Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Diabetes 56:2829-2833, 2007
DOI: 10.2337/db06-1709
© 2007 by the American Diabetes Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Doi, Y.
Right arrow Articles by Kiyohara, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Doi, Y.
Right arrow Articles by Kiyohara, Y.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Brief Report

Impact of Kir6.2 E23K Polymorphism on the Development of Type 2 Diabetes in a General Japanese Population

The Hisayama Study

Yasufumi Doi1, Michiaki Kubo1,3, Toshiharu Ninomiya2, Koji Yonemoto2, Masanori Iwase1, Hisatomi Arima2, Jun Hata2, Yumihiro Tanizaki1, Mitsuo Iida1, and Yutaka Kiyohara2

1 Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3 Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan

Address correspondence and reprint requests to Yasufumi Doi, MD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: doi{at}intmed2.med.kyushu-u.ac.jp

Abbreviations: IFG, impaired fasting glycemia; IGT, impaired glucose tolerance; KATP channel, ATP-sensitive K+ channel; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PAR, population-attributable risk


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE—The association between the E23K polymorphism of ATP-sensitive K+ channel subunit Kir6.2 and diabetes has been reported in Caucasians but not in Asians. We examined this issue in follow-up and cross-sectional studies in a general Japanese population.

RESEARCH DESIGN AND METHODS—In a 14-year follow-up study of 976 subjects aged 40–79 years with normal glucose tolerance (NGT), we investigated the impact of the E23K polymorphism on change of glucose tolerance status using a 75-g oral glucose tolerance test. Additionally, we confirmed this association in a cross-sectional survey of 2,862 subjects.

RESULTS—In the follow-up study, the frequencies of the K/K genotype or K-allele were significantly higher in subjects with conversion from NGT to diabetes than in those in whom NGT was maintained (genotypes, P = 0.01; alleles, P = 0.008). In multivariate analysis, the risk for progression to diabetes was significantly higher in subjects with the E/K (odds ratio 2.10 [95% CI 1.16–3.83]) and K/K (2.40 [1.01–5.70], P for trend = 0.01) genotypes than in those with the E/E genotype after adjustment for confounding factors, namely, age, sex, fasting plasma glucose, family history of diabetes, BMI, physical activity, current drinking, and current smoking. In the cross-sectional study, the frequencies of the K/K genotype or K-allele were also significantly higher in those with diabetes than in those with NGT (genotypes, P = 0.006; alleles, P = 0.001).

CONCLUSIONS—Our findings suggest that the Kir6.2 E23K polymorphism is an independent genetic risk factor for diabetes in the general Japanese population.

Variants in genes encoding key components of insulin secretion pathways may confer a susceptibility to type 2 diabetes. Among candidate genes for such variants, the ATP-sensitive K+ channel (KATP channel) genes play an essential role in glucose-stimulated insulin secretion (1). The KATP channel in pancreatic ß-cells is composed of an ATP-sensitive and pore-forming inwardly rectifying K+ channel (Kir6.2) subunit (2) and a regulatory sulfonylurea receptor 1 subunit (3). A single nucleotide polymorphism at codon 23 of the KCNJ11 gene (rs5219) results in a glutamic acid to lysine substitution (E23K) in the NH2-terminal tail of Kir6.2 (4–6), and this polymorphism may cause modest reductions in ATP sensitivity and insulin secretion (7). Although there is general consensus that this polymorphism is a risk factor for type 2 diabetes in Caucasian populations (8–12), very few studies have examined its effect in Asian populations. Recently, one study reported that the E23K polymorphism was not significantly related to diabetes in Japanese (13). The aim of the present article is to assess the association of this polymorphism with diabetes in a defined Japanese population after accounting for comprehensive risk factors for diabetes.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Follow-up study group.
In 1988, a screening survey for the present study was performed in the town of Hisayama, a suburb of Fukuoka, Japan (14). The age and occupational distributions for Hisayama were almost identical to those of Japan as a whole based on data from the national census. Of all residents aged 40–79 years in 1988, 2,587 participated in the baseline survey (participation rate 80.2%). After excluding 82 subjects who had already had breakfast, 15 who ceased taking a 75-g oral glucose tolerance test (OGTT) due to nausea or general fatigue during the ingestion of glucose, and 10 who were on insulin therapy, 2,480 subjects completed the OGTT. Of these, 1,561 subjects with normal glucose tolerance (NGT) were enrolled in the baseline examination. After the initial screening, glucose tolerance levels were measured again in 2002. The genotype data of the E23K polymorphism and glucose tolerance levels were successfully obtained for a total of 976 subjects (383 men and 593 women), and these were the subjects selected for the 14-year follow-up study.

