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. 2009 Aug;52(8):1537-42.
doi: 10.1007/s00125-009-1392-x. Epub 2009 May 20.

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response

C Langenberg  1 , L Pascoe, A Mari, A Tura, M Laakso, T M Frayling, I Barroso, R J F Loos, N J Wareham, M Walker; RISC Consortium
Affiliations

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response

C Langenberg et al. Diabetologia. 2009 Aug.

Abstract

Aims/hypothesis: We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity.

Methods: We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.

Results: The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 x 10(-5)), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p = 1.7 x 10(-5)), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).

Conclusions/interpretation: Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.

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Figures

Fig. 1
Fig. 1
Effect of rs10830963 in MTNR1B on glucose (a) and insulin (b) levels during the OGTT (per allele difference and 95% CI). aap = 5.8 × 10−5; bp = 4.7 × 10−4; cp = 2.3 × 10−3; dp = 0.211; ep = 0.926. bap = 0.135; bp = 8.0 × 10−4; cp = 0.868; dp = 0.259; ep = 0.727
Fig. 2
Fig. 2
Effect of rs10830963 in MTNR1B on early insulin response, beta cell glucose sensitivity and whole-body insulin sensitivity (M/I) (per allele difference and 95% CI). ap = 1.7 × 10−5; bp = 0.010; cp = 0.154
See this image and copyright information in PMC

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