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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Variation*
  • Glucose Tolerance Test*
  • Humans
  • Insulin / pharmacology
  • Insulin / physiology*
  • Insulin Resistance / genetics
  • Insulin-Secreting Cells / physiology*
  • Male
  • Middle Aged
  • Models, Genetic
  • Receptor, Melatonin, MT1 / genetics*
  • Receptor, Melatonin, MT2 / genetics

Substances

  • Insulin
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2