs selected capture about 80% of common variants [minor allele frequency (MAF) > 5%] with an r2 > 0.8. Genotyping success rate of eight SNPs was 100%. We repeated 8.6% of our genotypes and obtained 100% identical results.

Statistical analysis

Data analyses were carried out with the SPSS 11.0 for Windows programs (SPSS Inc., Chicago, IL), with the exception of the permutation analysis that was performed with the R 2.3.0 (http://www.r-project.org) (17) and car 1.1–0 package (http://socserv.socsci.mcmaster.ca/jfox/). The results for continuous variables are given as means ± SD. Variables with skewed distribution (glucose, insulin, triglycerides, FFAs, sc and intraabdominal fat) were logarithmically transformed for statistical analyses. The incremental area under the insulin curve in an IVGTT was calculated by the trapezoidal method. The differences between the two groups were assessed by the ANOVA for continuous variables and by the {chi}2 test for noncontinuous variables. Linear mixed model analysis was applied to adjust for confounding factors. For mixed model analysis, we included the pedigree (coded as a family number) as a random factor, the MC3R genotype and gender as fixed factors, and BMI and age as covariates. If the P value for the covariance parameter for the random effect was greater than 0.1, the pedigree membership was excluded from the model, and the analysis of covariance was used for additional adjustment. Haploview software (18), available at http://www.broad.mit.edu/mpg/haploview/, was used to calculate the LD statistics. Haplotype estimation from unrelated individuals was performed by using the SNPHAP, available at http://www-gene.cimr.cam.ac.uk/clayton/software/. The effect of each haplotype on quantitative parameters was analyzed as described above.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The location of eight SNPs of MC3R, their minor allele frequencies (MAF), and LD statistics are shown in Fig. 1Go. No carriers of the Ile/Asn 183 mutation were found in our study population. The coding region variants Lys/Thr 6 and Ile/Val 81 substitutions were almost in complete LD with each other but had a substantially lower LD with noncoding region variants. Altogether, 35 subjects had the Lys/Thr 6 genotype and five subjects the Thr/Thr 6 genotype (frequency of the Thr 6 allele, 0.10). The Ile/Val 81 genotype was found in 33 subjects, and the Val/Val 81 genotype in five subjects (frequency of the Val 81 allele, 0.10). The five subjects homozygous for both Thr 6 and Val 81 alleles were combined with heterozygotes in all statistical analyses. Two subjects carried the haplotypes, which did not include either the Lys 6 Ile 81 or Thr 6 Val 81 combinations, and therefore they were excluded from all statistical analyses.


Figure 1
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  		FIG. 1. A, Gene map shows SNPs genotyped in MC3R gene. Coding exon is marked by a black box. Genotyped SNPs are shown with the National Center for Biotechnology Information database SNP accession numbers. B, LD statistics (D', r2) and the MAFs are shown among the SNPs of the MC3R gene.

 
We found that lipid oxidation in the fasting state was significantly lower in carriers of the Thr 6 and Val 81 alleles compared with that of subjects with the Lys/Lys 6 and Val/Val 81 genotypes [0.85 ± 0.38 vs.1.00 ± 0.43, mg/kg of lean body mass (LBM)/min; P = 0.022, respectively, adjusted for BMI, age, sex, and family relationship; Fig. 2Go]. Similar results were obtained during the hyperinsulinemic clamp (0.32 ± 0.41 vs. 0.44 ± 0.34 mg/kg of LBM/min; P = 0.021, respectively). Glucose oxidation in the fasting state was significantly higher in carriers of the Thr 6 and Val 81 alleles compared with subjects with the Lys/Lys 6 and Ile/Ile 81 genotypes (11.28 ± 4.64 vs. 9.71 ± 4.53 µmol/kg of LBM/min, P = 0.031; Fig. 2Go), and similar, nonsignificant trend was observed during the hyperinsulinemic clamp. Levels of fasting FFAs were significantly lower in carriers of the Thr 6 and Val 81 alleles (0.50 ± 0.19 vs. 0.60 ± 0.24 mmol/liter; P = 0.003; Fig. 2Go), whereas no differences were found in levels of FFAs during the hyperinsulinemic clamp.