Cross-sectional study group.
A diabetes survey similar to that done in 1988 was performed in 2002. Of all residents aged 40 years or over, 3,328 underwent the examination (participation rate 77.6%). Among the participating residents, 3,196 subjects agreed to the genetic analysis. Of these, a total of 2,851 subjects completed the OGTT after excluding 234 who refused the OGTT, 76 who had already eaten breakfast, and 35 who were on insulin therapy. Among those who did not undergo the OGTT, the following 78 subjects were categorized as having diabetes and included in the cross-sectional study: 21 with fasting plasma glucose ≥7.0 mmol/l, 6 with plasma glucose ≥11.1 mmol/l after eating breakfast, 16 who were taking oral hypoglycemic agents, and 35 on insulin therapy. Consequently, 2,929 subjects whose glucose tolerance levels were determined underwent analysis of the E23K polymorphism. Of these, the genotype data were successfully obtained from a total of 2,862 subjects (1,268 men and 1,594 women), for a genotyping success rate of 97.7%.

Genotyping.
Genotyping of the Kir6.2 E23K polymorphism was done by a TaqMan assay at HuBit Genomix (Tokyo, Japan). The TaqMan genotyping reaction was amplified on a GeneAmp PCR System 9700, and fluorescence was detected on an ABIPRISM 7900HT Sequence Detection System. We confirmed the genotyping results of 376 randomly selected subjects by the direct sequencing method at the RIKEN Institute (Yokohama, Japan). Consequently, the concordance rate was 100% in the 369 subjects who were successfully genotyped by both the TaqMan and direct sequencing methods. The distributions of the E23K polymorphism were in Hardy-Weinberg equilibrium.

Clinical evaluation.
In both the 1988 and 2002 surveys, the study subjects underwent the OGTT between 8:00 and 10:30 A.M. after at least a 12-h overnight fast. The plasma glucose levels were determined by the glucose-oxidase method and serum insulin by a radioimmunoassay in 1988 and a chemiluminescent enzyme immunoassay in 2002. Plasma glucose levels were classified according to World Health Organization criteria (15). In the 2002 survey, the subjects who were taking antidiabetic medicine or had a glucose concentration of ≥11.1 mmol/l after eating breakfast were categorized as having diabetes. Homeostasis model assessment of insulin resistance was calculated from fasting plasma glucose and serum insulin (16). BMI was calculated from the height and weight. Diabetes in first- or second-degree relatives was taken to indicate a family history of diabetes. Alcohol intake and smoking habits were classified as either currently habitual or not. Subjects engaging in sports at least three times per week during their leisure time were classified into a regular exercise group.

Statistical analysis.
The distributions of the E23K polymorphism were analyzed according to glucose tolerance levels by {chi}2 test. Adjusted odds ratios (ORs) and 95% CIs were calculated by logistic regression model. The population-attributable risk (PAR) percentage and its 95% CI were estimated according to the method used in the previous report (17). If assuming a significance level of P < 0.05 and 80% power, it is estimated that the OR for the risk of diabetes between the E/E and K/K genotypes becomes significant at the difference of 1.37-fold or greater in our cross-sectional survey. In a meta-analysis of the cross-sectional studies (10), it has been reported that the OR for the risk of diabetes in the K/K genotype was 1.49, significantly higher than that for the E/E genotype. Thus, the sample size of our study seems to be enough for the detection of the significant association.

