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Departments of Medicine (O.L., J.P., M.L.) and Clinical Nutrition (M.U.), University of Kuopio, Kuopio 70210, Finland; Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit (J.L., J.E., T.T.V., J.T.), National Public Health Institute, Helsinki 00300, Finland; Research Department (H.H.), Social Insurance Institution, Turku 20720, Finland; Finnish Diabetes Association and Department of Internal Medicine (P.I.-P.), Tampere University Hospital, Tampere 33014, Finland; Department of Public Health Science and General Practice (S.K.-K.), University of Oulu, Oulu University Hospital and Department of Sport Medicine, Oulu Deaconess Institute, Oulu 90220, Finland; and Department of Public Health (J.T.), University of Helsinki, Helsinki 00300, Finland
Address all correspondence and requests for reprints to: Markku Laakso, Professor and Chair, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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2 gene (2). In addition to genetic predisposition, environmental risk factors, obesity, low physical activity, high intake of saturated fat, and low intake of dietary fiber predict the development of type 2 diabetes (3). ATP-sensitive potassium (KATP) channels in pancreatic ß-cells comprise two sub-units: a pore-forming, K+ inward rectifier Kir6.2 (KCNJ11) and a sulfonylurea receptor SUR1 (ABCC8), which is a target of sulfonylurea drugs (4). KATP channels regulate insulin secretion by coupling the metabolic state of the cell to membrane potential. Elevation of blood glucose level leads to an increase in the ATP to ADP ratio and a decrease in KATP channel permeability that in turn leads to membrane depolarization, activation of voltage-dependent calcium channels, Ca2+ influx into the cell, and finally insulin exocytosis (5).
The SUR1 and Kir6.2 genes are located on the same chromosome locus 11p15.1, only 4.5 kb apart (6). Several variants in both genes have been associated with disorders of insulin secretion including congenital hyperinsulinemia of infancy (7) and type 2 diabetes (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). A recent study found an association of the SUR1 and Kir6.2 genes with type 2 diabetes, but the contribution of different single nucleotide polymorphisms (SNPs) to the risk of type 2 diabetes remained unclear (8). A silent AGG1273AGA polymorphism of the SUR1 gene has been associated with elevated insulin levels in nondiabetic subjects (19) and with increased prevalence of type 2 diabetes in French Caucasians (9). Additionally, this polymorphism has been associated with type 2 diabetes and gestational diabetes in Finnish subjects (11). In contrast, SUR1 promoter SNPs have not been associated with increased risk of diabetes or altered ß-cell function (20). The E23K polymorphism of the Kir6.2 gene has been found to be consistently associated with increased diabetes risk in British and French subjects (16, 17, 18).
We investigated the role of the common SNPs of the SUR1 and Kir6.2 genes in the development of type 2 diabetes in subjects with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS) (3).
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Subjects and Methods |
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A detailed description of subjects, methods, and study design has been previously reported (3, 21, 22). The main objective of the Finnish DPS was to investigate whether lifestyle intervention influences the conversion to type 2 diabetes during a 3-yr follow-up. Altogether, 522 middle-aged (from 40–65 yr) and overweight [body mass index (BMI) 
25 kg/m2] Finnish subjects with IGT [fasting plasma glucose < 7.8 mmol/liter and 120-min plasma glucose 7.8–11.0 mmol/liter in an oral glucose tolerance test (OGTT) (23)] participated in the study. At baseline, age was 55 ± 7 yr, BMI 31.2 ± 4.6 kg/m2, glucose levels 6.13 ± 0.74 mmol/liter (fasting) and 8.86 ± 1.49 mmol/liter (120 min in an OGTT), and insulin levels 88.8 ± 44.8 pmol/liter (fasting) and 571.8 ± 389.0 pmol/liter (120 min in an OGTT). Subjects enrolled in the study were randomized into one of the two study groups, an intervention group or a control group. The intervention group was given intensive and individualized nutritional counseling as well as individual advice to increase physical activity and to reduce weight, whereas the control group was given only general advice about benefits of reducing weight, healthy food choices, and increasing physical activity. An OGTT was performed at each annual follow-up visit and if suggestive for diabetes, the diagnosis of diabetes was confirmed with a second test. The study protocol was approved by the Ethics Committee of the National Public Health Institute in Helsinki, and all study subjects gave a written informed consent.
Measurements
Weight change was calculated from the baseline value to the last weight measurement available which varied from 1–3 yr based on a new diagnosis of diabetes before the 3-yr follow-up visit. For those who did not convert to diabetes, weight change was calculated as a difference in weight between baseline and 3 yr. Changes in fasting and 120-min glucose and insulin levels in an OGTT were calculated respectively.