Figure 2
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  		FIG. 2. A, Lipid oxidation in the fasting state and during the hyperinsulinemic euglycemic clamp according to the Lys/Thr 6 and Ile/Val 81 polymorphisms of the MC3R gene. B, Glucose oxidation in the fasting state and during the hyperinsulinemic euglycemic clamp according to the Lys/Thr 6 and Ile/Val 81 polymorphisms of the MC3R gene. C, Fatty acid levels in the fasting state and during the hyperinsulinemic euglycemic clamp according to the Lys/Thr 6 and Ile/Val 81 polymorphisms of the MC3R gene. Subjects with the Lys/Lys 6 and Ile/Ile 81 genotypes (black bars, n = 176) vs. carriers of the Thr 6 and Val 81 alleles (open bars, n = 38). P values are adjusted for BMI, age, sex, and family relationship (linear mixed model analysis, n = 214). P values remained statistically significant (P < 0.05) in the permutation test.

 
Subjects with the A allele of rs6014649, which is in LD (r2 > 0.8) with the Lys/Thr 6 and Ile/Val 81 polymorphisms, had significantly higher rates of glucose oxidation in the fasting state compared with subjects with the GG genotypes (carriers of the A allele 11.30 ± 4.77 vs. subjects with the GG genotype 9.72 ± 4.50 µmol/kg of LBM/min; P = 0.048), whereas during the hyperinsulinemic clamp the differences in the rates of glucose oxidation and lipid oxidation remained nonsignificant. Carriers of the A allele also had lower levels of FFAs in the fasting state (0.50 ± 0.18 vs. 0.60 ± 0.24 mmol/liter; P = 0.003; Table 2Go). rs6127698 was also associated with lipid oxidation in the fasting state (GG genotype 0.97 ± 0.39, GT genotype 0.91 ± 0.43, TT genotype 1.11 ± 0.42 mg/kg of LBM/min; P = 0.017). No significant differences were observed in the rates of lipid oxidation, glucose oxidation, or FFA levels with respect to other SNPs. No differences were observed in the rates of energy expenditure in the fasting state or during the hyperinsulinemic clamp. Similarly, no statistically significant differences were observed in BMI, waist, BP, fasting glucose or insulin, sc or intra-abdominal fat measured by CT with respect to any SNPs screened (Table 2Go).


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  		TABLE 2. Fasting insulin, WBGU, first-phase insulin secretion in an IVGTT, fasting FFAs, and body composition according to SNPs of MC3R

 
We did not find differences in the rates of WBGU during the hyperinsulinemic euglycemic clamp between the risk alleles and the common genotypes of the SNPs. However, subjects with the Lys/Lys 6 and Ile/Ile 81 genotypes had lower first-phase insulin secretion (insulin under the curve during the first 10 min of the IVGTT) than did subjects with the Thr 6 and Val 81 alleles (2454 ± 1538 vs. 3220 ± 1765 pmol/liter x min; P = 0.025, respectively; Fig. 3Go).


Figure 3
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  		FIG. 3. The first-phase insulin secretion according to the Lys/Thr 6 and Ile/Val 81 polymorphisms of the MC3R gene. Subjects with the Lys/Lys 6 and Ile/Ile 81 genotypes (black bars, n = 176) vs. carriers of the Thr 6 and Val 81 alleles (open bars, n = 38). P value is adjusted for BMI, age, sex, and family relationship (linear mixed model analysis, n = 214). P value remained statistically significant (P < 0.05) in the permutation test.

 
Five haplogenotypes were formed from the three SNPs that were associated with metabolic phenotypes (rs6014649, Lys/Thr 6, and Val/Ile 81), haplogenotype 111/111 (n = 176, frequency 0.815), haplogenotype 111/222 (n = 27, 0.125), haplogenotype 222/222 (n = 5, 0.023), haplogenotype 111/122 (n = 6, 0.028) and haplogenotype 111/221 (n = 2, 0.009). Subjects with the 111/111 haplogenotype were compared with carriers of the 222 haplotype (haplogenotypes 111/222 and 222/222 combined). In the fasting state, the 222 haplotype was associated with lower rates of lipid oxidation than the 111/111 haplogenotype (0.86 ± 0.40 vs. 1.00 ± 0.43 mg/kg of LBM/min; P = 0.047) and higher rates of glucose oxidation (11.52 ± 4.82 vs. 9.71 ± 4.53 µmol/kg of LBM/min; P = 0.029). Thus, haplotype analysis did not identify haplogenotypes having an effect beyond those of individual SNPs.

