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Elevated HbA1c Is an Independent Predictor of Aggressive Clinical Behavior in Patients with Colorectal Cancer: A Case-Control Study

Digestive Diseases and Sciences volume 53, pages 2486–2494 (2008)Cite this article

Abstract

Aim The aim of this study was to seek an association between the control of type 2 diabetes mellitus (T2DM), as determined by hemoglobin A1c (HbA1c) levels, and the outcome of colorectal cancer (CRC). Methods We performed a retrospective review of patients with T2DM who had CRC diagnosed between 1997 and 2001. We defined well-controlled T2DM as HbA1c < 7.5% and poorly controlled T2DM as HbA1c ≥ 7.5%. A group of age- and gender-matched patients who had CRC without T2DM were used as controls. Forty clinical factors were reviewed, and those associated with poor clinical outcome in each group were examined by univariate analysis (UA) and by the maximum likelihood analysis of logistic regression to determine the independent predictors of cancer outcome. Results We identified 155 patients with T2DM and CRC, and 114 control patients who had CRC without T2DM. We found no significant differences in any clinical factor by UA between the patients with well-controlled T2DM and the patients who had CRC without T2DM. Compared to both of those patients groups, in contrast, the patients with poorly controlled T2DM had more right-sided CRCs (P = 0.04, OR = 2, 95% CI = 1–4.1), more advanced CRCs (P = 0.02, OR = 2.1, 95% CI = 1–4.4), a younger age of presentation (P = 0.05), greater use of exogenous insulin (P = 0.002), and a poorer 5-year survival (P = 0.001) by UA. Logistic regression showed that poorly controlled T2DM independently predicted the early onset of CRC, a more advanced stage at the time of presentation, poorer 5-year survival, and an increased incidence of right-sided CRCs. Conclusions In patients with T2DM who have CRC, poor glycemic control is associated with a clinically aggressive course for the cancer.

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References

  1. Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney EF, Rios-Burrows N, Mokdad AH, Ford ES, Imperatore G, Narayan KM (2004) The evolving diabetes burden in the United States. Ann Intern Med 140:945–950

    PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130

    PubMed  Article  Google Scholar 

  3. Schulze MB, Hu FB (2005) Primary prevention of diabetes: what can be done and how much can be prevented? Annu Rev Public Health 26:445–467. doi:10.1146/annurev.publhealth.26.021304.144532

    PubMed  Article  Google Scholar 

  4. Giovannucci E (2002) Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 31:925–943. doi:10.1016/S0889-8553(02)00057-2

    PubMed  Article  Google Scholar 

  5. Fung TT, Schulze M, Manson JE, Willett WC, Hu FB (2004) Dietary patterns, meat intake, and the risk of type 2 diabetes in women. Arch Intern Med 164:2235–2240. doi:10.1001/archinte.164.20.2235

    PubMed  Article  Google Scholar 

  6. Will JC, Galuska DA, Vinicor F, Calle EE (1998) Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 147:816–825

    PubMed  CAS  Google Scholar 

  7. Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, Speizer FE, Giovannucci E (1999) Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 91:542–547. doi:10.1093/jnci/91.6.542

    PubMed  Article  CAS  Google Scholar 

  8. Limburg PJ, Vierkant RA, Fredericksen ZS, Leibson CL, Rizza RA, Gupta AK, Ahlquist DA, Melton LJ 3rd, Sellers TA, Cerhan JR (2006) Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol 101:1872–1879. doi:10.1111/j.1572-0241.2006.00725.x

    PubMed  Article  Google Scholar 

  9. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N (2004) Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-Norfolk study. Cancer Epidemiol Biomarkers Prev 13:915–919

    PubMed  Google Scholar 

  10. Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SE, Giovannucci E (2005) A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 14:850–855. doi:10.1158/1055-9965.EPI-04-0661

    PubMed  Article  CAS  Google Scholar 

  11. Giovannucci E (1995) Insulin and colon cancer. Cancer Causes Control 6:164–179. doi:10.1007/BF00052777

    PubMed  Article  CAS  Google Scholar 

  12. Tran TT, Medline A, Bruce WR (1996) Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 5:1013–1015

    PubMed  CAS  Google Scholar 

  13. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J (1995) Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 95:1897–1905. doi:10.1172/JCI117871

    PubMed  Article  CAS  Google Scholar 

  14. Corpet DE, Jacquinet C, Peiffer G, Taché S (1997) Insulin injections promote the growth of aberrant crypt foci in the colon of rats. Nutr Cancer 27:316–320

