Skip to main content
SpringerLink
Log in

Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

An Erratum to this article was published on 31 May 2012

Abstract

Prostaglandins are potent modulators of insulin sensitivity. We systemically evaluated the association of 61 tag single-nucleotide polymorphisms (SNP) in 14 genes involved in prostaglandin metabolism with type 2 diabetes. Among all genotyped SNPs, rs10483032 in the CBR3 (carbonyl reductase 3) gene, which encodes for an enzyme converting prostaglandin E2 to prostaglandin F2α, was associated with type 2 diabetes in 760 type 2 diabetic cases and 760 controls (stage-1 study) (P = 2.0 × 10−4). The association was validated in 1,615 cases and 1,162 controls (stage-2 study) (P = 0.009). The A allele at rs10483032 was associated with increased risk of type 2 diabetes (odds ratio = 1.29; 95% confidence interval = 1.14–1.47; combined P < 0.0001). The association was externally validated in the Finland–United States Investigation of NIDDM Genetics (FUSION) study (P = 3.7 × 10−4). The risk A allele was associated with higher homeostasis model assessment of insulin resistance (HOMA-IR) in 1,012 non-diabetic controls and 1,138 non-diabetic subjects from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. CBR3 gene expression in human abdominal adipose tissue was negatively associated with fasting insulin and HOMA-IR. CBR3 gene expression increased during differentiation of 3T3-L1 preadipocytes into adipocytes. Knockdown of CBR3 in 3T3-L1 preadipocytes enhanced adipogenesis and peroxisome proliferator–activator receptor–γ response element reporter activity. Our results indicated that genetic polymorphism in the CBR3 gene conferred risk of type 2 diabetes and insulin resistance in Chinese. The association was probably mediated through modulation of adipogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875

    Article  PubMed  CAS  Google Scholar 

  2. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83:803–812

    Article  PubMed  CAS  Google Scholar 

  3. Chou WL, Chuang LM, Chou CC, Wang AH, Lawson JA, FitzGerald GA, Chang ZF (2007) Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor gamma activation. J Biol Chem 282:18162–18172

    Article  PubMed  CAS  Google Scholar 

  4. Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nüsing RM et al (2010) Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328:1158–1161

    Article  PubMed  CAS  Google Scholar 

  5. Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee HY, Samuel VT, Shulman GI, Kim KH et al (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15:159–168

    Article  PubMed  CAS  Google Scholar 

  6. Richelsen B, Pedersen SB (1987) Antilipolytic effect of prostaglandin E2 in perfused rat adipocytes. Endocrinology 121:1221–1226

    Article  PubMed  CAS  Google Scholar 

  7. Ragolia L, Palaia T, Hall CE, Maesaka JK, Eguchi N, Urade Y (2005) Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice. J Biol Chem 280:29946–29955

    Article  PubMed  CAS  Google Scholar 

  8. Fujitani Y, Aritake K, Kanaoka Y, Goto T, Takahashi N, Fujimori K, Kawada T (2010) Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2 in vivo. FEBS J 277:1410–1419

    Article  PubMed  CAS  Google Scholar 

  9. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, Miller YI (2009) 12/15-Lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice. PLoS One 4:e7250

    Article  PubMed  Google Scholar 

  10. González-Ortiz M, Martínez-Abundis E, Balcázar-Muñoz BR, Robles-Cervantes JA (2010) Inhibition of cyclooxygenase-1 or -2 on insulin sensitivity in healthy subjects. Horm Metab Res 33:250–253

    Article  Google Scholar 

  11. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, Miller YI (2008) Selective COX2 inhibition improves whole body and muscular insulin resistance in fructose-fed rats. Eur J Clin Invest 38:812–819

    Article  Google Scholar 

  12. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197

    Google Scholar 

  13. Chang YC, Chang TJ, Jiang YD, Kuo SS, Lee KC, Chiu KC, Chuang LM (2007) Association study of the genetic polymorphisms of the transcription factor7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 56:2631–2637

    Article  PubMed  CAS  Google Scholar 

  14. Chang CH, Shau WY, Jiang YD, Li HY, Chang TJ, Sheu WH-H, Kwok CF, Ho LT, Chuang LM (2010) Type 2 diabetes prevalence and incidence among adults in Taiwan during 1999–2004: a national health insurance data set study. Diabet Med 27:636–643

    Article  PubMed  CAS  Google Scholar 

  15. American Diabetes Association (2004) Standards of medical care in diabetes. Diabetes Care 27(Suppl 1):S15–S35

    Google Scholar 

  16. Chang TJ, Liu PH, Liang YC, Chang YC, Jiang YD, LI HY, Lo MT, Chen HS, Chuang LM (2011) Genetic predisposition and non-genetic risk factors of thiazolidinedione-related leg edema in patients with type 2 diabetes. Pharmagonent Genomics 21:829–36

    Article  CAS  Google Scholar 

  17. Lin JW, Chang YC, Li HY, Chien YF, Wu MY, Hsieh YC, Chen YJ, Hwang JJ, Chuang LM (2009) Cross-sectional validation of diabetes risk scores for predicting diabetes, metabolic syndrome, and chronic kidney disease in Taiwanese. Diabetes Care 32:2294–2296

