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The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

Holmkvist J, Banasik K, Andersen G, Unoki H, Jensen TS, Pisinger C, Borch-Johnsen K, Sandbaek A, Lauritzen T, Brunak S, Maeda S, Hansen T, Pedersen O - PLoS ONE (2009)

Bottom Line: Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant.The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals.The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Hagedorn Research Institute, Gentofte, Denmark.

ABSTRACT

Background: Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release.

Methodology/principal findings: Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228.

Conclusion: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

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Multivariate analysis on the effect of the minor C-allele of KCNQ1 rs2237895 on insulin release in response to the level of insulin sensitivity in 4,568 glucose tolerant individuals from Inter99.The multivariate method, Hotelling's T2 [36], was applied to test the simultaneous effect of genotype on insulinogenic index and HOMA-IR for rs2237895. Two-dimensional standard error of the means of each genotype level for insulinogenic index and HOMA-IR were calculated for KCNQ1 rs2237895. Significant multivariate association with the minor C-allele of rs2237895 was detected under an additive genetic model (p = 0.004) suggesting that the association with insulin release was not dependent on the level of insulin sensitivity but a true beta cell abnormality.
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pone-0005872-g001: Multivariate analysis on the effect of the minor C-allele of KCNQ1 rs2237895 on insulin release in response to the level of insulin sensitivity in 4,568 glucose tolerant individuals from Inter99.The multivariate method, Hotelling's T2 [36], was applied to test the simultaneous effect of genotype on insulinogenic index and HOMA-IR for rs2237895. Two-dimensional standard error of the means of each genotype level for insulinogenic index and HOMA-IR were calculated for KCNQ1 rs2237895. Significant multivariate association with the minor C-allele of rs2237895 was detected under an additive genetic model (p = 0.004) suggesting that the association with insulin release was not dependent on the level of insulin sensitivity but a true beta cell abnormality.

Mentions: In order to further investigate a putative beta cell abnormality, the interplay between insulin release (Insulinogenic index: I/G30), insulin resistance (Homeostasis model assessment of insulin resistance: HOMA-IR) and the genetic predisposition to type 2 diabetes with KCNQ1 rs2237895, we applied the multivariate Hotelling's T2 method to simultaneously test the effect of genotype on I/G30 and HOMA-IR in the sample of glucose tolerant individuals. Significant multivariate association with the rs2237895 C-risk-allele and the combination of I/G30 and HOMA-IR was demonstrated (p = 0.004; pdominant = 0.004) (Figure 1).


The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

Holmkvist J, Banasik K, Andersen G, Unoki H, Jensen TS, Pisinger C, Borch-Johnsen K, Sandbaek A, Lauritzen T, Brunak S, Maeda S, Hansen T, Pedersen O - PLoS ONE (2009)

Multivariate analysis on the effect of the minor C-allele of KCNQ1 rs2237895 on insulin release in response to the level of insulin sensitivity in 4,568 glucose tolerant individuals from Inter99.The multivariate method, Hotelling's T2 [36], was applied to test the simultaneous effect of genotype on insulinogenic index and HOMA-IR for rs2237895. Two-dimensional standard error of the means of each genotype level for insulinogenic index and HOMA-IR were calculated for KCNQ1 rs2237895. Significant multivariate association with the minor C-allele of rs2237895 was detected under an additive genetic model (p = 0.004) suggesting that the association with insulin release was not dependent on the level of insulin sensitivity but a true beta cell abnormality.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2689931&req=5

pone-0005872-g001: Multivariate analysis on the effect of the minor C-allele of KCNQ1 rs2237895 on insulin release in response to the level of insulin sensitivity in 4,568 glucose tolerant individuals from Inter99.The multivariate method, Hotelling's T2 [36], was applied to test the simultaneous effect of genotype on insulinogenic index and HOMA-IR for rs2237895. Two-dimensional standard error of the means of each genotype level for insulinogenic index and HOMA-IR were calculated for KCNQ1 rs2237895. Significant multivariate association with the minor C-allele of rs2237895 was detected under an additive genetic model (p = 0.004) suggesting that the association with insulin release was not dependent on the level of insulin sensitivity but a true beta cell abnormality.
Mentions: In order to further investigate a putative beta cell abnormality, the interplay between insulin release (Insulinogenic index: I/G30), insulin resistance (Homeostasis model assessment of insulin resistance: HOMA-IR) and the genetic predisposition to type 2 diabetes with KCNQ1 rs2237895, we applied the multivariate Hotelling's T2 method to simultaneously test the effect of genotype on I/G30 and HOMA-IR in the sample of glucose tolerant individuals. Significant multivariate association with the rs2237895 C-risk-allele and the combination of I/G30 and HOMA-IR was demonstrated (p = 0.004; pdominant = 0.004) (Figure 1).

Bottom Line: Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant.The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals.The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

View Article: PubMed Central - PubMed

Affiliation: Hagedorn Research Institute, Gentofte, Denmark.

ABSTRACT

Background: Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release.

Methodology/principal findings: Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228.

Conclusion: The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

Show MeSH
Related in: MedlinePlus