    PubMed  CAS  Google Scholar 

  15. Koenuma M, Yamori T, Tsuruo T (1989) Insulin and insulin-like growth factor 1 stimulate proliferation of metastatic variants of colon carcinoma 26. Jpn J Cancer Res 80:51–58

    PubMed  CAS  Google Scholar 

  16. Nilsen TI, Vatten LJ (2001) Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br J Cancer 84:417–422. doi:10.1054/bjoc.2000.1582

    PubMed  Article  CAS  Google Scholar 

  17. Saydah SH, Platz EA, Rifai N, Pollak MN, Brancati FL, Helzlsouer KJ (2003) Association of markers of insulin and glucose control with subsequent colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 12:412–418

    PubMed  CAS  Google Scholar 

  18. Bunn HF, Gabbay KH, Gallop PM (1978) The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200:21–27. doi:10.1126/science.635569

    PubMed  Article  CAS  Google Scholar 

  19. Davidson MB, Schriger DL, Peters AL, Lorber B (2000) Revisiting the oral glucose tolerance test criterion for the diagnosis of diabetes. J Gen Intern Med 15:551–555. doi:10.1046/j.1525-1497.2000.08024.x

    PubMed  Article  CAS  Google Scholar 

  20. Goldstein DE, Little RR, Wiedmeyer HM, England JD, McKenzie EM (1986) Glycated hemoglobin: methodologies and clinical applications. Clin Chem 32:B64–B70

    PubMed  CAS  Google Scholar 

  21. Miller DR, Safford MM, Pogach LM (2004) Who has diabetes? Best estimates of diabetes prevalence in the Department of Veterans Affairs based on computerized patient data. Diabetes Care 27(Suppl 2):B10–B21. doi:10.2337/diacare.27.suppl_2.B10

    PubMed  Article  Google Scholar 

  22. American Diabetes Association (2003) Standards of medical care for patients with diabetes mellitus. Diabetes Care 26(Suppl 1):S33-S50. doi:10.2337/diacare.26.2007.S33

    Google Scholar 

  23. [No authors listed] (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853. doi:10.1016/S0140-6736(98)07019-6

    Article  Google Scholar 

  24. Delmas-Beauvieux MC, Peuchant E, Thomas MJ, Dubourg L, Pinto AP, Clerc M, Gin H (1998) The place of electron spin resonance methods in the detection of oxidative stress in type 2 diabetes with poor glycemic control. Clin Biochem 31:221–228. doi:10.1016/S0009-9120(98)00019-8

    PubMed  Article  CAS  Google Scholar 

  25. Stamp D, Zhang XM, Medline A, Bruce WR, Archer MC (1993) Sucrose enhancement of the early steps of colon carcinogenesis in mice. Carcinogenesis 14:777–779. doi:10.1093/carcin/14.4.777

    PubMed  Article  CAS  Google Scholar 

  26. Bird RP, Medline A, Furrer R, Bruce WR (1985) Toxicity of orally administered fat to the colonic epithelium of mice. Carcinogenesis 6:1063–1066. doi:10.1093/carcin/6.7.1063

    PubMed  Article  CAS  Google Scholar 

  27. Bird CL, Ingles SA, Frankl HD, Lee ER, Longnecker MP, Haile RW (1996) Serum lipids and adenomas of the left colon and rectum. Cancer Epidemiol Biomarkers Prev 5:607–612

    PubMed  CAS  Google Scholar 

  28. Trevisan M, Liu J, Muti P, Misciagna G, Menotti A, Fucci F, Risk Factors and Life Expectancy Research Group (2001) Markers of insulin resistance and colorectal cancer mortality. Cancer Epidemiol Biomarkers Prev 10:937–941

    PubMed  CAS  Google Scholar 

  29. Yamada K, Araki S, Tamura M, Sakai I, Takahashi Y, Kashihara H, Kono S (1998) Relation of serum total cholesterol, serum triglycerides and fasting plasma glucose to colorectal carcinoma in situ. Int J Epidemiol 27:794–798. doi:10.1093/ije/27.5.794

    PubMed  Article  CAS  Google Scholar 

  30. McKeown-Eyssen G (1994) Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 3:687–695

    PubMed  CAS  Google Scholar 

  31. Harris MI, Klein R, Welborn TA, Knuiman MW (1992) Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 15:815–819. doi:10.2337/diacare.15.7.815

    PubMed  Article  CAS  Google Scholar 

  32. Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131:3109S–3120S

    PubMed  CAS  Google Scholar 

  33. Sandhu MS, Dunger DB, Giovannucci EL (2002) Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94:972–980

    PubMed  CAS  Google Scholar 

  34. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353. doi:10.1016/S0140-6736(04)16044-3

