help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1225
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Palmer, N. D.
Right arrow Articles by Bowden, D. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Palmer, N. D.
Right arrow Articles by Bowden, D. W.
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 1 304-309
Copyright © 2008 by The Endocrine Society

BRIEF REPORT

Association of TCF7L2 Gene Polymorphisms with Reduced Acute Insulin Response in Hispanic Americans

Nicholette D. Palmer, Allison B. Lehtinen, Carl D. Langefeld, Joel K. Campbell, Steven M. Haffner, Jill M. Norris, Richard N. Bergman, Mark O. Goodarzi, Jerome I. Rotter and Donald W. Bowden

Departments of Biochemistry (N.D.P., A.B.L., D.W.B.), Internal Medicine (D.W.B.), and Public Health Sciences (C.D.L., J.K.C.) and Center for Human Genomics (N.D.P., A.B.L., D.W.B.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, Department of Medicine (S.M.H.), University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229; Department of Preventive Medicine and Biometrics (J.M.N.), University of Colorado Health Sciences Center, Denver, Colorado 80262; Department of Physiology and Biophysics (R.N.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90089; and Medical Genetics Institute (M.O.G., J.I.R.), Cedars-Sinai Medical Center, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Donald W. Bowden, Ph.D., Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157. E-mail: dbowden{at}wfubmc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Genetic variation at the transcription factor 7-like 2 locus has been linked to type 2 diabetes in predominantly European-derived populations. The biological basis of these associations remains to be determined.

Objective: The objective of this study was to evaluate previously associated variants for association with measures of glucose homeostasis in Hispanic-Americans and African-Americans and determine the biological mechanism(s) through which these variants exert their effect.

Design: This study was the Insulin Resistance Atherosclerosis Family Study (IRAS-FS).

Setting: The 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-American and 500 African-American individuals from the IRAS-FS formed the basis of this study.

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

Results: In Hispanic-Americans, significant evidence of association was observed between single-nucleotide polymorphisms rs7903146 and rs112255372 with reduced insulin secretion as measured by acute insulin response and adjusted for the degree of insulin sensitivity (P = 0.032 and 0.036, respectively). Other quantitative measures, e.g. insulin sensitivity or disposition index, were not associated with the single nucleotide polymorphisms examined. In African-Americans there was no evidence of association observed.

Conclusions: These results suggest that transcription factor 7-like 2 variants could play a role in the pathogenesis of type 2 diabetes in the Hispanic-American population through a mechanism involving insulin secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
The transcription factor 7-like 2 (TCF7L2) gene belongs to the TCF/lymphoid enhancer-binding factor family of transcription factors. Members of this family influence the Wnt/β-catenin signaling pathway, which regulates gene expression (1). Recently TCF7L2 has been identified as a regulator of proglucagon gene expression in a cell type-specific manner whereby TCF7L2 and β-catenin bind and stimulate expression of the proglucagon gene (2). The proglucagon gene is posttranslationally processed to produce glucagon-like peptide-1, a powerful stimulator of insulin secretion and biosynthesis and an inhibitor of glucagon release, which acts to decrease blood glucose (3).

TCF7L2 is located on 10q25.2, a region linked to type 2 diabetes (T2D) in Mexican-Americans (4) and an Icelandic population (5). Grant et al. (6) reported association of a microsatellite marker (DG10S478) in intron 3 of the TCF7L2 gene with T2D in the Icelandic population. Additionally, single nucleotide polymorphisms (SNPs) were genotyped to evaluate the correlation of alleles within the linkage disequilibrium (LD) block and found to be significantly associated with T2D. Specifically, the strongest evidence of association was found with the T allele of SNPs rs7903146 and rs12255372. These findings were replicated in Danish female and European-American cohorts (6). Subsequently several studies reported similar findings in predominantly European-derived populations (7, 8, 9, 10, 11, 12, 13, 14, 15).

