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• W2014000186 abstract "Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention. Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention. Recent evidence has indicated that obesity is associated with an increased incidence or mortality rate for a number of cancers. Of the top 5 causes of cancer mortality in the United States, including those of the lung, colon, breast, prostate, and pancreas, obesity is likely to play an important role in all but lung cancer. Obesity has a complex relationship with premenopausal breast cancer, but it clearly increases the risk of postmenopausal breast cancer, which is most likely caused primarily by increasing serum concentrations of bioavailable estradiol. The role of obesity for cancers of the colon, prostate, and pancreas will be addressed in this review. Specifically, this review will focus on how the major metabolic consequences of excess energy consumption and obesity may influence carcinogenesis at these sites.Colon CancerObesityThe relationship between body mass index (BMI) and increased risk of colon cancer has been well studied. An association is quite consistent and is now generally accepted.1Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence.J Nutr. 2001; 131: 3109S-3120SPubMed Google Scholar In most studies of men, obesity is associated with approximately a relative risk (RR) of 1.5 to 2.0 compared with a low or normal BMI. However, for unclear reasons, this association has been generally stronger for men than for women. This difference by sex was illustrated in the recent European Prospective Investigation Into Cancer and Nutrition (EPIC) study. Consistent with other studies, in the EPIC, a 55% increased risk of colon cancer was observed between high and low quintiles of BMI in men, but no significant association was observed in women.2Pischon T. Lahmann P.H. Boeing H. Friedenreich C. Norat T. Tjonneland A. Halkjaer J. Overvad K. Clavel-Chapelon F. Boutron-Ruault M.C. Guernec G. Bergmann M.M. Linseisen J. Becker N. Trichopoulou A. Trichopoulos D. Sieri S. Palli D. Tumino R. Vineis P. Panico S. Peeters P.H. Bueno-de-Mesquita H.B. Boshuizen H.C. Van Guelpen B. Palmqvist R. Berglund G. Gonzalez C.A. Dorronsoro M. Barricarte A. Navarro C. Martinez C. Quiros J.R. Roddam A. Allen N. Bingham S. Khaw K.T. Ferrari P. Kaaks R. Slimani N. Riboli E. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).J Natl Cancer Inst. 2006; 98: 920-931Crossref PubMed Scopus (218) Google Scholar In most studies that have considered anthropometric measures of adipose distribution in addition to BMI, the association between waist circumference or waist-to-hip ratio and colon cancer risk has generally been more consistent than that for BMI.3Schoen R.E. Tangen C.M. Kuller L.H. Burke G.L. Cushman M. Tracy R.P. Dobs A. Savage P.J. Increased blood glucose and insulin, body size, and incident colorectal cancer.J Natl Cancer Inst. 1999; 91: 1147-1154Crossref PubMed Google Scholar, 4Giovannucci E. Ascherio A. Rimm E.B. Colditz G.A. Stampfer M.J. Willett W.C. Physical activity, obesity, and risk for colon cancer and adenoma in men.Ann Intern Med. 1995; 122: 327-334Crossref PubMed Google Scholar, 5Bostick R.M. Potter J.D. Kushi L.H. Sellers T.A. Steinmetz K.A. McKenzie D.R. Gapstur S.M. Folsom A.R. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States).Cancer Causes Control. 1994; 5: 38-52Crossref PubMed Google Scholar, 6Martinez M.E. Giovannucci E. Spiegelman D. Stampfer M.J. Hunter D.J. Speizer F.E. Willett W.C. Colditz G.A. Physical activity, body size, and colorectal cancer in women.Am J Epidemiol. 1996; 143 (abstr): S73Crossref PubMed Google Scholar, 7Russo A. Franceschi S. La Vecchia C. Dal Maso L. Montella M. Conti E. Giacosa A. Falcini F. Negri E. Body size and colorectal cancer risk.Int J Cancer. 