    PubMed  Article  CAS  Google Scholar 

  35. Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman M, Tracy RP, Dobs A, Savage PJ (1999) Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 91:1147–1154. doi:10.1093/jnci/91.13.1147

    PubMed  Article  CAS  Google Scholar 

  36. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ (1999) Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91:620–625. doi:10.1093/jnci/91.7.620

    PubMed  Article  CAS  Google Scholar 

  37. Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E (2000) Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92:1592–1600. doi:10.1093/jnci/92.19.1592

    PubMed  Article  CAS  Google Scholar 

  38. Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ (2004) A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 96:546–553

    PubMed  CAS  Google Scholar 

  39. Lyons TJ, Neel RL, Simpson CG, Moore VA, Van Syoc DL, Knowles JR, Salamanca VP (1997) East meets West: a comparison of eastern block/western aeromedical practices. Aviat Space Environ Med 68:1150–1153

    PubMed  CAS  Google Scholar 

  40. Rafter JJ, Eng VW, Furrer R, Medline A, Bruce WR (1986) Effects of calcium and pH on the mucosal damage produced by deoxycholic acid in the rat colon. Gut 27:1320–1329. doi:10.1136/gut.27.11.1320

    PubMed  Article  CAS  Google Scholar 

  41. Stadler J, Yeung KS, Furrer R, Marcon N, Himal HS, Bruce WR (1988) Proliferative activity of rectal mucosa and soluble fecal bile acids in patients with normal colons and in patients with colonic polyps or cancer. Cancer Lett 38:315–320. doi:10.1016/0304-3835(88)90023-7

    PubMed  Article  CAS  Google Scholar 

  42. Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ, Macdonald JS, Benson AB 3rd, Fuchs CS (2003) Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 21:433–440. doi:10.1200/JCO.2003.07.125

    PubMed  Article  Google Scholar 

  43. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 159:1160–1167. doi:10.1093/aje/kwh161

    PubMed  Article  Google Scholar 

  44. Liu LU, Holt PR, Krivosheyev V, Moss SF (1999) Human right and left colon differ in epithelial cell apoptosis and in expression of Bak, a pro-apoptotic Bcl-2 homologue. Gut 45:45–50

    PubMed  CAS  Article  Google Scholar 

  45. Yoshida I, Suzuki A, Vallée M, Matano Y, Masunaga T, Zenda T, Shinozaki K, Okada T (2006) Serum insulin levels and the prevalence of adenomatous and hyperplastic polyps in the proximal colon. Clin Gastroenterol Hepatol 4:1225–1231. doi:10.1016/j.cgh.2006.07.002

    PubMed  Article  CAS  Google Scholar 

  46. Sheehan KM, Sheahan K, O’Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257. doi:10.1001/jama.282.13.1254

    PubMed  Article  CAS  Google Scholar 

  47. Yang YX, Hennessy S, Lewis JD (2004) Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 127:1044–1050. doi:10.1053/j.gastro.2004.07.011

    PubMed  Article  CAS  Google Scholar 

  48. Singh SM, Paszat LF, Li C, He J, Vinden C, Rabeneck L (2004) Association of socioeconomic status and receipt of colorectal cancer investigations: a population-based retrospective cohort study. CMAJ 171:461–465. doi:10.1503/cmaj.1031921

    PubMed  Google Scholar 

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Acknowledgment

This study was funded entirely by the Dallas Veterans Affairs Medical Center, TX, through existing intramural funds and salary support.

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Affiliations

  1. Department of Internal Medicine, Dallas Veterans Affairs Medical Center, 4500 S. Lancaster Road (111B1), Dallas, TX, 75216, USA

    Ali A. Siddiqui, Stuart J. Spechler, Serag Dredar & Byron Cryer

  2. Division of GI/Endocrine Surgery, University of Texas Southwestern Medical School, Dallas, TX, USA

    Ali A. Siddiqui & Sergio Huerta

  3. The Texas Data Mining Research Institute, Tarleton State University, Stephenville, TX, USA

    Bertis B. Little

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  1. Ali A. Siddiqui
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  2. Stuart J. Spechler
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Correspondence to Ali A. Siddiqui.

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Siddiqui, A.A., Spechler, S.J., Huerta, S. et al. Elevated HbA1c Is an Independent Predictor of Aggressive Clinical Behavior in Patients with Colorectal Cancer: A Case-Control Study. Dig Dis Sci 53, 2486–2494 (2008). https://doi.org/10.1007/s10620-008-0264-4

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  • DOI: https://doi.org/10.1007/s10620-008-0264-4

Keywords

  • Colorectal cancer
  • Diabetes mellitus type 2
  • Epidemiology
  • Insulin-like growth factor I