Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function.
BACKGROUND
Very recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance.


RESULTS
We genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency > 0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p < 0.0001) and reduced OGTT- and IVGTT-induced insulin release (p < or = 0.0007 and p < or = 0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p < or = 0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p < or = 0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion.


CONCLUSIONS
In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on beta-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.
Staiger
Harald
H
Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
Machicao
Fausto
F
Schäfer
Silke A
SA
Kirchhoff
Kerstin
K
Kantartzis
Konstantinos
K
Guthoff
Martina
M
Silbernagel
Günther
G
Stefan
Norbert
N
Häring
Hans-Ulrich
HU
Fritsche
Andreas
A
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D012307:Risk Factors
D001786:Blood Glucose; D007328:Insulin; D044123:Receptor, Melatonin, MT2