Limits...
MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans.

Andersson EA, Holst B, Sparsø T, Grarup N, Banasik K, Holmkvist J, Jørgensen T, Borch-Johnsen K, Egerod KL, Lauritzen T, Sørensen TI, Bonnefond A, Meyre D, Froguel P, Schwartz TW, Pedersen O, Hansen T - Diabetes (2010)

Bottom Line: The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population.Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.MTNR1B 24E associates with increased body mass and decreased FPG.

View Article: PubMed Central - PubMed

Affiliation: Hagedorn Research Institute, Gentofte, Denmark. ehaa@hagedorn.dk

ABSTRACT

Objective: Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits.

Research design and methods: MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells.

Results: No mutations in MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.

Conclusions: Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes.

Show MeSH

Related in: MedlinePlus

The chimeric G-protein allows the Gαi-coupled receptors to signal through the signal transduction pathways known for the Gαq-coupled receptors. Data are from Inositol turnover after stimulation with various concentrations (conc.) of melatonin (n = 3). □, wild-type (WT) MT2 receptor; ■, 24E, 60R, or 124I mutant MT2 receptors. *P < 0.05 in unpaired t test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2874716&req=5

Figure 2: The chimeric G-protein allows the Gαi-coupled receptors to signal through the signal transduction pathways known for the Gαq-coupled receptors. Data are from Inositol turnover after stimulation with various concentrations (conc.) of melatonin (n = 3). □, wild-type (WT) MT2 receptor; ■, 24E, 60R, or 124I mutant MT2 receptors. *P < 0.05 in unpaired t test.

Mentions: The wild-type MT2 receptor displayed a relatively high degree of constitutive signaling activity and a clear dose-related increase in signaling in response to melatonin (Fig. 2). The dose-response curve for melatonin in the 24E mutant form of the MT2 receptor was similar to that of the wild-type receptor with respect to potency and efficacy; however, the ligand-independent constitutive signaling was slightly decreased (Fig. 2). Functional characterization of the 60R mutant receptor revealed that both constitutive and melatonin-induced signaling were completely disrupted for this mutant (Fig. 2). The 124I mutant receptor had decreased constitutive activity and maximal efficacy compared with the wild-type MT2 receptor.


MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans.

Andersson EA, Holst B, Sparsø T, Grarup N, Banasik K, Holmkvist J, Jørgensen T, Borch-Johnsen K, Egerod KL, Lauritzen T, Sørensen TI, Bonnefond A, Meyre D, Froguel P, Schwartz TW, Pedersen O, Hansen T - Diabetes (2010)

The chimeric G-protein allows the Gαi-coupled receptors to signal through the signal transduction pathways known for the Gαq-coupled receptors. Data are from Inositol turnover after stimulation with various concentrations (conc.) of melatonin (n = 3). □, wild-type (WT) MT2 receptor; ■, 24E, 60R, or 124I mutant MT2 receptors. *P < 0.05 in unpaired t test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874716&req=5

Figure 2: The chimeric G-protein allows the Gαi-coupled receptors to signal through the signal transduction pathways known for the Gαq-coupled receptors. Data are from Inositol turnover after stimulation with various concentrations (conc.) of melatonin (n = 3). □, wild-type (WT) MT2 receptor; ■, 24E, 60R, or 124I mutant MT2 receptors. *P < 0.05 in unpaired t test.
Mentions: The wild-type MT2 receptor displayed a relatively high degree of constitutive signaling activity and a clear dose-related increase in signaling in response to melatonin (Fig. 2). The dose-response curve for melatonin in the 24E mutant form of the MT2 receptor was similar to that of the wild-type receptor with respect to potency and efficacy; however, the ligand-independent constitutive signaling was slightly decreased (Fig. 2). Functional characterization of the 60R mutant receptor revealed that both constitutive and melatonin-induced signaling were completely disrupted for this mutant (Fig. 2). The 124I mutant receptor had decreased constitutive activity and maximal efficacy compared with the wild-type MT2 receptor.

Bottom Line: The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population.Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.MTNR1B 24E associates with increased body mass and decreased FPG.

View Article: PubMed Central - PubMed

Affiliation: Hagedorn Research Institute, Gentofte, Denmark. ehaa@hagedorn.dk

ABSTRACT

Objective: Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits.

Research design and methods: MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells.

Results: No mutations in MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.

Conclusions: Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes.

Show MeSH
Related in: MedlinePlus