DNA analysis
A DNA sample was available from 490 subjects (intervention group, 248 subjects; and control group, 242 subjects). SNPs of the SUR1 [G-2886A (rs3758947), G-1561A (rs2188966), A-1273G (rs3758953), and AGG1273AGA (rs1799859)] and Kir6.2 [E23K (rs5219)] genes were genotyped using the TaqMan Allelic Discrimination Assays (Applied Biosystems, Foster City, CA). Genotyping reaction was amplified on a GeneAmp PCR system 2700 (95 C for 10 min, followed by 40 cycles of 95 C for 15 sec and 60 C for 1 min), and fluorescence was detected on an ABI Prism 7000 sequence detector (Applied Biosystems). The primer and probe sequences are available from the authors.
Statistical analysis
All data were analyzed with the SPSS/Win programs (version 10.0; SPSS Inc., Chicago, IL). Results are given as mean ± SD or percentages. Variables, which were not normally distributed, were logarithmically transformed before statistical analyses. ANOVA was used to compare three groups and Student’s’ t test for independent samples or 
2 test to compare two groups. Nonparametric Mann-Whitney U test and Kruskal-Wallis H test were applied to compare weight change (percentage) and 0- and 120-min glucose change (percentage). Logistic regression analysis was performed to evaluate whether the polymorphisms investigated predicted the development of type 2 diabetes.
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Results |
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Altogether, 69 of 469 subjects whose DNA and follow-up data were available developed type 2 diabetes during a 3-yr follow-up. We first investigated whether the silent AGG1273AGA polymorphism of the SUR1 gene and the E23K polymorphism of the Kir6.2 gene predicted the conversion from IGT to type 2 diabetes (Table 1
). The carriers of the 1273AGA allele of the SUR1 gene developed significantly more often type 2 diabetes during the follow-up compared with those without this risk allele in the entire study population (P = 0.009) and in the control group (P = 0.001). Compared with subjects with the AGG1273AGG genotype, the carriers of the 1273AGA allele had a 2-fold risk of developing type 2 diabetes in the entire study population and an almost 3-fold risk in the control group. The E23K polymorphism of the Kir6.2 gene alone did not predict the development of type 2 diabetes. Furthermore, we found a larger increase (percentage) in 120-min plasma glucose in an OGTT from baseline to the last follow-up measurement in carriers of the 1273AGA allele than in carriers of the AGG1273AGG genotype in all study subjects (–0.4 ± 27.6 vs. 6.3 ± 31.4%, P = 0.030) and in the control group (3.2 ± 27.4 vs. 12.7 ± 32.2%, P = 0.028).
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). These promoter SNPs and the silent AGG1273AGA polymorphism formed eight haplotypes (GGAG, GGAA, GGGG, GGGA, GAGG, GAGA, AAGG, and AAGA). Of these haplotypes, only GGAA was associated with an increased risk of developing type 2 diabetes in the entire study population [odds ratio (OR), 1.89; 95% confidence interval (CI), 1.09–3.27; P = 0.023] and in the control group (OR, 2.62; 95% CI, 1.28–5.37; P = 0.008). In the intervention group, the risk was not significant (OR, 1.89; 95% CI, 0.73–4.93; P = 0.193).
Conversion to type 2 diabetes and weight change (percentage) according to the presence or the absence of the GGAA haplotype are presented in Fig. 1. Conversion to type 2 diabetes differed between GGAA carriers and noncarriers. Subjects with the GGAA haplotype developed more often diabetes compared with subjects without the GGAA haplotype in the entire study population (P = 0.021) and in the control group (P = 0.007). No statistically significant changes were found in weight change.
