Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.
OBJECTIVE
Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms.


METHODS
Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT). Participants were genotyped for 10 diabetes risk SNPs associated with β-cell dysfunction: rs5215 (KCNJ11), rs13266634 (SLC30A8), rs7754840 (CDKAL1), rs10811661 (CDKN2A/2B), rs10830963 (MTNR1B), rs7903146 (TCF7L2), rs10010131 (WFS1), rs7923837 (HHEX), rs151290 (KCNQ1), and rs4402960 (IGF2BP2). Furthermore, the impact of the interaction between genetic variation in TCF7L2 and glycemia on changes in insulin secretion was tested in 315 individuals taking part in a lifestyle intervention study.


RESULTS
For the SNPs in TCF7L2 and WFS1, we found a significant interaction between glucose control and insulin secretion (all P ≤ 0.0018 for glucose × genotype). When plotting insulin secretion against glucose at 120 min OGTT, the compromising SNP effects on insulin secretion are most apparent under high glucose. In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027). Increased glucose levels at baseline predicted an increase in insulin secretion upon improvement of glycemia by lifestyle intervention only in carriers of the risk alleles.


CONCLUSIONS
For the diabetes risk genes TCF7L2 and WFS1, which are associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicates the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt type 2 diabetes.
Heni
Martin
M
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
Ketterer
Caroline
C
Thamer
Claus
C
Herzberg-Schäfer
Silke A
SA
Guthoff
Martina
M
Stefan
Norbert
N
Machicao
Fausto
F
Staiger
Harald
H
Fritsche
Andreas
A
Häring
Hans-Ulrich
HU
D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D054795:Incretins / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
D001786:Blood Glucose; D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D008565:Membrane Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C114987:wolframin protein
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