Diabetes, insulin therapy, and colorectal cancer

For two decades, investigators have recognised the overlapping risk factors for type 2 diabetes mellitus and colorectal cancer—obesity, Western diet, and sedentary lifestyle—and speculated about a link between these two common diseases. Accumulating evidence shows that type 2 diabetes mellitus is associated with a 40-60% increased risk of cancer of the large bowel,¹,² and specifically, proximal colonic malignancy.³ These associations are independent of body mass index and are more consistently reported than those with breast and endometrial cancers. Recent data from the European Prospective Investigation into Cancer (EPIC-Norfolk) study show that this increased risk is largely explained by changes in glycated haemoglobin (HbA_1c) concentrations.⁴ This implies that glycaemic control is likely to be important in determining which patients develop colorectal cancer. In contrast to type 2 diabetes mellitus, no associations have been found between colorectal cancer risk and type 1 diabetes mellitus, nor gestational diabetes.⁵

Recently published data from the large US Cancer Prevention Study II (1.2 million men and women) confirmed findings from previous small studies that the presence of diabetes may influence outcome in patients with malignancy of the large bowel.⁶ Furthermore, in the setting of a large randomised controlled trial of adjuvant chemotherapy of stages II and III colon cancer, Meyerhardt et al reported among people with diabetes mellitus (categorisation into types was not reported) significantly higher rates of overall mortality and reduced disease free and recurrence free survivals—even after other predictors of outcome had been adjusted for.⁷ Importantly, this study showed that the disease free and overall survival curves in the first two years were almost identical for patients with and without diabetes. Although these observations need to be replicated, they imply that among people with diabetes who have colorectal cancer, some unidentified mechanism may influence progression of disease unfavourably some time after initial treatment, rather than the perception that diabetes is associated with advanced presentation, compromised initial treatment, and increased early postoperative mortality.

The effects of diabetes mellitus on colorectal cancer may be mediated through mechanisms ranging from increased colonic transit time to hyperinsulinaemia. In relation to the latter, at least in the early phase of development, type 2 diabetes mellitus is associated with increased circulating insulin concentrations. Insulin may stimulate cell proliferation through two pathways: a minor pathway that entails direct activation of the insulin receptor or insulin-like growth factor (IGF)-I receptor, and a major pathway via inhibition of IGF binding proteins (in particular, IGFBP-1 and IGFBP-2), resulting theoretically in increased bioavailability of IGF-I to the IGF-I receptor. An important role for IGF-I in colorectal carcinogenesis is supported by epidemiological studies and animal models.⁸,⁹ Clinical studies also independently link high circulating concentrations of C-peptide, as a marker of insulin production, with increased colorectal cancer risk.¹⁰

A further dimension to the role of insulin and the development of colorectal cancer has recently been revealed from the UK General Practice Research Database.¹¹ From a study cohort of some 24 000 patients with type 2 diabetes mellitus, 125 developed colorectal cancer after a median follow up of seven years. Importantly, among the users of insulin for at least one year (n = 3160), the age and sex adjusted hazard ratio was 2.1 (95% CI: 1.2 to 3.4, P = 0.005), a positive association that was strengthened after adjustment for potential confounders. Although it had been shown that exogenous insulin injections stimulate the growth of precursors of colorectal cancer in animals, this study provides the strongest evidence in humans to date that an increased risk of large bowel cancer may be an unfavourable side effect of long term treatment with insulin. However, after a half century of critical clinical use, insulin is unlikely to undergo the “hormone bashing” that has been the recent fate for hormone replacement therapy containing oestrogen. The indispensable contribution of insulin to diabetes care and the reductions in non-neoplastic complications from optimisation of glycaemic control clearly outweigh the absolute risk of colorectal cancer.

Yang et al draw an analogy to risk among individuals with a family history of colorectal cancer and, by implication, suggest a more stringent approach to screening in people on insulin for diabetes.¹¹ Such a proposal is questionable as it is based on an estimated only twofold increased risk in patients. Experience should be drawn from the debate on colorectal cancer screening in patients with acromegaly, another endocrine disorder characterised by a modest (twofold) increase in the risk of colorectal cancer.¹² Screening for colorectal cancer is not without its potential morbidities, and detailed analyses of risks and benefits need to be undertaken before a widespread recommendation for aggressive screening is advocated in patients with type 2 diabetes mellitus. As the prevalence of type 2 diabetes mellitus will undoubtedly increase in line with the growing epidemic of obesity, the associations between diabetes and risk of colorectal cancer will be the subject of increasing scrutiny and research.