The purpose of this study was to evaluate association of TCF7L2 SNPs with quantitative measures of glucose homeostasis in Hispanic- and African-American subjects from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS). Quantitative trait analysis in appropriately phenotyped families is a powerful approach for gaining insights into complex biological diseases, e.g. T2D. Our extensive phenotypic data should facilitate assessment of the genetic impact of TCF7L2 SNPs on metabolic pathways (i.e. insulin sensitivity or insulin secretion) in which the protein product exerts its effects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Recruitment

Study design and recruitment have been described in detail (16). Briefly, the IRAS-FS is a multicenter study designed to identify the genetic determinants of glucose homeostasis. Large families of Hispanic-Americans (n = 1417; San Antonio, TX; San Luis Valley, CO) and African-Americans (n = 605; Los Angeles, CA) were recruited. A clinical examination included frequently sampled iv glucose tolerance test (FSIGT), anthropometric measurements, and blood collection. Specific to this report, measures of glucose homeostasis included those from the FSIGT (17, 18, 19) calculated by mathematical modeling methods (MINMOD) (20): insulin sensitivity (SI), acute insulin response (AIR), and disposition index (DI).

Genotyping

Five SNPs (rs7901695, rs7903146, rs7895340, rs11196205, and rs12255372) previously reported (6) to be correlated with marker DG10S478 were genotyped. Genotyping was performed using the Sequenom MassArray. Seventy blind duplicates were included to evaluate genotyping accuracy.

Statistical analysis

Mendelian inconsistencies were identified with PedCheck (21) and converted to missing. Maximum likelihood estimates of allele frequencies were computed using unrelated Hispanic- and African-American individuals (n = 229 and 58, respectively), tested for departures from Hardy-Weinberg proportions and used to compute LD statistics. Association between individual SNPs and each quantitative phenotype was performed in SOLAR (22) using variance component analysis. When necessary, quantitative traits were transformed to approximate the distributional assumptions of the test and minimize variance heterogeneity. For each phenotype, the two degree of freedom test of genotypic association was performed. Adjustments for multiple comparison tests were not performed due to the high correlation between the SNPs examined and the a priori hypotheses. Subjects with T2D were excluded from the analysis of glucose homeostasis traits.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
This study genotyped 1849 IRAS-FS participants, 1268 Hispanic-Americans and 581 African-Americans. Table 1Go summarizes descriptive statistics by ethnicity. On average, both ethnicities had a higher proportion of females (59%), were of similar age, and had comparable body mass index (BMI) values. Compared with African-Americans, Hispanic-Americans were insulin sensitive [SI = 2.15 vs. 1.63 x 10–5min–1/(pmol/liter)] and had reduced insulin secretion (AIR = 760 vs. 1006 pmol/liter) and DI (1317 vs. 1426 x 10–5min–1).


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

  		TABLE 1. Demographic summary of genotyped IRAS-FS Hispanic- and African-American participants

 
Genotyping success rates were greater than 94.6% for all SNPs examined, and blind duplicates included in genotyping (n = 70) were concordant. PedCheck analysis resulted in exclusion of 17 of 9240 genotypes. All SNPs were consistent with Hardy-Weinberg proportions. In Hispanic-Americans, SNPs fell into two LD blocks as defined by the confidence interval method (appendix Fig. 1A, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). Block 1 contained intron 3 SNPs rs7901695 and rs7903146 (D' = 1.00; r2 = 0.81) whereas block 2 contained intron 4 SNPs rs7895340-rs12255372 (D' = 0.94–1.00; r2 = 0.42–0.96). In African-Americans, the SNPs composed two LD blocks (appendix Fig. 1B). Block 1 contained SNPs rs7901695 and rs7903146 (D' = 1.00, r2=0.51) and block 2 contained SNPs rs7895340 and rs11196205 (D' = 1.00, r2 = 1.00).

Association results are summarized in Tables 2Go and 3Go. In Hispanic-Americans (Table 2Go), SNPs rs7903146 and rs12255372 were significantly associated (P = 0.032 and 0.036, respectively) with AIR. These associations were consistent with an additive model in which copy number of the minor allele T corresponded to the effect size as evidenced from the phenotypic means. Association with AIR in Hispanic-Americans is driven by the San Antonio subpopulation, whereas no associations were seen in the San Luis Valley population when analyzed separately (appendix Table 1).