1998; 78: 161-165Crossref PubMed Scopus (90) Google Scholar In fact, unlike for BMI, clearer associations between waist circumference and colon cancer risk have been observed for women.2Pischon T. Lahmann P.H. Boeing H. Friedenreich C. Norat T. Tjonneland A. Halkjaer J. Overvad K. Clavel-Chapelon F. Boutron-Ruault M.C. Guernec G. Bergmann M.M. Linseisen J. Becker N. Trichopoulou A. Trichopoulos D. Sieri S. Palli D. Tumino R. Vineis P. Panico S. Peeters P.H. Bueno-de-Mesquita H.B. Boshuizen H.C. Van Guelpen B. Palmqvist R. Berglund G. Gonzalez C.A. Dorronsoro M. Barricarte A. Navarro C. Martinez C. Quiros J.R. Roddam A. Allen N. Bingham S. Khaw K.T. Ferrari P. Kaaks R. Slimani N. Riboli E. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).J Natl Cancer Inst. 2006; 98: 920-931Crossref PubMed Scopus (218) Google Scholar, 5Bostick R.M. Potter J.D. Kushi L.H. Sellers T.A. Steinmetz K.A. McKenzie D.R. Gapstur S.M. Folsom A.R. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States).Cancer Causes Control. 1994; 5: 38-52Crossref PubMed Google Scholar, 6Martinez M.E. Giovannucci E. Spiegelman D. Stampfer M.J. Hunter D.J. Speizer F.E. Willett W.C. Colditz G.A. Physical activity, body size, and colorectal cancer in women.Am J Epidemiol. 1996; 143 (abstr): S73Crossref PubMed Google Scholar, 7Russo A. Franceschi S. La Vecchia C. Dal Maso L. Montella M. Conti E. Giacosa A. Falcini F. Negri E. Body size and colorectal cancer risk.Int J Cancer. 1998; 78: 161-165Crossref PubMed Scopus (90) Google Scholar, 8Giovannucci E. Colditz G.A. Stampfer M.J. Willett W.C. Physical activity, obesity, and risk of colorectal adenoma in women (United States).Cancer Causes Control. 1996; 7: 253-263Crossref PubMed Scopus (171) Google Scholar For example, in the aforementioned EPIC study, higher waist-to-hip ratio was indeed associated with an increased risk of colon cancer for women (RR, 1.52) as well as for men (RR, 1.51).2Pischon T. Lahmann P.H. Boeing H. Friedenreich C. Norat T. Tjonneland A. Halkjaer J. Overvad K. Clavel-Chapelon F. Boutron-Ruault M.C. Guernec G. Bergmann M.M. Linseisen J. Becker N. Trichopoulou A. Trichopoulos D. Sieri S. Palli D. Tumino R. Vineis P. Panico S. Peeters P.H. Bueno-de-Mesquita H.B. Boshuizen H.C. Van Guelpen B. Palmqvist R. Berglund G. Gonzalez C.A. Dorronsoro M. Barricarte A. Navarro C. Martinez C. Quiros J.R. Roddam A. Allen N. Bingham S. Khaw K.T. Ferrari P. Kaaks R. Slimani N. Riboli E. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).J Natl Cancer Inst. 2006; 98: 920-931Crossref PubMed Scopus (218) Google ScholarSimilarly, associations for circumference measures have been noted for large or advanced adenoma, the proximate precursor to most colon cancers.4Giovannucci E. Ascherio A. Rimm E.B. Colditz G.A. Stampfer M.J. Willett W.C. Physical activity, obesity, and risk for colon cancer and adenoma in men.Ann Intern Med. 1995; 122: 327-334Crossref PubMed Google Scholar, 8Giovannucci E. Colditz G.A. Stampfer M.J. Willett W.C. Physical activity, obesity, and risk of colorectal adenoma in women (United States).Cancer Causes Control. 1996; 7: 253-263Crossref PubMed Scopus (171) Google Scholar, 9Shinchi K. Kono S. Honjo S. Todoroki I. Sakurai Y. Imanishi K. Nishikawa H. Ogawa S. Katsurada M. Hirohata T. Obesity and adenomatous polyps of the sigmoid colon.Jpn J Cancer Res. 1994; 85: 479-484Crossref PubMed Google Scholar In one study that directly measured visceral fat accumulation through computerized tomography scanning, a strong association between visceral fat and colorectal adenoma was observed.10Otake S. Takeda H. Suzuki Y. Fukui T. Watanabe S. Ishihama K. Saito T. Togashi H. Nakamura T. Matsuzawa Y. Kawata S. Association of visceral fat accumulation and plasma adiponectin with colorectal adenoma: evidence for participation of insulin resistance.Clin Cancer Res. 2005; 11: 3642-3646Crossref PubMed Scopus (103) Google Scholar However, no association was observed with recurrent adenomas in another study using a similar approach.11Sass D.A. Schoen R.E. Weissfeld J.L. Weissfeld L. Thaete F.L. Kuller L.H. McAdams M. Lanza E. Schatzkin A. Relationship of visceral adipose tissue to recurrence of adenomatous polyps.Am J Gastroenterol. 