    Article  PubMed  Google Scholar 

  18. Ranade K, Wu KD, Risch N, Olivier M, Pei D, Hsiao CF, Chuang LM, Ho LT, Jorgenson E, Pesich R et al (2001) Genetic variation in aldosterone synthase predicts plasma glucose levels. Proc Natl Acad Sci USA 98:13219–13224

    Article  PubMed  CAS  Google Scholar 

  19. 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 8:412–419

    Article  Google Scholar 

  20. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  21. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  Google Scholar 

  22. Johnson AD, O’Donnell CJ (2009) An open access database of genome-wide association results. BMC Med Genet 10:6

    Article  PubMed  Google Scholar 

  23. Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306

    Article  PubMed  CAS  Google Scholar 

  24. Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association mapping studies of complex traits. Bioinfromatics 19:149–150

    Article  CAS  Google Scholar 

  25. 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 

  26. Nitz I, Fisher E, Grallert H, Li Y, Gieger C, Rubin D, Boeing H, Spranger J, Lindner I, Schreiber S et al (2007) Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations. J Clin Endocrinol Metab 92:3183–3188

    Article  PubMed  CAS  Google Scholar 

  27. Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Döring F, Schrezenmeir J (2007) Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome. Mol Nutr Food Res 51:1447–1451

    Article  PubMed  CAS  Google Scholar 

  28. Konheim YL, Wolford JK (2003) Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima India. Hum Genet 113:377–381

    Article  PubMed  CAS  Google Scholar 

  29. Pilka ES, Niesen FH, Lee WH, El-Hawari Y, Dunford JE, Kochan G, Wsol V, Martin HJ, Maser E, Oppermann U (2009) Structural basis for substrate specificity in human monomeric carbonyl reductases. PLoS One 4:e7113

    Article  PubMed  Google Scholar 

  30. Forrest GL, Gonzalez B (2000) Carbonyl reductase. Chem Biol Interact 129:21–40

    Article  PubMed  CAS  Google Scholar 

  31. Sanchez-Alavez M, Klein I, Brownell SE, Tabarean IV, Davis CN, Conti B, Bartfai T (2007) Night eating and obesity in the EP3R-deficient mouse. Proc Natl Acad Sci U S A 104:3009–3014

    Article  PubMed  CAS  Google Scholar 

  32. Miller CW, Casimir DA, Ntambi JM (1996) The mechanism of inhibition of 3T3-L1 preadipocyte differentiation by prostaglandin F2alpha. Endocrinology 137:5641–5650

    Article  PubMed  CAS  Google Scholar 

  33. Wang P, Renes J, Bouwman F, Bunschoten A, Mariman E, Keijer J (2007) Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression. Diabetologia 50:654–665

    Article  PubMed  Google Scholar 

  34. Dahlman I, Linder K, Arvidsson Nordstrom E, Andersson I, Liden J, Verdich C, Sorensen TI, Arner P (2005) Changes in adipose tissue gene expression with energy-restricted diets in obese women. Am J Clin Nutr 81:1275–1285

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank all the patients for their cooperation in this study. The authors would like to thank National Genotyping Center of National Research Program for Genomic Medicine, National Science Council, for the support in SNP genotyping. This work was supported by the grants of the National Research Program for Genomic Medicine [NSC97-3112-B-002-040, NSC98-3112-B-001-037] from the National Science Council, Taiwan.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan

    Yi-Cheng Chang, Yun-Chih Tsai, Shyang-Rong Shih, Juey-Jen Hwang, Shu-Huei Tsai & Lee-Ming Chuang

  2. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Yi-Cheng Chang

  3. Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan

    Pi-Hua Liu

  4. Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan

    Pi-Hua Liu

  5. Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan

    Yen-Feng Chiu

  6. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

    Low-Tone Ho

  7. Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Low-Tone Ho

  8. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Low-Tone Ho

  9. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Wen-Jane Lee

  10. Division of Endocrinology and Metabolism, Tri-Service General Hospital, Taipei, Taiwan

    Chieh-Hua Lu

  11. Division of Cardiovascular Medicine, Falk Cardiovascular Research Building, Stanford University School of Medicine, Stanford, CA, USA

    Thomas Quertermous

  12. John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    J. David Curb

  13. Department of Surgery, Ming-Sheng General Hospital, Taoyuan, Taiwan

    Wei-Jei Lee

  14. Department of General Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Po-Chu Lee

  15. Department of Laboratory Medicine, National Taiwan University Hospital Yunlin branch, Doaliao, Taiwan

    You-Han He

  16. Department of Family Medicine, Buddhist Tzu Chi General Hospital, Hualien’, Taiwan

    Jih-I Yeh

  17. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Lee-Ming Chuang

Authors
  1. Yi-Cheng Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pi-Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun-Chih Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yen-Feng Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shyang-Rong Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Low-Tone Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-Jane Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chieh-Hua Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Quertermous
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. David Curb
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei-Jei Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Po-Chu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. You-Han He
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jih-I Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Juey-Jen Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shu-Huei Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Lee-Ming Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lee-Ming Chuang.

Additional information

Yi-Cheng Chang and Pi-Hua Liu contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 265 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, YC., Liu, PH., Tsai, YC. et al. Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis. J Mol Med 90, 847–858 (2012). https://doi.org/10.1007/s00109-012-0898-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0898-8

Keywords

Search

Navigation