Diabetes and cancer – where do we stand?

Ulf Smith, Dept of Molecular and Clinical Medicine, University of Gothenburg, Sweden.

The five publications in Diabetologia last year about a potentially increased treatment-related cancer risk in Type 2 diabetes elicited an explosion of interest in this previously underexplored area. Although an association between cancer and diabetes had been suggested long time ago, only small advances had been made and the associations and potential mechanisms were generally not recognized or understood.

In order to define our current knowledge, gaps and the directions for future research ,the American Diabetes Association (ADA) together with the American Cancer Society (ACS) and with representations by the European Association for the Study of Diabetes (EASD) and the European Cancer Organization (ECCO) convened a forum in Atlanta in December 2009 with expert cancer and diabetes scientists. This forum has now produced a consensus document which will be published in Diabetes Care shortly and with Commentaries in both Diabetologia and Lancet. It does not contain any unexpected conclusions but gives an updated state of the art and defines a number of areas which need to be explored.This short summary tries to incorporate the conclusions from the consensus document with the presentations given by Prof Edwin Gale and myself at the recent SDF meeting in Gothenburg. The expert forum focused on four key questions:

1. Is there a meaningful association between diabetes and cancer incidence or prognosis?
2. What risk factors are common to both diabetes and cancer?
3. What are possible biological links between diabetes and cancer risk?
4. Do diabetes treatments influence risk of cancer or cancer prognosis?

1. Is there a meaningful association between diabetes and cancer incidence or prognosis?

The key conclusions are that diabetes (primarily Type 2) is associated with an increased risk for some cancers (liver, pancreas, endometrium, colon and rectum, breast, bladder), but a reduced risk of prostate cancer. For other cancer sites the evidence is either inconclusive or negative.

The reasons for an increased risk of cancer in diabetes remain unclear, but there are three leading possibilities. The first is that the increased cancer risk is directly related to hyperglycemia, the second is that hyperinsulinemia and insulin resistance are common factors in the development of both diabetes and cancer, and the third is that the association is indirect, and mediated by risk factors common to both conditions, such as obesity. Furthermore, cancer risk might also be modulated by the direct actions or indirect consequences of therapies used to treat diabetes.

There is no doubt that obesity plays an important role but it can not alone explain all associations and mortality in cancer in Type 2 diabetes is increased above and beyond any associated effect of obesity. Cancer develops in at least three defined steps; initiation, promotion and progression. Type 2 diabetes and its treatment may involve different aspects of this triad. Obesity, commonly associated with Type 2 diabetes, is a well recognized risk for very similar cancers as seen in diabetes with the exception of prostate cancer which is actually less frequent in Type 2 diabetes than in non-diabetic subjects. The reason for this is unclear but may be linked to the fact that some genetic causes of Type 2 diabetes are in fact protective against prostate cancer.

2.What risk factors are common to both diabetes and cancer?

Cancer, like type 2 diabetes, is an age-related condition and it is slightly more common in men. There are important differences between geographical regions, between socioeconomic groups, and between different ethnic groups sharing a common environment. The extent to which these differences are caused by genes, environmental exposures, lifestyle, risk factor distribution or access to medical screening and therapy remains unclear.

It is, however, clear from both human and animal studies that modifiable environmental factors such as energy balance and weight gain contribute to the burden of cancer, whereas weight loss reduces cancer risk in women following successful diet-induced weight loss or bariatric surgery. Conversely, weight gain increases the risk of a number of cancers, notably of the breast.

3.What are possible biological links between diabetes and cancer risk?

Possible mechanisms for a direct link between diabetes and cancer include hyperinsulinemia/insulin resistance, hyperglycemia, and inflammation.