2004; 99: 687-693Crossref PubMed Scopus (23) Google Scholar The lack of an association with recurrent adenomas probably reflects that adiposity promotes adenoma growth rather than increasing occurrence of this lesion.12Almendingen K. Hofstad B. Vatn M.H. Does high body fatness increase the risk of presence and growth of colorectal adenomas followed up in situ for 3 years?.Am J Gastroenterol. 2001; 96: 2238-2246Crossref PubMed Google Scholar Overall, the data strongly support that some metabolic characteristics associated with central or abdominal adiposity increases risk of colon cancer. Correspondingly, consistent evidence indicates that physical activity protects against colon cancer.8Giovannucci E. Colditz G.A. Stampfer M.J. Willett W.C. Physical activity, obesity, and risk of colorectal adenoma in women (United States).Cancer Causes Control. 1996; 7: 253-263Crossref PubMed Scopus (171) Google Scholar Neither BMI nor physical activity has been consistently associated with rectal cancer risk.Diabetes Mellitus and HyperglycemiaObesity and physical inactivity are strong risk factors for adult-onset or type 2 diabetes mellitus. Individuals with diabetes initially experience hyperglycemia and hyperinsulinemia, but insulin concentrations wane eventually from pancreatic β-cell depletion. If type 2 diabetes is associated with increased risk of colon cancer, this would provide some evidence that metabolic consequences associated with obesity and diabetes may play a role in colon cancer. Indeed, many studies have found that individuals with adult-onset diabetes mellitus are at increased risk of colon cancer. A recent metaanalysis of studies published through July 31, 2005, demonstrated a highly significant summary RR of 1.43 for colon cancer among diabetic individuals, with no heterogeneity among studies noted.13Larsson S.C. Orsini N. Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis.J Natl Cancer Inst. 2005; 97: 1679-1687Crossref PubMed Scopus (332) Google Scholar This association was observed for men and women and was consistent between case-control and cohort studies and between studies conducted in the United States and in Europe. A recent study confirmed this association in an Asian population, the Singapore Chinese.14Seow A. Yuan J.M. Koh W.P. Lee H.P. Yu M.C. Diabetes mellitus and risk of colorectal cancer in the Singapore Chinese Health Study.J Natl Cancer Inst. 2006; 98: 135-138Crossref PubMed Scopus (74) Google Scholar The association between type 2 diabetes and risk of colon adenoma has not been as well studied, but a recent study reported that diabetic individuals, especially those who are obese, have an increased risk of prevalent colon adenoma and particularly for advanced adenoma.15Elwing J.E. Gao F. Davidson N.O. Early D.S. Type 2 diabetes mellitus: the impact on colorectal adenoma risk in women.Am J Gastroenterol. 2006; 101: 1866-1871Crossref PubMed Scopus (41) Google Scholar Some studies have examined blood glucose levels in relation to colorectal cancer and adenoma in nondiabetic individuals. Most studies, although not all,16Platz E.A. Hankinson S.E. Rifai N. Colditz G.A. Speizer F.E. Giovannucci E. Glycosylated hemoglobin and risk of colorectal cancer and adenoma (United States).Cancer Causes Control. 1999; 10: 379-386Crossref PubMed Scopus (38) Google Scholar have found that hyperglycemia is associated with an increased risk of colon cancer.17Nilsen T.I. Vatten L.J. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis.Br J Cancer. 2001; 84: 417-422Crossref PubMed Scopus (170) Google Scholar, 18Trevisan M. Liu J. Muti P. Misciagna G. Menotti A. Fucci F. Risk Factors and Life Expectancy Research GroupMarkers of insulin resistance and colorectal cancer mortality.Cancer Epidemiol Biomarkers Prev. 2001; 10: 937-941PubMed Google Scholar, 19Saydah S.H. Loria C.M. Eberhardt M.S. Brancati F.L. Abnormal glucose tolerance and the risk of cancer death in the United States.Am J Epidemiol. 2003; 157: 1092-1100Crossref PubMed Scopus (95) Google Scholar, 20Colangelo L.A. Gapstur S.M. Gann P.H. Dyer A.R. Liu K. Colorectal cancer mortality and factors related to the insulin resistance syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 385-391PubMed Google Scholar, 21Saydah S.H. Platz E.A. Rifai N. Pollak M.N. Brancati F.L. Helzlsouer K.J. Association of markers of insulin and glucose control with subsequent colorectal cancer risk.Cancer Epidemiol Biomarkers Prev. 2003; 12: 412-418PubMed Google ScholarThe Metabolic Syndrome and HypertriglyceridemiaObesity, particularly visceral adiposity, physical inactivity, and insulin resistance are underlying factors in the etiology of the metabolic syndrome. Some studies have examined the metabolic syndrome in relation to risk of colon neoplasia. The specific criteria (based on standard or modified definitions of obesity, high blood pressure, high serum triglycerides, high blood glucose, and low serum high-density lipoprotein [HDL]-cholesterol) have varied across the studies. Although the results were not always statistically significant among the studies, most found that individuals with the metabolic syndrome had an elevated risk of developing colon cancer.18Trevisan M. Liu J. Muti P. Misciagna G. Menotti A. Fucci F. Risk Factors and Life Expectancy Research GroupMarkers of insulin resistance and colorectal cancer mortality.Cancer Epidemiol Biomarkers Prev. 2001; 10: 937-941PubMed Google Scholar, 20Colangelo L.A. Gapstur S.M. Gann P.H. Dyer A.R. Liu K. Colorectal cancer mortality and factors related to the insulin resistance syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 385-391PubMed Google Scholar, 22Ahmed R.L. Schmitz K.H. Anderson K.E. Rosamond W.D. Folsom A.R. The metabolic syndrome and risk of incident colorectal cancer.Cancer. 2006; 107: 28-36Crossref PubMed Scopus (125) Google Scholar, 23Bowers K. Albanes D. Limburg P. Pietinen P. Taylor P.R. Virtamo J. Stolzenberg-Solomon R. A prospective study of anthropometric and clinical measurements associated with insulin resistance syndrome and colorectal cancer in male smokers.Am J Epidemiol. 2006; 164: 652-654Crossref PubMed Scopus (57) Google ScholarHypertriglyceridemia is typically a component of the definition of metabolic syndrome24Tobey T.A. Greenfield M. Kraemer F. Reaven G.M. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man.Metabolism. 1981; 30: 165-171Abstract Full Text PDF PubMed Google Scholar and may be a particularly important component of this syndrome. In fact, a recent alternative definition of the metabolic syndrome, termed “the hypertriglyceridemic waist,” has been proposed for men based solely on waist circumference >90 cm and triglyceride levels >2.0 nmol/L.25Lemieux I. Pascot A. Couillard C. Lamarche B. Tchernof A. Almeras N. Bergeron J. Gaudet D. Tremblay G. Prudhomme D. Nadeau A. Despres J.P. Hypertriglyceridemic waist: a marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men?.Circulation. 2000; 102: 179-184Crossref PubMed Google Scholar The results for studies that have examined hypertriglyceridemia in relation to risk of colorectal or colon cancer have been inconsistent and only suggestive at best,3Schoen R.E. Tangen C.M. Kuller L.H. Burke G.L. Cushman M. Tracy R.P. Dobs A. Savage P.J. Increased blood glucose and insulin, body size, and incident colorectal cancer.J Natl Cancer Inst. 1999; 91: 1147-1154Crossref PubMed Google Scholar, 18Trevisan M. Liu J. Muti P. Misciagna G. Menotti A. Fucci F. Risk Factors and Life Expectancy Research GroupMarkers of insulin resistance and colorectal cancer mortality.Cancer Epidemiol Biomarkers Prev. 2001; 10: 937-941PubMed Google Scholar, 21Saydah S.H. Platz E.A. Rifai N. Pollak M.N. Brancati F.L. Helzlsouer K.J. Association of markers of insulin and glucose control with subsequent colorectal cancer risk.Cancer Epidemiol Biomarkers Prev. 2003; 12: 412-418PubMed Google Scholar, 22Ahmed R.L. Schmitz K.H. Anderson K.E. Rosamond W.D. Folsom A.R. The metabolic syndrome and risk of incident colorectal cancer.Cancer. 2006; 107: 28-36Crossref PubMed Scopus (125) Google Scholar, 26Tsushima M. Nomura A.M. Lee J. Stemmermann G.N. Prospective study of the association of serum triglyceride and glucose with colorectal cancer.Dig Dis Sci. 2005; 50: 499-505Crossref PubMed Scopus (18) Google Scholar but these studies have been hindered by small sample sizes or by long duration of follow-up after the blood assessment was taken. A Japanese case-control study reported that hypertriglyceridemia was associated with a 3-fold higher risk of colorectal carcinoma in situ in multivariate analysis.27Yamada K. Araki S. Tamura M. Saka Takahashi Y. Kashihara H. Kono S. Relation of serum total cholesterol, serum triglycerides and fasting plasma glucose to colorectal carcinoma in situ.Int J Epidemiol. 1998; 27 (iI): 794-798Crossref PubMed Scopus (78) Google Scholar Hypertriglyceridemia has also been associated with colorectal adenoma risk in studies conducted in diverse populations, including in Germany,28Bayerdorffer E. Mannes G.A. Richter W.O. Ochsenkuhn T. Seeholzer G. Kopke W. Wiebecke B. Paumgartner G. Decreased high-density lipoprotein cholesterol and increased low-density cholesterol levels in patients with colorectal adenomas.Ann Intern Med. 1993; 118: 481-487Crossref Google Scholar Korea,29Park S.K. Joo J.S. Kim D.H. Kim Y.E. Kang D. Yoo K.Y. Association of serum lipids and glucose with the risk of colorectal adenomatous polyp in men: a case-control study in Korea.J Korean Med Sci. 2000; 15: 690-695Crossref Google Scholar Japan,30Tabuchi M. Kitayama J. Nagawa H. Hypertriglyceridemia is positively correlated with the development of colorectal tubular adenoma in Japanese men.World J Gastroenterol. 2006; 12: 1261-1264Crossref Scopus (50) Google Scholar and China.31Wang Y.Y. Lin S.Y. Lai W.A. Liu P.H. Sheu W.H. Association between adenomas of rectosigmoid colon and metabolic syndrome features in a Chinese population.J Gastroenterol Hepatol. 2005; 20: 1410-1415Crossref Scopus (44) Google ScholarHyperinsulinemiaHyperinsulinemia has been hypothesized to be an underlying factor linking obesity, physical inactivity, type 2 diabetes mellitus, and certain factors associated with a Western dietary pattern as risk factors for colon neoplasia (Figure 1).32Giovannucci E. Insulin and colon cancer.Cancer Causes Control. 1995; 6: 164-179Crossref PubMed Scopus (486) Google Scholar Obesity and physical inactivity are the main determinants of insulin resistance and hyperinsulinemia (in the nondiabetic state). Independent of its influence on adiposity, physical activity increases insulin sensitivity and lowers circulating insulin.33Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer.Horm Metab Res. 2003; 35: 694-704Crossref PubMed Scopus (155) Google Scholar Insulin has growth-promoting properties and increases free insulin-like growth factor (IGF-I) levels,33Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer.Horm Metab Res. 2003; 35: 694-704Crossref PubMed Scopus (155) Google Scholar which is discussed below.Figure 1A model whereby nutritional factors affect colon cancer risk through an influence on the insulin and IGF-I axis. In this model, factors related to energy balance and diet influence growth hormone secretion, insulin resistance, and insulin secretion dependent on competent pancreatic β cells. Either an increase in IGF-I, or the IGF-I/IGFBP-III ratio, or insulin that decreases IGFBP-I and IGFBP-II could alter the levels of free or bioactive IGF-I, a stimulant of tumor growth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)A number of epidemiologic studies have now examined hyperinsulinemia assessed in several ways (eg, fasting, nonfasting, postglucose load, and C-peptide, an indicator of insulin secretion) in relation to risk of colon cancer or adenoma. The first report was in a cohort study3Schoen R.E. Tangen C.M. Kuller L.H. Burke G.L. Cushman M. Tracy R.P. Dobs A. Savage P.J. Increased blood glucose and insulin, body size, and incident colorectal cancer.J Natl Cancer Inst. 1999; 91: 1147-1154Crossref PubMed Google Scholar and found that fasting insulin was not related to an increased risk (RR, 1.2), but 2-hour insulin postglucose load level was related to a significantly increased risk (RR, 2.0). In a following prospective study of women in New York State, a 3-fold higher risk of colorectal cancer was observed in those in the top quartile of C-peptide,34Bonser A.M. Garcia-Webb P. C-peptide measurement: methods and clinical utility.Crit Rev Clin Lab Sci. 1984; 19: 297-352Crossref Google Scholar and a 4-fold higher risk was seen for colon cancer alone.35Kaaks R. Toniolo P. Akhmedkhanov A. Lukanova A. Biessy C. Dechaud H. Rinaldi S. Zeleniuch-Jacquotte A. Shore R.E. Riboli E. Serum C-peptide, insulin-like growth factor (IGF)-1, IGF-binding proteins, and colorectal cancer risk in women.J Natl Cancer Inst. 2000; 92: 1592-1600Crossref PubMed Google Scholar Another study in northern Sweden did not find an appreciably elevated risk associated with fasting and nonfasting insulin (RR, 1.2), although a suggestive association was observed in analyses based on fasting (>4 hours) cases alone (RR, 1.68).36Palmqvist R. Stattin P. Rinaldi S. Biessey C. Stenling R. Riboli E. Hallmans G. Kaaks R. Plasma insulin, IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in Northern Sweden.Int J Cancer. 2003; 107: 89-93Crossref PubMed Scopus (51) Google Scholar In the CLUE II cohort, baseline insulin levels (a mixture of fasting and nonfasting samples) were not related to risk of colorectal cancer.21Saydah S.H. Platz E.A. Rifai N. Pollak M.N. Brancati F.L. Helzlsouer K.J. Association of markers of insulin and glucose control with subsequent colorectal cancer risk.Cancer Epidemiol Biomarkers Prev. 2003; 12: 412-418PubMed Google Scholar The 2 largest studies were the Physicians’ Health Study and the Nurses’ Health Study. In the Physicians’ Health Study, men with C-peptide in the top vs the bottom quintile had a 2.7-fold significant increased risk of colorectal cancer, controlling for BMI and exercise; this RR increased to 3.4 after controlling for the indicators of the metabolic syndrome.37Ma J. Giovannucci E. Pollak M. Leavitt A. Tao Y. Gaziano J.M. Stampfer M. A prospective study of plasma C-peptide and colorectal cancer risk in men.J Natl Cancer Inst. 2004; 96: 546-553Crossref PubMed Google Scholar In the Nurses’ Health Study, women in the top quartile of C-peptide had a borderline increased multivariate risk of colon cancer (RR, 1.76) compared with women in the lowest quartile, also controlling for BMI and physical activity.38Wei E.K. Ma J. Pollak M.N. Rifai N. Fuchs C.S. Hankinson S.E. Giovannucci E. 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. 2005; 14: 850-855Crossref PubMed Scopus (108) Google ScholarThree studies have considered insulin or C-peptide levels in relation to adenoma risk. In one study, fasting plasma insulin was not related to an appreciably increased risk of adenomas.39Nishii T. Kono S. Abe H. Eguchi H. Shimazaki K. Hatano B. Hamada H. Glucose intolerance, plasma insulin levels, and colon adenomas in Japanese men.Jpn J Cancer Res. 2001; 92: 836-840Crossref PubMed Google Scholar In contrast, in a study of patients undergoing colonoscopy at the University of Carolina hospitals, those in the highest quartile of insulin had a 2.2-fold significantly higher risk of adenoma.40Keku T.O. Lund P.K. Galanko J. Simmons J.G. Woosley J.T. Sandler R.S. Insulin resistance, apoptosis, and colorectal adenoma risk.Cancer Epidemiol Biomarkers Prev. 2005; 14: 2076-2081Crossref PubMed Scopus (48) Google Scholar In the Nurses’ Health Study, high concentrations of C-peptide were statistically significantly associated with risk of distal colorectal adenoma (RR, 1.63) controlling for BMI and physical activity level.41Wei E.K. Ma J. Pollak M.N. Rifai N. Fuchs C.S. Hankinson S.E. Giovannucci E. C-peptide, insulin-like growth factor binding protein-1, glycosylated hemoglobin, and the risk of distal colorectal adenoma in women.Cancer Epidemiol Biomarkers Prev. 2006; 15: 750-755Crossref PubMed Scopus (39) Google ScholarBecause a number of metabolic consequences are associated with insulin resistance and hyperinsulinemia, it is difficult to settle which is most critical based solely on epidemiologic data. Of note, one rat model suggests that hyperinsulinemia may be the most important factor. In that study, insulin level, during a 10-hour euglycemic clamp, correlated with colorectal epithelial proliferation in a dose-dependent manner.42Tran T.T. Naigamwalla D. Oprescu A.I. Lam L. McKeown-Eyssen G. Bruce W.R. Giacca A. Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo.Endocrinology. 2006; 147: 1830-1837Crossref PubMed Scopus (54) Google Scholar Importantly, the addition of hyperglycemia did not further increase proliferation, and an intralipid infusion alone did not increase cell proliferation. Based on this study, hyperinsulinemia, rather than hyperglycemia or hypertriglyceridemia, was the metabolic component primarily associated with proliferation, a risk factor for enhanced carcinogenesis.For humans, although such experimentation is not feasible, the natural history of type 2 diabetes mellitus can be exploited. The initial cause of type 2 diabetes is insulin resistance, a condition for which higher levels of insulin are required to achieve normal utilization of circulating glucose. Initially, levels of glucose are stabilized through increased circulating insulin levels. In the early stages of impaired glucose tolerance, glucose levels may be not elevated or are only slightly increased. However, over many years or decades of this compensatory hyperinsulinemia, pancreatic β-cell failure occurs in susceptible individuals, eventually leading to reduced secretion of insulin. The hypoinsulinemia is most evident in the postprandial phase, when insulin demand is greatest.43DeFronzo R.A. Bonadonna R.C. Ferrannini E. Pathogenesis of NIDDM A balanced overview.Diabetes Care. 1992; 15: 318-368Crossref PubMed Google Scholar Thus, in" @default.
• W2014000186 created "2016-06-24" @default.
• W2014000186 creator A5038373228 @default.
• W2014000186 creator A5062350265 @default.
• W2014000186 date "2007-05-01" @default.
• W2014000186 modified "2023-10-16" @default.
• W2014000186 title "The Role of Obesity and Related Metabolic Disturbances in Cancers of the Colon, Prostate, and Pancreas" @default.
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