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Next, we investigated whether the E23K polymorphism of the Kir6.2 gene increased the risk associated with the GGAA haplotype of the SUR1 gene by classifying the study subjects into four groups: subjects without the GGAA haplotype and the Kir6.2 risk allele (23K), subjects with only the Kir6.2 risk allele, subjects with only the GGAA haplotype, and subjects with both the GGAA haplotype and the Kir6.2 risk allele. Conversion to type 2 diabetes and weight change according to the presence or the absence of the GGAA haplotype and the 23K allele of the Kir6.2 gene are presented in Fig. 2. Conversion to type 2 diabetes increased significantly with the presence of the SUR1 haplotype and the Kir6.2 risk allele in the entire study population and in the control group, but no statistically significant difference with respect to weight change (%) was found. Subjects having both the GGAA haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene had a more than 5-fold risk for the conversion to type 2 diabetes compared with those having neither the SUR1 nor Kir6.2 risk genotypes in the entire study population (OR, 5.68; 95% CI, 1.75–18.32; P = 0.004) and in the control group (OR, 6.67; 95% CI, 1.62–27.46; P = 0.009).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We showed that carriers of the 1273AGA allele and the GGAA haplotype of the SUR1 gene had a 2-fold risk for diabetes, whereas the 23K allele of the Kir6.2 gene alone did not predict the conversion to diabetes. However, in subjects who carried risk alleles in both of these genes, the risk of diabetes was increased by 6-fold. Interestingly, we observed an increased risk in the control group only, probably due to an intensive diet and exercise program that resulted in weight loss, improvement in insulin sensitivity (24), and a marked reduction of the risk of diabetes.
The SUR1 gene variant (AGG1273AGA) is a nonfunctional substitution; therefore, it is unlikely that this variant contributes directly to increased risk for diabetes. In previous studies, the association of the AGG1273AGA polymorphism of the SUR1 gene with insulin levels (19) and the risk of type 2 diabetes has been inconsistent (9, 11). The most likely explanation for elevated risk is that this variant is in linkage disequilibrium with some other locus in the SUR1 gene itself or in some other gene. Therefore, we studied the possibility that this polymorphism is in linkage disequilibrium with some of the SUR1 promoter polymorphisms. We found that the GGAA haplotype of the SUR1 gene was associated with an almost 2-fold risk of diabetes, quite similar to the risk observed with the AGG1273AGA polymorphism alone. The GGAA haplotype contributed more to the risk of type 2 diabetes than did the E23K polymorphism of the Kir6.2 gene in contrast to previous findings (8, 18). The functionality of this SUR1 gene haplotype remains to be determined. An additional explanation for varying results is the possibility that variants in the SUR1 gene first increase insulin secretion due to down-regulation of the KATP channels but later on lead to impaired insulin secretion similarly to a dominantly inherited form of diabetes that causes hyperinsulinemia in infancy but diabetes in adulthood (25).
Studies on the E23K polymorphism of the Kir6.2 gene suggest that overactivity of the KATP channel is a key factor in the development of defective insulin secretion (26, 27). Both SUR1 and Kir6.2 knockout mice lacking KATP channels have defective glucose-stimulated insulin secretion (28, 29), supporting the crucial role of the SUR1 and Kir6.2 genes in insulin secretion disorders. No differences in insulin levels between the subjects with and without SUR1 and Kir6.2 gene variants were found in our study. However, this does not imply that the variants in these genes do not affect insulin secretion because lifestyle intervention increases insulin sensitivity and lowers insulin levels (24). Therefore, changes in insulin levels in the Finnish DPS can reflect changes in insulin sensitivity, insulin secretion, or both.
Weight changes in the control group were small, and they did not explain increased risk for diabetes associated with the SUR1 and Kir6.2 risk alleles. Therefore, it is possible that the risk for diabetes was substantially increased in these individuals due to impairment in insulin secretion. This finding, if verified in studies directly measuring insulin secretion capacity in subjects carrying the GGAA haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene, would be highly important. It would demonstrate that impaired insulin secretion can lead to diabetes also in obese individuals having IGT. Obviously the restoration of sufficient insulin secretion in people with IGT would be a step toward the prevention of type 2 diabetes. However, high expression of the SUR1 and Kir6.2 genes has also been found throughout the brain, particularly in the hippocampus and hypothalamus (30). Therefore, the effects of the risk alleles in the SUR1 and Kir6.2 genes on the conversion to diabetes could be, at least in part, centrally mediated.
In conclusion, the GGAA haplotype of the SUR1 gene predicts the conversion from IGT to type 2 diabetes in Finnish subjects with IGT. Moreover, we demonstrated that the SUR1 and Kir6.2 gene polymorphisms have an additive effect on the risk of type 2 diabetes. Finally, SNPs in the SUR1 gene seem to be more important predictors for the development of type 2 diabetes than are SNPs in the Kir6.2 gene, at least in Finnish subjects with IGT.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CI, confidence interval; DPS, Finnish Diabetes Prevention Study; IGT, impaired glucose tolerance; KATP, ATP-sensitive potassium; OGTT, oral glucose tolerance test; OR, odds ratio(s); SNP, single nucleotide polymorphism.
Received June 24, 2004.
Accepted September 2, 2004.
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References |
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Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80[CrossRef][Medline]
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