Insulin Analogues and Cancer Risk: Cause for Concern or Cause Célèbre?

M. Pollak; D. Russell-Jones

Disclosures

Int J Clin Pract. 2010;65(5):628-636. 

In This Article

The Biological Plausibility of a Link between Diabetes, Diabetes Therapies and Cancer

Diabetes appears to be associated with an intrinsic increase in cancer incidence.[11] Meta-analysis of six case-control and nine cohort studies, with a total of more than 2.5 million subjects, found a risk ratio (RR) for colorectal cancer of 1.30 [95% confidence interval (CI) 1.20–1.40] for subjects with diabetes vs. no diabetes.[12] The findings were consistent for studies in Europe and the USA and applied to both men and women. A further meta-analysis of 20 studies (five case-control and 15 cohort studies) showed that women with (vs. without) diabetes had a statistically significant 20% increased risk of breast cancer (RR 1.20; 95% CI, 1.12–1.28).[13] The summary estimates were similar for case-control studies (RR 1.18; 95% CI, 1.05–1.32) and cohort studies (RR, 1.20; 95% CI, 1.11–1.30). Meanwhile, Huxley and colleagues reviewed 36 studies (17 case-control, 19 cohort; n = 9220) suggesting a combined odds ratio for pancreatic cancer of 1.82 (95% CI, 1.66–1.99) for subjects with diabetes.[14] The excess risk was highest among those with a shorter duration of diabetes, which supports the hypothesis that diabetes is often a consequence of pancreatic cancer (rather than vice versa). However, the existence of a residual excess cancer risk in subjects with diabetes duration longer than 5 years does support some intrinsic risk resulting from the diabetic state.

Reasons for an intrinsic elevated risk of cancers in subjects with diabetes remain to be established. Type 2 diabetes is associated with comorbidities and risk factors, such as obesity and physical inactivity, which may increase the risk of certain cancers (e.g. colorectal). However, type 2 diabetes is also associated with an altered metabolic and endocrine environment, including hyperglycaemia and hyperinsulinaemia, that may influence cancer biology. In a murine xenograft model of prostate cancer (LNCaP), a high-carbohydrate diet resulting in elevated insulin levels (1.45 vs. 0.45 ng/ml, p = 0.039) also resulted in significantly elevated tumour growth (0.88 vs. 0.51 g, p = 0.04), with evidence of increased insulin receptor levels in neoplastic tissue and increased signalling downstream of insulin and/or IGF-1 receptors.[15]

There is evidence that hyperglycemia is associated with increased cancer risk.[16] However, as cancer cells have active and insulin-independent glucose uptake, it is not clear that glucose availability is limiting for neoplastic growth in vivo. It is possible that the hyperglycemia in this study was associated with hyperinsulemia, but the insulin levels were not measured. Many cancers do, however, have a high glucose requirement as they are more dependent on glycolysis than normal tissues to generate ATP,[17] and this requires more glucose than oxidative phosphorylation. If there are cases where hyperglycemia directly facilitates neoplastic growth, then it is possible that optimization of glycemic control could indeed reduce cancer risk.

A link between circulating insulin and IGF-1 levels and neoplasia has been observed [reviewed in Pollak et al. 2004[18] and Pollak et al. 2008 [19]]. For example, a number of case-control studies have found an association between elevated IGF-1 levels, prostate cancer[20,21] and breast cancer,[22–25] although some studies have failed to detect an association.[26,27] High insulin or c-peptide levels have been associated with poor prognosis of breast[28] and prostate[29] cancers, among others.

Activation of insulin or IGF-1 receptors appears to be associated with poor prognosis; in a study of more than 400 cases of invasive breast cancer spanning multiple cancer subtypes, Law and colleagues found phosphorylated insulin receptor or IGF-1 receptor levels and total insulin receptor levels to be associated with poor survival.[30] Cox and co-workers found expression of both insulin receptors and IGF-1 receptors in malignant prostate tissue.[31]

Transgenic mice over-expressing IGF-1 in mammary tissue showed ductal hyperplasia and spontaneous mammary tumorigenesis,[32] and other models show influences of insulin on experimental cancers.[15,33]

A growth-promoting effect of insulin on cancer cells has been known for more than 30 years, with these findings pre-dating the commercial availability of insulin analogues or even of recombinant human insulin.[34] Neoplastic cells commonly express the IR-A subtype of the insulin receptor and this foetal isoform of the insulin receptor differs in binding IGF-2 as well as insulin.[35–38] Hybrid receptors are formed in cells where the insulin receptor and the IGF receptor are co-expressed, and this is common in neoplastic tissue. Thus, the relative expression levels of IR-A, IR-B, and IGF-1R will influence sensitivity to the ligands IGF-1, IGF-2 and insulin.

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