Hyperinsulinemia and cancer
There is a strong overlap between cancer risks associated with obesity and those associated with diabetes. Both conditions are associated with insulin resistance. The insulin-cancer hypothesis proposes that chronic hyperinsulinemia leads to reduced concentrations of IGF binding proteins 1 & 2, leading to increased tissue levels of IGF-I which then plays a leading role in the development and progression of cancers. This hypothesis receives strong support from the observation that diabetes and obesity-related cancers typically over-express both the insulin and IGF receptors, profiting from the growth signals which each of these can deliver. Epidemiological evidence also links hyperinsulinemia or other markers of insulin resistance to cancer risk, lending further support to the hypothesis. These interactions are still poorly understood and are likely to prove more complex than the simpler statements of the hypothesis would suggest. For example, hyperinsulinemia also leads to changes in sex steroids and adipocytokines which may also play an important role in cancer development.
The overlap between the cancer epidemiology of obesity and insulin resistance was first noted in the 1990s, and the importance of obesity itself as a determinant of cancer was not fully recognised until 2002
There are a number of potentially plausible explanations for the observed association between diabetes and cancer, including shared risk factors, and metabolic derangements such as the metabolic syndrome. Insulin resistance and hyperinsulinemia are hallmarks of cancers associated with these conditions.
In the early stages of type 2 diabetes the pancreas oversecretes insulin in order to compensate for insulin resistance. Chronic hyperinsulinemia results and leads to a chain of metabolic responses, including changes in IGF binding proteins which result in increased tissue availability of both IGF-I and IGF-II.
Insulin is itself a growth-promoting hormone with mitogenic (but not mutagenic) effects and diabetes-associated cancer cells express insulin and IGF-1 receptors which play a key role in cell growth and differentiation.
The historical steps showing our growing understanding of the relationship between insulin, IGFs and cancer are shown in the figure:
Animal studies, complemented by case studies in humans, have demonstrated the critical role of insulin-like growth factor (IGF) in all stages of mammalian growth. IGF binding protein-1 (IGF-1) is suppressed by insulin and as a result, this increases the levels of bioavailable IGF-1. Therefore, the leading hypothesis for the relationship between type 2 diabetes and cancer is that insulin resistance and consequent hyperinsulinemia may promote tumour cell growth directly via insulin receptors, or indirectly via the IGF-1 receptor.
Hyperinsulinemia is also considered to underlie the associations of several shared risk factors for diabetes and cancer, such as waist circumference, visceral fat, waist-to-hip ratio, body mass index (BMI), sedentary lifestyle, and energy intake.
The hyperinsulinemia hypothesis
This hyperinsulinemia hypothesis is also supported by a meta-analysis of epidemiological studies, which demonstrated that elevated serum insulin or C-peptide levels are associated with increased risk of certain cancers. In addition, increased endogenous insulin levels have been associated with a worse prognosis for breast cancer patients.
Insulin resistance may also promote cancer risk via other mechanisms, such as decreased sex-hormone binding globulins leading to excess oestrogen and stimulation of oestrogen-dependent tumours or inflammation. Altered secretion of adipocytokines may also play a role.
Does insulin injection increase cancer risk?
Insulin itself might influence cancer development directly by binding to receptors on cancer cells and promoting growth effects. Alternatively, its effects on tumor development might be mediated indirectly via changes in binding protein levels leading to altered concentrations of the IGFs or oestrogens.
Endogenous insulin is "seen" at much higher concentrations in the portal circulation and liver than in the periphery. Exogenous insulin, in contrast, is injected into the systemic circulation, reversing the ratio between portal and systemic hyperinsulinemia. This would therefore be expected to increase the likelihood of cancer development within the teritory of the systemic circulation. The evidence implicating injected insulin as a primary risk factor for cancer (as against the underlying insulin resistance which may have made insulin therapy necessary in type 2 diabetes) is however weak.
For example, the ORIGIN trial found no difference in incident cancers with use of basal insulin (insulin glargine) for over 6 years, as compared with standard care (metformin and sulfonylurea therapy). Therefore, their data do not support previous epidemiologic analyses that have linked insulin use or insulin glargine use specifically to incident cancer. See Insulin and cancer.
These observations do not necessarily invalidate the insulin-cancer hypothesis, but they do indicate that the indirect effects of insulin mediated by e.g. IGF-I are likely to be more important than its direct effects.
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