Most cancer cells express or over-express IGF-1, IGF-2 and insulin receptors, the latter most commonly as the A isoform, which is particularly promitogenic similar to activation of the IGF-1 receptors. The ”metabolic” insulin receptor,the Type B, is different from the Type A isoform and is mostly functional in the tissues involved in glucose-and lipid metabolism (liver,muscles and adipose tissue).The A isoform of the insulin receptor can stimulate insulin-mediated mitogenesis even when IGF-1 receptors are lacking. Since glucose uptake in cancer cells is constitutive and unrelated to insulin binding, activation of the insulin receptor likely benefits the cancer cell by promoting cell survival and growth. In all events, multiple downstream signaling events resulting from activation of the IGF-insulin axis contribute to cancer cell growth and this may also be a reason for the reported association between insulin/SU therapy and cancer risk.

Hyperinsulinemia may not only impact tumour growth directly, but also indirectly by inhibiting hepatic production of IGF binding protein-1 (IGFBP-1), and possibly also of IGFBP-2, thus increasing levels of bioactive IGF1.In addition to hyperinsulinemia itself playing a role, the underlying insulin resistance in both obesity and Type 2 diabetes may also contribute. Cellular insulin resistance has been shown to promote a promitogenic effect of insulin. Insulin is, in fact, a growth-promoting molecule and in many regards similar to the classical growth-promoting molecule IGF-1.

Hyperglycemia might also potentially promote cancer progression since tumour cells are highly dependent on glycolysis rather than using other substrates. However, the cells are also adapted to maximise glucose uptake by insulin-independent constitutive mechanisms, and, given that these pathways are already functioning at near-maximal efficiency, the added effect of hyperglycemia is likely to be limited. Yet unpublished epidemiological studies support this conclusion.

Inflammation is the third alternative pathway linking Type 2 diabetes with both obesity with cancer. Inflammation has long been known as a riskfactor in cancer development and fat cells release a range of cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein, plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin and tumour-necrosis factor-á, all of which have the potential to influence cancer cell growth and survival. Recent experimental results have also shown that elevated local IL-6 levels may induce epigenetic changes in the cells leading to transformation of breast cells to an invasive phenotype .

4.Do diabetes treatments influence risk of cancer or cancer prognosis?

This question has become a major focus of interest and concern for those treating diabetes. There is now abundant evidence that metformin has properties that render it of great interest as a possible anti-cancer agent, and this has already translated into apparent clinical benefit in a number of cancer treatment scenarios. Several observational studies indicate that metformin-treated diabetic patients have a lower risk of several cancers, but these should be interpreted with some caution because of potential confounders, most notably confounding by indication. Thiazolidinediones have also attracted interest as a possible adjunct to cancer therapy, although studies in cancer patients have largely been negative. Sulfonylureas have been associated with an increased risk of cancer in observational studies, although this appearance might also have been produced by a protective effect of metformin in the comparator group.

Insulin therapy is typically given to people who have already been exposed to high levels of endogenous insulin, and the estimated duration of such exposure should be taken into consideration, as should the use of multiple treatments for diabetes. With regard to the insulin analogues, the panel of experts in the forum acknowledged that in vitro studies of binding affinity and mitogenic potency showed a greater affinity of some insulin analogues, and insulin glargine in particular, for the IGF-1 receptor, but also noted that it would be simplistic to assume that these effects were directly transposable to a clinical context. Observational studies linking increased cancer risk to insulin glargine have not fully accounted for all potential confounders, whereas published trial-based data relating to cancer risk in those treated with insulin glargine or NPH insulins, although negative, have limited power to exclude such an association.

In addition to the points discussed above,it also seems clear that patients with diabetes have a less favorable prognosis once a cancer has developed. The reason for this is also unclear but probably relates to an increased vulnerability of the diabetic patients to intense chemotherapy or following extensive surgery with regards to the associated complications and/or that they receive less extensive therapy for this reason. There is also some evidence that, in fact, patients with diabetes are less likely to undergo routine screening procedures for cancer! If this is true in Sweden is currently unclear but should be examined and all diabetic patients should be encouraged to follow the routine screening procedures.

A general conclusion from the forum discussion is that much work needs to be done to increase our knowledge on the diabetes-cancer associations. Many studies have already been initiated or planned and we can expect the coming years to provide us with new important information.

Ulf Smith,
profDiabetescentrum SU/Sahlgrenska
President EASD

|Upp|