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

  		TABLE 2. Association with glucose homeostasis traits in the IRAS-FS Hispanic-American population

 

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

  		TABLE 3. Association with glucose homeostasis traits in the IRAS-FS African-American population

 
Association results for the African-American sample are presented in Table 3Go. Notably, there were significant allele frequency differences for SNPs rs7901695, rs7895340, and rs11196205, resulting in a change of the minor allele as compared with the Hispanic-American population. Quantitative trait analysis revealed no evidence of association between TCF7L2 SNPs and glucose homeostasis traits examined.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The TCF7L2 gene has been implicated in the pathogenesis of T2D in predominantly European-derived populations. New reports of association in additional ethnicities, however, are emerging. We examined five previously evaluated variants in large samples of Hispanic- and African-Americans subjects from the IRAS-FS. This multiethnic cohort has been extensively phenotyped for quantitative measures of glucose homeostasis, which enabled exploration of the biological mechanism of action for this gene product in vivo.

In Hispanic-Americans the SNPs genotyped were contained in two LD blocks. In comparison with European ancestry centre d’Etude du Polymorphisme Humain (CEPH) samples genotyped by HapMap, block boundaries are disparate when using the confidence interval method with four SNPs (rs7901695-rs11196205) comprising one block; however, block boundaries are the same when using the solid spine method. Slight differences in block structure could be attributed to slightly increased minor allele frequencies (MAFs) in Hispanic-Americans possibly due to modest admixture.

Significant association was observed between AIR adjusted for age, gender, recruitment center, BMI, and SI and rs7903146 and rs12255372 (P = 0.036 and 0.032, respectively), which were strongly associated with T2D in the initial report (6). Exclusion of SI as a covariate resulted in marginally less significant associations (P = 0.055 and 0.047, respectively). These associations were driven by the San Antonio population and are not attributed to power issues; individual cohorts have approximately equivalent power or phenotypic differences for AIR (P = 0.034) but more likely due to increased MAF of variants in the San Luis Valley population or environmental contributions. The minor allele T for both SNPs, associated with T2D risk (6, 7, 8, 9, 10, 11, 12, 13, 14, 15), were associated with decreased AIR following an additive model. Notably, the exclusion of BMI as a covariate resulted in marginally more significant associations (P = 0.034 and 0.051, respectively), suggesting that adiposity is not a major contributor (data not shown). Although modestly associated with reduced AIR, the T alleles for rs7903146 and rs12255372 were not associated with future T2D in Hispanic-Americans, as assessed during follow-up studies of limited sample size (n = 65; data not shown). Such an association has been observed in studies of European-derived populations (23). The marginal associations observed with insulin secretion calculated from the FSIGT as compared with the oral glucose tolerance test (OGTT) (23), which was not performed in IRAS-FS, are consistent with emerging data suggesting variants in TCF7L2 effect the enteroinsular axis (23).

Evidence of association with only two of five SNPs could be attributed to low correlation (r2 < 0.54) between associated variants in this study and other SNPs. Lack of evidence for association with SI is unlikely a false-negative result, given the study has 80% power when examining a variant with a MAF = 0.20, to detect an SI difference as small as 15%. In addition, there was no evidence of association with fasting glucose observed (appendix Table 2). Evaluation of TCF7L2 SNPs for association with T2D resulted in a lack of association (data not shown), which could be attributed modest sample size (n = 186).

Additional studies have evaluated TCF7L2 variants in Hispanic-Americans (8, 24, 25). In comparison with the study by Florez et al. (8), MAFs for SNPs rs7903146 and rs12255372 were slightly higher (0.27 and 0.24, respectively; n = 497), but direct comparison of association analysis results is not possible due to their combining of ethnicities for analysis. Lehman et al. (24) evaluated TCF7L2 variants in a T2D cohort containing a nondiabetic subset (n = 367) but that did not have FSIGT data. Similar to results presented here, they observed modest attributable risk, compared with the magnitude of associations observed in European-derived populations. Using an iv glucose tolerance test, Watanabe et al. (25) assessed the impact of previously associated TCF7L2 variants (rs7901695 and rs12255372; n < 537) on measures of glucose homeostasis and observed no evidence of association with AIR. In the same study, rs12255372 was associated with fasting plasma insulin concentration from an OGTT modified by percent body fat, an effect not directly assessed in IRAS-FS due to absence of OGTT data. Overall the results reported here are from a sample that is comparable in size with each of these prior studies combined.

