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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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Association between IGI and glucose 120 min by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Association between AUCC-peptide/AUCGlucose and glucose120 by TCF7L2 SNP rs7903146 (C) and WFS1 SNP rs10010131 (D). Lines represent regression lines. Data were loge-transformed prior to statistical analysis and adjusted for sex, age, BMI, and OGTT-derived insulin sensitivity index by multivariate linear regression analysis.
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Figure 1: Association between IGI and glucose 120 min by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Association between AUCC-peptide/AUCGlucose and glucose120 by TCF7L2 SNP rs7903146 (C) and WFS1 SNP rs10010131 (D). Lines represent regression lines. Data were loge-transformed prior to statistical analysis and adjusted for sex, age, BMI, and OGTT-derived insulin sensitivity index by multivariate linear regression analysis.

Mentions: The two SNPs that were affected by glucose control were investigated in detail. Therefore, we stratified the cohort for genotypes and plotted insulin secretion values against glucose120 as a proxy for glycemia. Insulin secretion was adjusted for possible confounders (sex, age, BMI, and insulin sensitivity) by multivariate linear regression analysis. Regression lines of these analyses are shown in Fig. 1. The compromising effect of the risk alleles on insulin secretion is most apparent under high glucose conditions for the TCF7L2 SNP rs7903146 as well as for the WFS1 SNP rs10010131. By contrast, when glucose levels are low, no SNP effect on insulin secretion is obvious or the risk allele may even be beneficial. In this respect, the T-allele of TCF7L2 SNP rs7903146 appears to affect insulin secretion in a recessive way, whereas the mode of action of the G-allele of WFS1 SNP rs10010131 is less clear. Performing similar analyses for the other eight SNPs resulted in no significant interactions (supplementary Fig. 2).


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 IGI and glucose 120 min by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Association between AUCC-peptide/AUCGlucose and glucose120 by TCF7L2 SNP rs7903146 (C) and WFS1 SNP rs10010131 (D). Lines represent regression lines. Data were loge-transformed prior to statistical analysis and adjusted for sex, age, BMI, and OGTT-derived insulin sensitivity index by multivariate linear regression analysis.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Association between IGI and glucose 120 min by TCF7L2 SNP rs7903146 (A) and WFS1 SNP rs10010131 (B). Association between AUCC-peptide/AUCGlucose and glucose120 by TCF7L2 SNP rs7903146 (C) and WFS1 SNP rs10010131 (D). Lines represent regression lines. Data were loge-transformed prior to statistical analysis and adjusted for sex, age, BMI, and OGTT-derived insulin sensitivity index by multivariate linear regression analysis.
Mentions: The two SNPs that were affected by glucose control were investigated in detail. Therefore, we stratified the cohort for genotypes and plotted insulin secretion values against glucose120 as a proxy for glycemia. Insulin secretion was adjusted for possible confounders (sex, age, BMI, and insulin sensitivity) by multivariate linear regression analysis. Regression lines of these analyses are shown in Fig. 1. The compromising effect of the risk alleles on insulin secretion is most apparent under high glucose conditions for the TCF7L2 SNP rs7903146 as well as for the WFS1 SNP rs10010131. By contrast, when glucose levels are low, no SNP effect on insulin secretion is obvious or the risk allele may even be beneficial. In this respect, the T-allele of TCF7L2 SNP rs7903146 appears to affect insulin secretion in a recessive way, whereas the mode of action of the G-allele of WFS1 SNP rs10010131 is less clear. Performing similar analyses for the other eight SNPs resulted in no significant interactions (supplementary Fig. 2).

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