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Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies

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Abstract

Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 ≤ P ≤ 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R 2 was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0–8.5% of the variance of T2DM-related traits.

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References

  1. Frayling TM (2007) Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 8:657–662

    Article  PubMed  CAS  Google Scholar 

  2. Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson JT, Thorleifsson G, Manolescu A, Rafnar T, Gudbjartsson D, Agnarsson BA, Baker A et al (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39:977–983

    Article  PubMed  CAS  Google Scholar 

  3. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336

    Article  PubMed  CAS  Google Scholar 

  4. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345

    Article  PubMed  CAS  Google Scholar 

  5. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    Article  PubMed  CAS  Google Scholar 

  6. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S, Emilsson V, Ghosh S et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775

    Article  PubMed  CAS  Google Scholar 

  7. WTCCC (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  CAS  Google Scholar 

  8. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645

    Article  PubMed  CAS  Google Scholar 

  9. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341

    Article  PubMed  CAS  Google Scholar 

  10. Weyer C, Tataranni PA, Bogardus C, Pratley RE (2001) Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 24:89–94

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M et al (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

    Article  PubMed  CAS  Google Scholar 

  13. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL et al (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117:2155–2163

    Article  PubMed  CAS  Google Scholar 

  14. Vaxillaire M, Veslot J, Dina C, Proenca C, Cauchi S, Charpentier G, Tichet J, Fumeron F, Marre M, Meyre D et al (2008) Impact of common type 2 diabetes risk polymorphisms in the DESIR prospective study. Diabetes 57:244–254

    Article  PubMed  CAS  Google Scholar 

  15. Cauchi S, Meyre D, Choquet H, Dina C, Born C, Marre M, Balkau B, Froguel P (2006) TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the insulin resistance syndrome (DESIR) study. Diabetes 55:3189–3192

    Article  PubMed  CAS  Google Scholar 

  16. Marzi C, Huth C, Kolz M, Grallert H, Meisinger C, Wichmann HE, Rathmann W, Herder C, Illig T (2007) Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys. Horm Metab Res 39:46–52

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman RN, Goodarzi MO, Rotter JI, Bowden DW (2008) Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans. J Clin Endocrinol Metab 93:304–309

    Article  PubMed  CAS  Google Scholar 

  20. Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, Frayling TM, Yajnik CS (2007) Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50:63–67

    Article  PubMed  CAS  Google Scholar 

  21. 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 US participants of European and African descent. Diabetologia 50:1621–1630

    Article  PubMed  CAS  Google Scholar 

  22. Guo T, Hanson RL, Traurig M, Muller YL, Ma L, Mack J, Kobes S, Knowler WC, Bogardus C, Baier LJ (2007) TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3, 501 individuals. Diabetes 56:3082–3088

    Article  PubMed  CAS  Google Scholar 

  23. Wang J, Kuusisto J, Vanttinen M, Kuulasmaa T, Lindstrom J, Tuomilehto J, Uusitupa M, Laakso M (2007) Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia 50:1192–1200

    Article  PubMed  CAS  Google Scholar 

  24. Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger H, Stefan N, Haring HU, Fritsche A (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601

    Article  PubMed  CAS  Google Scholar 

  25. Loos RJ, Franks PW, Francis RW, Barroso I, Gribble FM, Savage DB, Ong KK, O’Rahilly S, Wareham NJ (2007) TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. Diabetes 56:1943–1947

    Article  PubMed  CAS  Google Scholar 

  26. Dahlgren A, Zethelius B, Jensevik K, Syvanen AC, Berne C (2007) Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men. Diabetologia 50:1852–1857

    Article  PubMed  CAS  Google Scholar 

  27. Cauchi S, Proenca C, Choquet H, Gaget S, De Graeve F, Marre M, Balkau B, Tichet J, Meyre D, Vaxillaire M et al (2008) Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study. J Mol Med 86:341–348

    Article  PubMed  CAS  Google Scholar 

  28. Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, Froguel P, Kadowaki T (2007) Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia 50:2461–2466

    Article  PubMed  CAS  Google Scholar 

  29. Palmer ND, Goodarzi MO, Langefeld CD, Ziegler J, Norris JM, Haffner SM, Bryer-Ash M, Bergman RN, Wagenknecht LE, Taylor KD et al (2008) Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the insulin resistance atherosclerosis family study. Diabetes 57:1093–1100

    Article  PubMed  CAS  Google Scholar 

  30. Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI et al (2007) Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes 56:3101–3104

    Article  PubMed  CAS  Google Scholar 

  31. Stancakova A, Pihlajamaki J, Kuusisto J, Stefan N, Fritsche A, Haring H, Andreozzi F, Succurro E, Sesti G, Boesgaard TW et al (2008) Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance. J Clin Endocrinol Metab 93:1924–1930