This study was conducted with the approval of the ethics committee of the Faculty of Medicine, Kyushu University, and written informed consent was obtained from all study subjects.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1 shows the clinical characteristics of NGT subjects in 1988 and total subjects in 2002 according to Kir6.2 E23K genotypes.


View this table:
[in this window]
[in a new window]

  		TABLE 1 Clinical characteristics of subjects according to the Kir6.2 E23K polymorphism in NGT subjects in 1988 and total subjects in 2002

 
The frequencies of the E23K polymorphism based on change of glucose tolerance status are shown in Table 2. The distributions of the E23K polymorphism in subjects with conversion from NGT to impaired fasting glycemia (IFG) or impaired glucose tolerance (IGT) were not significantly different from those in whom NGT was maintained over the 14-year follow-up. The frequencies of the E/K and K/K genotypes or K-allele, however, were significantly higher in individuals with progression to diabetes than in those in whom NGT was maintained (genotypes, P = 0.01; alleles, P = 0.008).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Genotype and allele frequencies of the Kir6.2 E23K polymorphism according to change of glucose tolerance status in the follow-up study, 1988–2002

 
The age- and sex-adjusted or multivariate-adjusted ORs of the E23K polymorphism for the development of diabetes were analyzed between subjects with conversion from NGT to diabetes during the follow-up period and subjects with NGT maintained (Table 3). The risk for progression from NGT to diabetes was more than twofold higher in the E/K and K/K genotypes than in the E/E genotype after age and sex adjustment. This association remained significant even after adjustment for confounding factors at baseline, i.e., age, sex, fasting plasma glucose, family history of diabetes, BMI, physical activity, current drinking, and current smoking (E/K genotype, adjusted OR 2.10 [95% CI 1.16–3.83]; K/K genotype, 2.40, [1.01–5.70]; P for trend = 0.01). A similar result was revealed in the allele frequency model; the risk for conversion to diabetes was higher in subjects with the minor K-allele than in those with the major E-allele (1.58 [1.09–2.30], P = 0.01). The likelihood ratio in the multivariate-adjusted model that included the above-mentioned confounding risk factors and the E23K polymorphism was significantly higher than that in the model with only the confounding factors (genotypes, P = 0.02; alleles, P = 0.01). Furthermore, the multivariate-adjusted OR of the dominant model in which the E/K and K/K genotypes were combined was 2.16 (95% CI 1.21–3.85) compared with the E/E genotype. When estimating the PAR percentage, 40.1% (10.8–62.2) of the progression to diabetes among NGT subjects was attributable to these dominant genotypes.


View this table:
[in this window]
[in a new window]

  		TABLE 3 Age- and sex-adjusted or multivariate-adjusted ORs and 95% CIs for the progression to diabetes from NGT by the Kir6.2 E23K genotype and allele in the follow-up study, 1988–2002

 
Furthermore, we investigated the association between the E23K polymorphism and the risk of diabetes in the total subject group in 2002 (Table 4). The genotype and allele frequencies of the E23K polymorphism in subjects with IFG and IGT were not significantly different from those in the subjects with NGT, while the frequencies of the K/K genotype or K-allele were significantly higher in those with diabetes than in those with NGT (genotypes, P = 0.006; alleles, P = 0.001).


View this table:
[in this window]
[in a new window]

  		TABLE 4 Genotype and allele frequencies of the Kir6.2 E23K polymorphism according to glucose tolerance status in the cross-sectional study, 2002

 

   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In our follow-up and large cross-sectional studies, we showed a positive association between the Kir6.2 E23K polymorphism and type 2 diabetes. These associations remained significant even after adjusting for other confounding factors. The likelihood ratio was significantly higher in the multivariate-adjusted model with the polymorphism than in that without. These findings suggest that the E23K polymorphism is a significant predictor of future diabetes in the general Japanese population.

Several case-control studies indicated that the E23K polymorphism is a risk factor for type 2 diabetes (8–12), but this association was not observed in cohort studies—two Finnish prospective studies showed that the E23K polymorphism had no effect on the development of diabetes (18,19). The present study is the first to indicate an association between the E23K polymorphism and diabetes using a follow-up design. Our study group consisted of exclusively Japanese subjects, with no population stratifications (20), and their glucose tolerance levels were determined in principle using an OGTT. This study design provided us an opportunity to precisely examine the ability of the E23K polymorphism to predict diabetes.

In our follow-up study, the PAR percentage for progression to diabetes was 40.1% in the NGT subjects, which was higher than that reported in previous studies of this gene (8,12). This difference seems to be attributable to the fact that we used control subjects in whom NGT was maintained, as confirmed by the OGTT, over a 14-year interval. However, since our result was based on a small number of subjects, it is better to confirm this value in other large populations.

The present study is the first to show a significant association between the E23K polymorphism and diabetes in Japanese. Recently, it was reported that this polymorphism was not associated with diabetes in Japanese individuals (13). In that study, subjects were recruited from university hospitals and the control subjects defined as subjects with A1C levels <5.6%. However, a group of subjects with A1C <5.6% could include individuals with diabetes, as well as IFG and IGT (21). Actually, the frequency of the minor K-allele in the control subjects of that report was significantly higher than that in our NGT subjects, although the K-allele frequencies in the respective groups of diabetic subjects were similar. The different criteria used to define the phenotype are partly responsible for these different outcomes.

Some limitations of our study must be mentioned. First, there is an overlap of subjects used in both the cross-sectional and follow-up analyses—34% of the subjects in the cross-sectional analysis were also enrolled in the follow-up analysis, and thus our results are not really replicated. Further investigations will be needed to confirm our results in other Asian populations. Second, a 75-g OGTT has low reproducibility (22). Some of the participants might have been categorized into different glucose tolerance levels after repeat testing. Nonetheless, any misclassification would be expected to weaken rather than strengthen the association found in this study. Thus, the true association may be stronger than that shown in our results. Third, subjects with type 1 diabetes may have been included in our study population. In a clinical study, 3–4% of the group of nonobese Japanese diabetic patients were positive for the GAD antibody (23). Immune abnormality in pancreatic ß-cells is considered to lead to diabetes independently of the E23K polymorphism, suggesting that subjects with type 1 diabetes are distributed equally among the genotypes. Thus, this limitation does not seem to invalidate the association of the E23K polymorphism with the risk of type 2 diabetes.

In conclusion, we confirmed the association between the E23K polymorphism of the KATP channel subunit Kir6.2 and susceptibility to type 2 diabetes in a follow-up study and a large cross-sectional study in a general Japanese population. Considering that populations throughout the world have a high frequency of the E23K polymorphism, this polymorphism may be a pathogenic gene for diabetes worldwide.


   FOOTNOTES
 
Published ahead of print at http://diabetes.diabetesjournals.org on 17 August 2007. DOI: 10.2337/db06-1709.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication December 7, 2006 and accepted in revised form August 10, 2007