In parallel with the association studies in Hispanic-Americans, we also evaluated these variants in a similarly phenotyped African-American population. The SNPs genotyped formed two LD blocks with variable intrablock SNP correlations. The same set of quantitative traits was evaluated and no evidence of association was observed. This lack of association could be attributed to an ungenotyped variant(s), which is tagged by this SNP subset in Hispanic-Americans due to LD and MAF differences. Alternatively, these results could be attributed to ethnic-specific effects because previous associations have been limited to predominantly European-derived populations. This report is contrary to the findings of Munoz et al. (26), which reported association of rs12255372 with a reduction in DI and AIRG adjusted for SI but consistent with the lack of association with insulin secretion observed by Elbein et al. (27), both in African-Americans. One potential source of variation between the conflicting report could be attributed to age of the recruited subjects. IRAS-FS had a mean recruitment age of 42.9 ± 14, whereas Munoz et al. recruited individuals aged 7–57 yr for a mean age of 31 ± 12 yr. Because T2D has a later age of onset, the hallmarks of the disease, insulin resistance and defective insulin secretion, may not be pronounced in younger, genetically predisposed individuals. This rationale could explain their loss of significance after adjustment for age (26).

Previous studies in other ethnicities examining the influence of TCF7L2 on measures of glucose metabolism are also inconsistent. Methods chosen to derive measures of glucose homeostasis and sample sizes differ significantly between studies. Two recent studies derived quantitative measures of glucose homeostasis from the OGTT (8, 13). Florez et al. (8) evaluated two correlated measures of insulin secretion (fasting insulin to fasting glucose ratio and corrected insulin response) and two correlated measures of insulin sensitivity (reciprocal of insulin resistance and the insulin sensitivity index) in a multiethnic cohort (n = 554). This study observed the T allele of SNPs rs7901695 and rs12255372 to be associated with decreased insulin secretion and increased insulin sensitivity. Saxena et al. (13) evaluated measures of insulin resistance and insulin secretion in a northern European-derived sample (n = 995 and 721, respectively) and found a decrease in insulin secretion associated with the T allele of rs7903146. The authors concluded that TCF7L2 variants influence first-phase insulin response and overall capacity of β-cells to secrete insulin. Complimentary to this approach, Damcott et al. (12) used the iv glucose tolerance test in a sample of European-American subjects (n = 48) and observed evidence of association with SI, AIR, and DI, although the magnitude of the effect was reduced after adjustment for BMI.

This study represents an attempt to assess the contribution of TCF7L2 variants to alterations in quantitative measures of glucose homeostasis in large Hispanic- and African-American cohorts. Whereas this study does not elucidate a causal variant, it supports a probable mechanism whereby variants contribute to T2D susceptibility by decreasing insulin secretion. Further investigations of TCF7L2 across additional ethnicities are warranted to evaluate possible ethnic-specific effects. In addition, functional studies are needed to confirm associations observed with insulin secretion.


   Footnotes
 
This work was supported by National Institutes of Health Grant R01 DK56289 to D.W.B.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 30, 2007

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; LD, linkage disequilibrium; MAF, minor allele frequency; OGTT, oral glucose tolerance test; SI, insulin sensitivity; SNP, single nucleotide polymorphism; TCF7L2, transcription factor 7-like 2 locus; T2D, type 2 diabetes.

Received June 1, 2007.