All statistical analyses with respect to variables having a P value < 0.050 [genotype combinations of rs6014649, rs3746619 (Lys/Thr 6), rs3827103 (Ile/Val 81); Table 2Go and Figs. 2Go and 3Go] were also evaluated with the permutation test (ANCOVA). For each variable, the actual dataset was resampled 1000 times, and statistical analyses were performed. The P value of the permutation test for each variable of interest was from 0.001 to 0.049, supporting that P values reported in the Results section are likely to be statistically significant (P < 0.050).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We investigated the associations of SNPs of MC3R with glucose, lipid, and energy metabolism in a large and metabolically well-characterized sample of offspring of type 2 diabetic subjects. We reported for the first time that carriers of the Thr 6 and Val 81 alleles in the coding region of MC3R had lower lipid oxidation, higher glucose oxidation, and lower FFA levels compared with those of subjects with the Lys/Lys 6 and Val/Val 81 genotypes.

Melanocortin receptors play a role in energy, glucose, and lipid metabolism. Hoggard et al. (19) found that obese men had higher peripheral levels of {alpha}-MSH, melanocortin receptor antagonist agouti-related peptide and leptin than normal weight control subjects. Dysfunction of MC3R is considered to increase adiposity. However, we did not observe changes in body composition in carriers of the Thr 6 and Val 81 alleles of MC3R. A recent study demonstrated that homozygous carriers of the Thr 6 and Val 81 alleles of MC3R developed obesity at young ages (9). Only five subjects in our study were homozygous for the Thr 6 and Val 81 alleles, and therefore the number of subjects is too small to make reliable conclusions about the effect of homozygosity of the Thr 6 and Val 81 alleles on obesity and distribution of obesity.

Our study suggests that carriers of the 6Thr and 81Val alleles have decreased lipid oxidation, which can cause increased rates of glucose oxidation in these subjects. These findings are in line with the results in MC3R-KO mice, which showed that these mice have low rates of lipid oxidation (11). Carriers of the Thr 6 and Val 81 alleles had low levels of FFAs, suggesting that decreased lipid oxidation is probably attributable to low rates of lipolysis.

Our second main finding was that carriers of the Thr 6 and Val 81 alleles had higher insulin levels during the first 10 min of the IVGTT without a difference in the rates of WBGU during the hyperinsulinemic clamp. Thus, these subjects had high first-phase insulin secretion that was not entirely explained by insulin resistance. In several earlier studies carriers of the Thr 6 and Ile 81 alleles of MC3R had high fasting plasma insulin levels (9, 10, 20). We also observed a similar trend although it was not statistically significant, which suggests that carriers of these alleles have high insulin secretion partly attributable to other mechanisms. Insulin is an important central signaling molecule in the CNS, and it forms a complex network with the melanocortin system (21). Insulin increases the activity of the melanocortin system in the CNS that seems to inhibit appetite in rats (22). Therefore, it is possible that the melanocortin system has a feedback loop to inhibit insulin secretion and that MC3R dysfunction could lead to high insulin levels. Actually, a recent study showed that autonomic nerve fibers form neuron pathways between hypothalamus and peripheral organs like pancreas, liver, and adipose tissue (23).

In conclusion, we have reported for the first time that the Thr 6 and Val 81 alleles of MC3R are associated with low lipid oxidation, high glucose oxidation, and high insulin levels. However, our findings need to be confirmed in other populations. Although we cannot exclude the possibility that our findings are caused by LD with some other gene locus on chromosome 20, the functionality of these polymorphisms and animal studies suggest that MC3R has a role in peripheral FFA metabolism.


   Footnotes
 
Correspondence and requests for reprints to: Markku Laakso, M.D., Academy Professor, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi.

This study was financially supported by grants to M.L. from the Academy of Finland, the EVO Fund of the Kuopio University Hospital (5194), and the European Union (EUGENE2, LSHM-CT-2004-512013).

Disclosure Statement: The authors have nothing to disclose.

First Published Online December 27, 2006

Abbreviations: BMI, Body mass index; BP, blood pressure; CNS, central nervous system; CT, computed tomography; FFA, free fatty acid; IVGTT, iv glucose tolerance test; LBM, lean body mass; LD, linkage disequilibrium; MAF, minor allele frequency; MC3R, melanocortin-3 receptor; SNP, single nucleotide polymorphism; WBGU, whole body glucose uptake.

Received June 5, 2006.

Accepted December 20, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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