    Article  PubMed  CAS  Google Scholar 

  32. Grarup N, Rose CS, Andersson EA, Andersen G, Nielsen AL, Albrechtsen A, Clausen JO, Rasmussen SS, Jorgensen T, Sandbaek A et al (2007) Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes 56:3105–3111

    Article  PubMed  CAS  Google Scholar 

  33. Staiger H, Machicao F, Stefan N, Tschritter O, Thamer C, Kantartzis K, Schafer SA, Kirchhoff K, Fritsche A, Haring HU (2007) Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function. PLoS ONE 2:e832

    Article  PubMed  CAS  Google Scholar 

  34. Staiger H, Stancakova A, Zilinskaite J, Vanttinen M, Hansen T, Marini MA, Hammarstedt A, Jansson PA, Sesti G, Smith U et al (2008) A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study. Diabetes 57:514–517

    Article  PubMed  CAS  Google Scholar 

  35. Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, Smith U, Stefan N, Fritsche A, Haring H et al (2008) The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients-the EUGENE2 study. Diabetologia 51:816–820

    Article  PubMed  CAS  Google Scholar 

  36. Bouchard C (1994) Genetic epidemiology, association and sib-pair linkage: results from the Quebec Family Study. In: Bray G, Ryan D (eds) Molecular and genetic aspects of obesity. Louisiana State University Press, Baton Rouge, pp 470–481

    Google Scholar 

  37. Rice T, Nadeau A, Perusse L, Bouchard C, Rao DC (1996) Familial correlations in the Quebec family study: cross-trait familial resemblance for body fat with plasma glucose and insulin. Diabetologia 39:1357–1364

    Article  PubMed  CAS  Google Scholar 

  38. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  PubMed  CAS  Google Scholar 

  39. Cederholm J, Wibell L (1990) Insulin release and peripheral sensitivity at the oral glucose tolerance test. Diabetes Res Clin Pract 10:167–175

    Article  PubMed  CAS  Google Scholar 

  40. Bergstrom RW, Wahl PW, Leonetti DL, Fujimoto WY (1990) Association of fasting glucose levels with a delayed secretion of insulin after oral glucose in subjects with glucose intolerance. J Clin Endocrinol Metab 71:1447–1453

    Article  PubMed  CAS  Google Scholar 

  41. Seltzer HS, Allen EW, Herron AL Jr, Brennan MT (1967) Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest 46:323–335

    Article  PubMed  CAS  Google Scholar 

  42. Bergman RN, Ader M, Huecking K, Van Citters G (2002) Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes 51(suppl 1):S212–S220

    Article  PubMed  CAS  Google Scholar 

  43. Hanson RL, Pratley RE, Bogardus C, Narayan KM, Roumain JM, Imperatore G, Fagot-Campagna A, Pettitt DJ, Bennett PH, Knowler WC (2000) Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 151:190–198

    PubMed  CAS  Google Scholar 

  44. Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301

    Article  PubMed  CAS  Google Scholar 

  45. Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14:143–149

    PubMed  CAS  Google Scholar 

  46. Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322

    Article  PubMed  CAS  Google Scholar 

  47. Frayling TM (2007) A new era in finding Type 2 diabetes genes-the unusual suspects. Diabet Med 24:696–701

    Article  PubMed  CAS  Google Scholar 

  48. Schafer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, t’Hart LM, Nijpels G et al (2007) Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 50:2443–2450

    Article  PubMed  CAS  Google Scholar 

  49. Florez JC (2008) Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51:1100–1110

    Article  PubMed  CAS  Google Scholar 

  50. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The Quebec Family Study was supported over the years by multiple grants from the Medical Research Council of Canada and the Canadian Institutes for Health Research (PG-11811, MT-13960 and GR-15187) as well as other agencies. This work was supported by grant from the Canadian Institutes of Health Research (CIHR)-New Emerging Team Program (NET) (#OHN-63276). S-M Ruchat is supported by a scholarship from the Canadian Diabetes Association. C. Bouchard is partially funded by the Gary A. Bray Chair in Nutrition. Thanks are expressed to Dr G. Theriault and to G. Fournier, L. Allard, M. Chagnon and C. Leblanc for their contributions to the recruitment and data collection of QFS.

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Correspondence to Louis Pérusse.

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Ruchat, SM., Elks, C.E., Loos, R.J.F. et al. Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies. Acta Diabetol 46, 217–226 (2009). https://doi.org/10.1007/s00592-008-0080-5

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  • DOI: https://doi.org/10.1007/s00592-008-0080-5

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