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. 2008 Sep 16;93(12):4979–4983. doi: 10.1210/jc.2008-0543

Association of the Kir6.2 E23K Variant with Reduced Acute Insulin Response in African-Americans

Nicholette D Palmer 1, Carl D Langefeld 1, Michael Bryer-Ash 1, Jerome I Rotter 1, Kent D Taylor 1, Donald W Bowden 1
PMCID: PMC2626454  PMID: 18796522

Abstract

Context: ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis.

Objective: The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo.

Design and Setting: The Insulin Resistance Atherosclerosis Family Study (IRAS-FS) is a community-based study of Hispanic-Americans (San Antonio, TX, and San Luis Valley, CO) and African-Americans (Los Angeles, CA).

Participants: A total of 1040 Hispanic-Americans and 500 African-American individuals formed the basis of this study.

Main Outcome Measure(s): The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and included insulin sensitivity (SI), acute insulin response, and disposition index.

Results: In African-Americans, both variants were associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles (additive P = 0.00053). SI, a measure of insulin sensitivity, was not associated. In Hispanic-Americans, there was no association with measures of glucose homeostasis.

Conclusions: We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population.

In African Americans, Kir6.2 E23K and SUR1 A1369S mutations are associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles.

ATP-sensitive potassium (KATP) channels couple cell metabolism to electrical activity by regulating K+ flux through the plasma membrane. The protein is a heterooctamer composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits (1). Different combinations of Kir6.1/Kir6.2 and SUR1/SUR2 constitute channels with distinct properties in multiple tissue types. These channels are present in pancreatic islets (Kir6.2 and SUR1) and skeletal muscle (Kir6.2 and SUR2A) (2,3).

KCNJ11 and ABCC8 have been implicated in glucose homeostasis regulation through their genetic contribution to monogenic forms of diabetes and population genetic studies. Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes characterized by insulin-requiring hyperglycemia (4). KCNJ11-activating mutations have been identified in patients with NDM that exhibited profound β-cell dysfunction. This observation was attributed to the reduced ATP sensitivity of the KATP channel inhibiting insulin release (5,6,7). More recently, activating mutations in ABCC8 were identified in patients with NDM that exhibited β-cell dysfunction. This observation was attributed to increased Mg2+-dependent stimulation of the KATP channel, thereby inhibiting insulin secretion (8).

Population-based studies of KCNJ11 and ABCC8, adjacent and functionally related genes, in humans have implicated them in glucose homeostasis maintenance. Specifically, the Kir6.2 E23K and SUR1 A1369S variants, which are highly correlated, have been reproducibly implicated in type 2 diabetes (T2D) susceptibility (9,10). The mechanism by which this effect is mediated, either through insulin secretion via the pancreatic β-cells or glucose disposal via peripheral tissues, i.e. skeletal muscle, has not been conclusively determined (9,11,12,13,14). Previous quantitative trait studies have drawn inconsistent conclusions concerning the effects on β-cell function and whole-body insulin sensitivity and have been limited to European-derived populations (9,11,12,13,14). Thus, although the association of the E23K variant with T2D is widely accepted, the contribution of the SUR1 A1369S has not been delineated, and results of studies in human populations and model systems have not provided a consistent mechanism for T2D susceptibility.

The purpose of this study was to evaluate the association of the Kir6.2 E23K and SUR1 A1369S variants with quantitative measures of glucose homeostasis in carefully phenotyped African-American and Hispanic-American subjects from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS). The extensive phenotypic data in the IRAS-FS should facilitate assessment of the genetic impact of these variants and identify the physiological pathway(s) (i.e. insulin sensitivity or insulin secretion) in which the protein(s) would exert their effects.

Subjects and Methods

Recruitment of participants

IRAS-FS design, recruitment, and phenotyping have been previously described (15). Briefly, IRAS-FS is a multicenter study designed to identify the genetic determinants of insulin resistance through quantitative measures of glucose homeostasis. Members of large families of self-reported Hispanic-Americans (n = 1268 individuals in 92 pedigrees; San Antonio, TX, and San Luis Valley, CO) and African-Americans (n = 581 individuals in 42 pedigrees; Los Angeles, CA) were recruited. Clinical examination included interviews, frequently sampled iv glucose tolerance tests (FSIGTs), and anthropometric measurements. Informed consent was obtained from all subjects. Specific to this report, measures of glucose homeostasis included those from the FSIGT using the reduced sampling protocol (16,17,18,19) calculated by mathematical modeling methods (MINMOD) (20): insulin sensitivity (SI) and acute insulin response (AIR). Disposition index (DI) was calculated as the product of SI and AIR. Distributions of the primary phenotypes are listed in Table 1.

Table 1.

Summary statistics for IRAS-FS participants with measures of glucose homeostasis

African-Americans
Hispanic-Americans
n Mean ± sd Median n Mean ± sd Median
Demographics
 Age (yr) 500 41.1 ± 13.6 39.9 1040 40.7 ± 13.7 39.4
 Gender (% female) 500 57.6% 1040 59.0%
 BMI (kg/m2) 498 29.4 ± 6.6 28.4 1033 28.3 ± 5.8 27.5
Glucose homeostasis
 SI (×10−5 × min−1/ [pmol/liter]) 500 1.63 ± 1.17 1.41 1040 2.15 ± 1.86 1.70
 AIR (pmol/liter) 499 1006 ± 826 772 1040 760 ± 649 587
 DI (AIR × SI; × 10−5 × min−1) 499 1426 ± 1269 1152 1040 1317 ± 1236 1005
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Genotyping

SNP rs5219 corresponding to the glutamate→lysine mutation at position 23 of Kir6.2 and SNP rs757110 corresponding to the alanine→serine mutation at position 1369 of SUR1 were genotyped on the Sequenom MassArray Genotyping System (Sequenom, Inc., San Diego, CA).

Statistical analysis

SNPs were examined for Mendelian inconsistencies using PedCheck (21). Maximum-likelihood estimates of allele frequencies and linkage disequilibrium (LD) statistics were computed using the largest set of unrelated African-American and Hispanic-American individuals (n = 58 and 229, respectively), and genotypes were tested for departures from Hardy-Weinberg proportions.

Quantitative trait data were statistically transformed to approximate univariate normality before analyses, i.e. log of (SI + 1) and signed square root of AIR and DI. The measured genotypes approach under a variance components framework was used to test single nucleotide polymorphism (SNP) associations with continuous phenotypes in extended pedigrees and implemented using SOLAR (22). For each phenotype, the two degrees of freedom test of genotypic association was performed. In addition, three individual contrasts defined by the genetic models (dominant, additive, and recessive) were computed. Tests reported here were adjusted for age, gender, and body mass index (BMI). Additionally, tests for association with AIR were adjusted for age, gender, BMI, and SI. It has been proposed that adjusting for SI is a better measure of pancreatic β-cell function (23,24) because this adjustment takes into account compensation of β-cell function in response to changing insulin sensitivity. Adjustments for multiple comparisons were not performed due to the high correlation between the two SNPs evaluated and the three traits examined. To determine whether the level of SI would affect the results of the association with AIR, analysis was stratified by SI quartile. Study power was approximated for continuous traits using the program QUANTO (25).

Results

This study evaluated 1040 Hispanic-Americans and 500 African-Americans with quantitative measures of glucose homeostasis. Table 1 summarizes descriptive statistics by ethnicity. On average, the Hispanic-American and African-American participants had a similar proportion of females and age. BMI values varied between the ethnicities, with African-Americans having a higher BMI (29.4 vs. 28.3 kg/m2; P = 0.0010). Compared with African-Americans, Hispanic-Americans had increased SI (2.15 vs. 1.63 × 10−5 min−1/[pmol/liter]; P < 0.0010), reduced AIR (760 vs. 1006 pmol/liter; P < 0.0010), and comparable DI (1317 vs. 1426 × 10−5 min−1; P = 0.11) values.

Blind duplicates included in genotyping were concordant (0 discordances of 70 comparisons), and PedCheck analysis identified zero Mendelian errors. Genotype frequencies were consistent with Hardy-Weinberg proportions in both samples. Examination of LD between rs5219 and rs757110 revealed strong LD (African-Americans: D′ = 1.0, r2 = 1.0; Hispanic-Americans: D′ = 0.98, r2 = 0.98). Due to strong LD and consistent cosegregation of the minor alleles, analysis focused on the Kir6.2 E23K variant because either SNP would result in the same observations.

The allelic frequency of E23K was 7% in the African-American sample and 36% in the Hispanic-American sample. Association analyses are summarized in Table 2. Three distinct quantitative traits were examined to assess the impact of variants on glucose homeostasis. In African-Americans, the E23K variant was associated with AIR (additive P = 0.0053) and consistent with stepwise decrease in AIR associated with the number of K alleles present (E/E, 1059.48 ± 863.24; E/K, 809.03 ± 709.24; and K/K, 664.93 ± 627.57 pmol/liter). SI was not significantly associated (additive P = 0.73). Conversely, in Hispanic-Americans, the E23K variant was not associated with measures of glucose homeostasis.

Table 2.

Association analysis results of the Kir6.2 E23K variant with glucose homeostasis traits in the IRAS-FS African-American and Hispanic-American populations

Trait Genotypic mean ± sda
Additive P value
E/E (n) E/K (n) K/K (n)
African-Americans
 SI 1.58 ± 1.12 (362) 1.81 ± 1.37 (60) 1.82 ± 1.35 (9) 0.73
2.36 ± 1.52 (362)b 2.54 ± 1.56 (60)b 2.57 ± 1.57 (9)b
 AIR 1059 ± 863 (361) 809 ± 709 (60) 665 ± 628 (9) 0.0053
 DI 1470 ± 1342 (361) 1273 ± 1052 (60) 922 ± 671 (9) 0.030
Hispanic-Americans
 SI 2.28 ± 1.92 (389) 2.16 ± 1.87 (452) 1.92 ± 1.74 (137) 0.31
2.86 ± 1.68 (389)b 2.73 ± 1.71 (452)b 2.52 ± 1.71 (137)b
 AIR 760 ± 667 (389) 743 ± 631 (452) 785 ± 664 (137) 0.11
 DI 1397 ± 1271 (389) 1328 ± 1281 (452) 1096 ± 1029 (137) 0.66
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a

The untransformed mean trait and sd values for each genotype (EE, EK, KK) are listed, followed by the number of individuals (n) with each genotype included in the analysis. 

b

The geometric mean SI and sd values for each genotype (EE, EK, KK) are listed, followed by the number of individuals (n) with each genotype included in the analysis. 

Discussion

The goal of this study was to assess the impact of Kir6.2 E23K and SUR1 A1369S variants on quantitative measures of glucose homeostasis to determine their probable role in vivo. In African-Americans we observed significant association of the Kir6.2 E23K variant with AIR. The association was consistent with an additive genetic model (P = 0.0053), with heterozygotes E/K and homozygotes K/K exhibiting a 24 and 37% reduction, respectively, in AIR relative to the E/E homozygote. This association remained significant (additive P = 0.0060) with adjustment for SI (data not shown). This phenotypic characterization is consistent with in vitro studies that found heterozygotes and homozygotes (K/K) had stepwise decreases in ATP sensitivity, which corresponded to overactive pancreatic ß-cell KATP channels and ultimately resulted in inhibition of insulin secretion (26). The relatively modest magnitude of the genotypic associations observed could be attributed to reduced power to detect diabetes-related trait associations in glucose-tolerant subjects or an unmeasured contribution to β-cell destruction as seen in animal models (27). Although Kir6.2 is expressed in skeletal muscle (3), we did not observe any effect of the E23K variant on SI. Association analysis with T2D in this population did not reveal significant evidence of association (data not shown); however, the power to detect T2D-susceptibility loci is relatively limited due to modest sample size (n = 71 diabetics).

In parallel, we also evaluated the effect of this variant in a similarly phenotyped Hispanic-American population. Quantitative trait analyses revealed no evidence of association between the E23K variant and measures of glucose homeostasis. Upon further examination of the phenotypic means by genotype, no trends in AIR genotypic means were observed (Table 2). However, significant differences in glucose homeostasis phenotypes were observed between the Hispanic-American and African-American cohorts. Given the significant results in the African-American population, we would have anticipated an association with AIR in the presence of reduced SI in the Hispanic-American population; however, results of the analysis stratified on SI quartile were nonsignificant (P = 0.39; data not shown). Additionally, no association was observed with T2D (data not shown), possibly due to modest sample size (n = 181 diabetics).

In the first study to explore these effects, Hansen et al. (11) examined Kir6.2 variants for association with phenotypes from iv glucose and tolbutamide tolerance tests in 346 young healthy Danish Caucasians. No significant alterations in glucose-induced insulin secretion or glucose effectiveness were observed; however, increased SI was detected when considering E23K in concert with additional T2D-associated variants. Consistent with Hansen et al. (11), two additional studies of European-derived populations observed no significant difference in AIR using hyperglycemic clamp techniques (12) or oral glucose tolerance tests (13). In contrast to Hansen et al., hyperglycemic clamp technique studies did not detect a significant difference in SI based on the E23K locus (12). Contradictory to these findings, more recent studies using the oral glucose tolerance test have found significant evidence that the lysine allele of E23K is associated with decreased insulin secretion in Danish (n = 519) (14) and Scandinavian (n = 674) (9) subjects; however, the impact on SI was not assessed.

Taken together, the population genetic study reported herein and previously published studies of monogenic diabetes and population genetic studies provide additional support for the role of common variants in Kir6.2 in regulation of insulin secretion. However, pancreatic β-cell KATP channels are composed of Kir6.2 and SUR1, which are encoded 4.5 kb apart on chromosome 11p15.1. Previous studies of Kir6.2 and SUR1 have demonstrated a lack of KATP channel activity when either component is expressed alone (28,29). Evaluation of the common nonsynonymous mutation (A1369S, rs757110) resulted in the same associations as observed with the E23K mutation due to the strong allelic association. In Hispanic-Americans, there was strong allelic association (D′ = 0.98, r2 = 0.98); however, both variants lacked statistical evidence to support an involvement in glucose homeostasis. The high LD existing between these markers makes it difficult to determine the origin of association in African-Americans. In addition, we cannot rule out the possibility of additional variants that contribute to the observed association through LD. The lack of association in Hispanic-Americans is likely not a result of decreased power (80% power when examining a minor allele frequency of 0.20 to detect an AIR difference of >16%) but could represent the contribution of additional variants not assessed in this study.

These data provide support for the hypothesis that the E23K variant of Kir6.2, a component of the KATP channel, plays a role in glucose homeostasis mediated through insulin secretion. This study represents the first attempt to assess the impact of these variants on quantitative measures of glucose homeostasis measured by the FSIGT in large African-American and Hispanic-American cohorts. These results provide human physiological evidence for a probable mechanism by which variants of Kir6.2 contribute to T2D susceptibility. Given that the E23K polymorphism is widely accepted as a diabetes-susceptibility allele, the modest magnitude of effect on insulin secretion in physiologically normal adults suggests that even subtle metabolic variation can have a significant effect on T2D susceptibility. However, the contribution of variation in the ABCC8 gene cannot be discounted. Further investigations of the KCNJ11 gene across additional ethnic populations are warranted to evaluate the possibility of ethnic-specific effects. In addition, functional studies are needed to delineate the contributions of Kir6.2 and SUR1 variations to insulin secretion.

Footnotes

This work was supported by National Institutes of Health Grants HL060894, HL060931, HL060944, HL061019, and HL061210.

Disclosure Statement: N.D.P., C.D.L., M.B.-A., J.I.R., K.D.T. and D.W.B. have nothing to declare.

First Published Online September 16, 2008

Abbreviations: AIR, Acute insulin response; BMI, body mass index; DI, disposition index; FSIGT, frequently sampled iv glucose tolerance test; IRAS-FS, Insulin Resistance Atherosclerosis Family Study; KATP, ATP-sensitive potassium; LD, linkage disequilibrium; NDM, neonatal diabetes mellitus; SI, insulin sensitivity; SNP, single nucleotide polymorphism; SUR, sulfonylurea receptor; T2D, type 2 diabetes.

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