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ashcroft FM, Rorsman P: ATP-sensitive K+ channels: a link between ß-cell metabolism and insulin secretion. Biochem Soc Trans 18:109–111, 1990[Medline]
  2. Seino S, Inagaki N, Namba N, Gonoi T: Molecular biology of the ß-cell ATP-sensitive K+ channel. Diabetes Rev 4:177–190, 1996
  3. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP 4th, Boyd AE 3rd, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA: Cloning of the ß cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268:423–426, 1995[Abstract/Free Full Text]
  4. Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM: Sequence variations in the human Kir6.2 gene, a subunit of the ß-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia 39:1233–1236, 1996[Medline]
  5. Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, Elbein SC, Hampe CL, Suarez BK, Inagaki N, Seino S, Permutt MA: Sequence variants in the pancreatic islet ß-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes 46:502–507, 1997[Abstract]
  6. Hansen L, Echwald SM, Hansen T, Urhammer SA, Clausen JO, Pedersen O: Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes 46:508–512, 1997[Abstract]
  7. Schwanstecher C, Meyer U, Schwanstecher M: Kir6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic ß-cell ATP-sensitive K+ channels. Diabetes 51:875–879, 2002[Abstract/Free Full Text]
  8. Schwanstecher C, Schwanstecher M: Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51 (Suppl. 3):S358–S362, 2002
  9. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM: Large-scale association studies of variants in genes encoding the pancreatic ß-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572, 2003[Abstract/Free Full Text]
  10. Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O: The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 52:573–577, 2003[Abstract/Free Full Text]
  11. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive K+ channel gene region. Diabetes 53:1360–1368, 2004[Abstract/Free Full Text]
  12. Hansen SK, Nielsen EM, Ek J, Andersen G, Glumer C, Carstensen B, Mouritzen P, Drivsholm T, Borch-Johnsen K, Jorgensen T, Hansen T, Pedersen O: Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J Clin Endocrinol Metab 90:3629–3637, 2005[Abstract/Free Full Text]
  13. Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S: Association studies of variants in the genes involved in pancreatic ß-cell function in type 2 diabetes in Japanese subjects. Diabetes 55:2379–2386, 2006[Abstract/Free Full Text]
  14. Ohmura T, Ueda K, Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Nomiyama K, Ohmori S, Yoshitake T, Shinkawa A, Hasuo Y, Fujishima M: Prevalence of type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in the Japanese general population: the Hisayama Study. Diabetologia 36:1198–1203, 1993[Medline]
  15. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553, 1998[Medline]
  16. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419, 1985[Medline]
  17. Daly LE: Confidence limits made easy: interval estimation using a substitution method. Am J Epidemiol 147:783–790, 1998[Abstract/Free Full Text]
  18. Laukkanen O, Pihlajamaki J, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M: Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. J Clin Endocrinol Metab 89:6286–6290, 2004[Abstract/Free Full Text]
  19. Lyssenko V, Anevski D, Almgren P, Sjogren M, Svensson M, Orho-Melander M, Tuomi T, Groop L: Genetic prediction of type 2 diabetes. PloS Medicine 2:1299–1308, 2005
  20. Kubo M, Hata J, Ninomiya T, Matsuda K, Yonemoto K, Nakano T, Matsushita T, Yamazaki K, Ohnishi Y, Saito S, Kitazono T, Ibayashi S, Sueishi K, Iida M, Nakamura Y, Kiyohara Y: A nonsynonymous SNP in PRKCH (protein kinase C {eta}) increases the risk of cerebral infarction. Nat Genet 39:529–533, 2007[Medline]
  21. Ko GT, Chan JC, Yeung VT, Chow CC, Tsang LW, Li JK, So WY, Wai HP, Cockram CS: Combined use of a fasting plasma glucose concentration and HbA1c or fructosamine predicts the likelihood of having diabetes in high-risk subjects. Diabetes Care 21:1221–1225, 1998[Abstract]
  22. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197, 1997[Medline]
  23. Bando Y, Ushiogi Y, Toya D, Tanaka N, Fujisawa M: Antibodies to glutamic acid decarboxylase (GAD) in non-obese Japanese diabetics without insulin therapy: a comparison of two commercial RIA kits based on recombinant and pig brain GAD. Diabetes Res Clin Pract 41:25–33, 1998[Medline]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Doi, Y.
Right arrow Articles by Kiyohara, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Doi, Y.
Right arrow Articles by Kiyohara, Y.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum