Journal
PLOS MEDICINE
Volume 13, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1001988
Keywords
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Categories
Funding
- European Commission (DG-SANCO)
- International Agency for Research on Cancer
- Danish Cancer Society (Denmark)
- Ligue Contre le Cancer
- Institut Gustave Roussy
- Mutuelle Generale de l'Education Nationale
- Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
- Deutsche Krebshilfe, Deutsches Krebsforschungszentrum
- Federal Ministry of Education and Research (Germany)
- Hellenic Health Foundation
- Stavros Niarchos Foundation
- Hellenic Ministry of Health and Social Solidarity (Greece)
- Italian Association for Research on Cancer (AIRC)
- National Research Council
- Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa
- Associazione Volontari Italiani Sangu (AVIS) Ragusa
- Sicilian Government (Italy)
- Dutch Ministry of Public Health, Welfare and Sports (VWS)
- Netherlands Cancer Registry (NKR)
- LK Research Funds
- Dutch Prevention Funds
- Dutch ZON (Zorg Onderzoek Nederland)
- World Cancer Research Fund (WCRF)
- Statistics Netherlands (the Netherlands)
- European Research Council (ERC) [ERC-2009-AdG 232997]
- Nordforsk
- Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway)
- Health Research Fund (FIS)
- Regional Government of Andalucia [6236]
- Regional Government of Asturias [6236]
- Regional Government of Basque Country [6236]
- Regional Government of Murcia [6236]
- Regional Government of Navarra [6236]
- Centro de Investigacion Biomedica en Red en Epidemiologia y Salud Publica and Instituto de Salud Carlos II (ISCIII RETIC) (Spain) [RD06/0020]
- Swedish Cancer Society
- Swedish Scientific Council
- Regional Government of Skane
- Vasterbotten (Sweden)
- Cancer Research UK
- Medical Research Council
- Stroke Association
- British Heart Foundation
- Department of Health
- Food Standards Agency
- Wellcome Trust (UK)
- National Cancer Institute (USA) [1RO1CA102460]
- MRC [MR/N003284/1, MC_UU_12015/1] Funding Source: UKRI
- Cancer Research UK [16491, 14136] Funding Source: researchfish
- Medical Research Council [MC_U106179471, MC_UU_12015/1, MR/N003284/1, MC_PC_13048, G0401527] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114, NF-SI-0512-10135] Funding Source: researchfish
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Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m(2)), (2) metabolically healthy/overweight (BMI >= 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI >= 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [>= 80 cm for women and >= 94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. Conclusions These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
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