title: Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes.
abstract: The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic β-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r² ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤ .0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P = .0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P = .0097), but not in men (P = .3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P = .0124), whereas in male subjects, no significant differences were found (P = .3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Karsten
authors.initials: K
authors.lastname: Müssig
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Dudziak
authors.forename: Elko
authors.initials: E
authors.lastname: Randrianarisoa
authors.forename: Robert
authors.initials: R
authors.lastname: Wagner
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000235:genetics*; D012306:Risk; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: D007328:Insulin; D050053:TRPM Cation Channels; C404409:TRPM5 protein, human