Accepted October 24, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Nelson WJ, Nusse R 2004 Convergence of Wnt, β-catenin, and cadherin pathways. Science 303:1483–1487[Abstract/Free Full Text]
  2. Yi F, Brubaker PL, Jin T 2005 TCF-4 mediates cell type-specific regulation of proglucagon gene expression by β-catenin and glycogen synthase kinase-3β. J Biol Chem 280:1457–1464[Abstract/Free Full Text]
  3. Deacon CF 2004 Therapeutic strategies based on glucagon-like peptide 1. Diabetes 53:2181–2189[Abstract/Free Full Text]
  4. Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O’Connell P, Stern MP 1999 Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet 64:1127–1140[CrossRef][Medline]
  5. Reynisdottir I, Thorleifsson G, Benediktsson R, Sigurdsson G, Emilsson V, Einarsdottir AS, Hjorleifsdottir EE, Orlygsdottir GT, Bjornsdottir GT, Saemundsdottir J, Halldorsson S, Hrafnkelsdottir S, Sigurjonsdottir SB, Steinsdottir S, Martin M, Kochan JP, Rhees BK, Grant SF, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR 2003 Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34–q35.2. Am J Hum Genet 73:323–335[CrossRef][Medline]
  6. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K 2006 Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323[CrossRef][Medline]
  7. Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, McCarthy MI 2006 Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 55:2640–2644[Abstract/Free Full Text]
  8. Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D 2006 TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355:241–250[Abstract/Free Full Text]
  9. Zhang C, Qi L, Hunter DJ, Meigs JB, Manson JE, van Dam RM, Hu FB 2006 Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men. Diabetes 55:2645–2648[Abstract/Free Full Text]
  10. Scott LJ, Bonnycastle LL, Willer CJ, Sprau AG, Jackson AU, Narisu N, Duren WL, Chines PS, Stringham HM, Erdos MR, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Collins FS, Boehnke M 2006 Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes 55:2649–2653[Abstract/Free Full Text]
  11. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, Stetsyuk V, Scharfmann R, Staels B, Fruhbeck G, Froguel P 2006 Transcription factor TCF7L2 genetic study in the French population: expression in human β-cells and adipose tissue and strong association with type 2 diabetes. Diabetes 55:2903–2908[Abstract/Free Full Text]
  12. Damcott CM, Pollin TI, Reinhart LJ, Ott SH, Shen H, Silver KD, Mitchell BD, Shuldiner AR 2006 Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes 55:2654–2659[Abstract/Free Full Text]
  13. Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, Lindblad U, Daly MJ, Tuomi T, Hirschhorn JN, Ardlie KG, Groop LC, Altshuler D 2006 Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55:2890–2895[Abstract/Free Full Text]
  14. Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, Li KW, Palmen J, Miller MA, Cappuccio FP, Elkeles R, Godsland I, Miller GJ, Talmud PJ 2006 Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med 84:1–10[CrossRef][Medline]
  15. van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, Strengman E, van Haeften TW, Hofker MH, Wijmenga C 2007 Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia 50:59–62[CrossRef][Medline]
  16. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS 2003 Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol 13:211–217[CrossRef][Medline]
  17. Bergman RN, Finegood DT, Ader M 1985 Assessment of insulin sensitivity in vivo. Endocr Rev 6:45–86[Abstract/Free Full Text]
  18. Bergman RN, Ider YZ, Bowden CR, Cobelli C 1979 Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667–E677
  19. Steil GM, Volund A, Kahn SE, Bergman RN 1993 Reduced sample number for calculation of insulin sensitivity and glucose effectiveness from the minimal model. Suitability for use in population studies. Diabetes 42:250–256[Abstract]
  20. Pacini G, Bergman RN 1986 MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput Methods Programs Biomed 23:113–122[CrossRef][Medline]
  21. O’Connell JR, Weeks DE 1998 PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266[CrossRef][Medline]
  22. Almasy L, Blangero J 1998 Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211[CrossRef][Medline]
  23. Lyssenko V, Lupi R, Marchetti P, Guerra SD, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson K, Lethagen A, Mancarella R, Berglund G, Tuomi T, Nilsson P, Prato SD, Groop LC 2007 Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117:2155–2163[CrossRef][Medline]
  24. Lehman DM, Hunt KJ, Leach RJ, Hamlington J, Arya R, Abboud HE, Duggirala R, Blangero J, Goring HH, Stern MP 2007 Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes 56:389–393[Abstract/Free Full Text]
  25. Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, Buchanan TA 2007 Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes 56:1481–1485
  26. Munoz J, Lok KH, Gower BA, Fernandez JR, Hunter GR, Lara-Castro C, De Luca M, Garvey WT 2006 Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women. Diabetes 55:3630–3634[Abstract/Free Full Text]
  27. Elbein SC, Chu WS, Das SK, Yao-Borengasser A, Hasstedt SJ, Wang H, Rasouli N, Kern PA 2007 Transcription factor 7-like 2 polymorphisms and type 2 diabetes, glucose homeostasis traits and gene expression in U.S. participants of European and African descent. Diabetologia 50:1621–1630[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Palmer, N. D.
Right arrow Articles by Bowden, D. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Palmer, N. D.
Right arrow Articles by Bowden, D. W.
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals