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Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.

Heni M, Ketterer C, Thamer C, Herzberg-Schäfer SA, Guthoff M, Stefan N, Machicao F, Staiger H, Fritsche A, Häring HU - Diabetes (2010)

Bottom Line: 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).In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.

ABSTRACT

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.

Research design and 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.

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Related in: MedlinePlus

Association between C-peptide levels at 30 min of the OGTT and glucose levels at 30 min during the OGTT by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Lines represent regression lines. Data were loge-transformed prior to statistical analysis. C-peptide data are adjusted for sex, age, and BMI by multivariate linear regression analysis.
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Figure 2: Association between C-peptide levels at 30 min of the OGTT and glucose levels at 30 min during the OGTT by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Lines represent regression lines. Data were loge-transformed prior to statistical analysis. C-peptide data are adjusted for sex, age, and BMI by multivariate linear regression analysis.

Mentions: To further evaluate the interaction of TCF7L2 rs7903146 and WFS1 rs10010131 with acute glucose-dependent insulin secretion, we plotted C-peptide levels at 30 min of the OGTT against glucose levels at the same time point. At this time, variation of glucose is most pronounced and C-peptide levels are hardly influenced by clearance. C-peptide was adjusted for possible confounders (sex, age, and BMI) by multivariate linear regression analysis. In carriers of the nonrisk alleles of the TCF7L2 and WFS1 SNPs, the C-peptide rises with higher glucose concentrations. By contrast, this relation is blunted in carriers of the risk alleles (Fig. 2). Using insulin instead of C-peptide yielded comparable results (supplementary Fig. 1).


Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.

Heni M, Ketterer C, Thamer C, Herzberg-Schäfer SA, Guthoff M, Stefan N, Machicao F, Staiger H, Fritsche A, Häring HU - Diabetes (2010)

Association between C-peptide levels at 30 min of the OGTT and glucose levels at 30 min during the OGTT by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Lines represent regression lines. Data were loge-transformed prior to statistical analysis. C-peptide data are adjusted for sex, age, and BMI by multivariate linear regression analysis.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992789&req=5

Figure 2: Association between C-peptide levels at 30 min of the OGTT and glucose levels at 30 min during the OGTT by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Lines represent regression lines. Data were loge-transformed prior to statistical analysis. C-peptide data are adjusted for sex, age, and BMI by multivariate linear regression analysis.
Mentions: To further evaluate the interaction of TCF7L2 rs7903146 and WFS1 rs10010131 with acute glucose-dependent insulin secretion, we plotted C-peptide levels at 30 min of the OGTT against glucose levels at the same time point. At this time, variation of glucose is most pronounced and C-peptide levels are hardly influenced by clearance. C-peptide was adjusted for possible confounders (sex, age, and BMI) by multivariate linear regression analysis. In carriers of the nonrisk alleles of the TCF7L2 and WFS1 SNPs, the C-peptide rises with higher glucose concentrations. By contrast, this relation is blunted in carriers of the risk alleles (Fig. 2). Using insulin instead of C-peptide yielded comparable results (supplementary Fig. 1).

Bottom Line: 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).In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus