| 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. |
| Authors | C Langenberg, L Pascoe, A Mari, A Tura, M Laakso, T M Frayling, I Barroso, R J F Loos, N J Wareham, M Walker, RISC Consortium
(Affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. claudia.langenberg at mrc-epid.cam.ac.uk)
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| Journal | Diabetologia
(Diabetologia)
Vol. 52
Issue 8
Pg. 1537-42
(Aug 2009)
ISSN: 1432-0428 [Electronic] Germany |
| PMID | 19455304
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Receptor, Melatonin, MT1
- Receptor, Melatonin, MT2
- Insulin
|
| Topics |
- Adult
- European Continental Ancestry Group
(genetics)
- Female
- Genetic Variation
- Glucose Tolerance Test
- Humans
- Insulin
(pharmacology, physiology)
- Insulin Resistance
(genetics)
- Insulin-Secreting Cells
(physiology)
- Male
- Middle Aged
- Models, Genetic
- Receptor, Melatonin, MT1
(genetics)
- Receptor, Melatonin, MT2
(genetics)
|
