Diabetes mellitus (DM) is one of the most common chronic diseases characterised by hyperglycaemia.1 With a global prevalence in those aged over 18, rising from 4.7 per cent in 1980 to 8.5 per cent in 2014, it heralds a huge burden of disease.2 The World Health Organization (WHO) predicts that by 2030, diabetes will be the seventh leading cause of death worldwide.3

Given the exponential growth of diabetes, many researchers are now investigating the association between diabetes and its related diseases, particularly cancer, with this association first being reported more than 100 years ago.4 There is now a growing body of research that has associated diabetes with an increased risk of gynaecological cancers. In addition to this, there is evidence showing that gestational diabetes mellitus (GDM) also increases a woman’s risk of developing a gynaecological malignancy.5

Endometrial cancer has a well-known association with type 2 diabetes, increasing a woman’s risk of developing the disease two-fold.6 Interestingly, despite endometrial cancer and type 2 diabetes sharing similar modifiable risk factors such as obesity,7 a woman with type 2 diabetes is still at increased risk of developing endometrial cancer after controlling for body mass index (BMI).8 Some studies have quoted an excess risk of developing endometrial cancer in women with type 2 diabetes of up to 30–400 per cent.9 Additionally, most research has indicated that type 2 diabetes not only increases the risk of developing an endometrial cancer, but also increases a woman’s risk of dying from it.10

When considering the association of diabetes with ovarian cancer, studies have been more limited, with some failing to show an elevated risk whereas others do.11 However, a recent meta-analysis looking at 19 studies indicated that women with diabetes had an increased risk of ovarian cancer with a risk ratio (RR) of 1.17.12 Moreover, other researchers have noted the outcomes of patients with ovarian cancer who have diabetes are poorer than those who do not, with median survival being four versus six years.13 Furthermore, as a direct result of its co-morbidities, women with diabetes may undergo different treatment plans or less radical cytoreductive surgery, which may also affect outcomes.14

Mechanisms of carcinogenesis in diabetes mellitus

Glucose levels

In addition to glucose being an energy source that stimulates cellular proliferation in tumours, hyperglycaemia causes oxidated stress and glycation of proteins, which subsequently can lead to apoptosis and the activation of protein kinase C.15 This oxidation process releases free radicals, also associated with cellular death.16 In turn, these apoptotic changes can lead to the transformation of normal cells to dysplastic and malignant cells due to the imbalance between cellular repair and injury.17

Ovarian steroid hormone and sex hormone-binding globulin regulation

Steroid hormones regulate the balance between cellular proliferation, differentiation and apoptosis in dysplastic and neoplastic cells.18 Specifically, ovarian hormones are some of the most common hormones related to cancer generation and progression, in particular, endometrial, ovarian and breast cancers.19 When considering sex hormone-binding globulin (SHBG), its level is one of the most important factors in cancer generation and development in postmenopausal women, as reduced levels lead to increased levels of bio-available ovarian steroid hormones.20

The hyperinsulinaemia and insulin resistance from type 2 diabetes not only induces ovarian steroid hormone production, but also causes a depression in the hepatic production of SHBG, leading to increased bio-availablility of ovarian steroid hormones.21 In addition to this, and exacerbating this effect, is the increased insulin and insulin-like growth factor-1 (IGF-1) levels in type 2 diabetes, with these also increasing oestrogen receptor alpha (ERα) signalling, hence leading to a carcinogenic cellular environment.

Chronic inflammation

Diabetes is associated with chronic inflammation, a known entity for cancer development and progression.22 23 Several mediators of inflammatory pathways, including interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), and cyclooxygenase-2 (COX-2), are known to reduce tumour suppressor function and increase oncogene expression and cell cycling.24

In terms of the effect of diabetes on chronic inflammation, insulin resistance and hyperinsulinaemia are known to promote a low-grade chronic inflammatory environment, which in turn aggravates insulin resistance.25 Additionally, oestrogen, the levels of which are increased in women with diabetes, promotes increased gene expression of inflammatory mediators, further exacerbating this process.26

Insulin and insulin-like growth factor signalling

Insulin growth factors (IGF) and insulin are involved in carbohydrate metabolism, cellular survival and proliferation.27 They have important systemic regulatory roles in the body and show hormonal effects through insulin receptors (IR) and IGF receptors (IGFRs), which are widely expressed throughout the body.28

Many studies have shown an association between insulin and IGF-1 in the regulation of cancer, whereby increased levels such as those seen in type 2 diabetes are strongly associated with an increased risk of cancer and mortality.29 In fact, some studies have demonstrated not only this point, but also that IGF-1 levels are proportional to cancer-related mortality.30 Following on from this, it is now well-recognised that the presence of insulin resistance and hyperinsulinaemia are associated with an increased risk and mortality in women with cancer, particularly breast, endometrial and ovarian.31

Gestational diabetes and gynaecological cancer

In addition to the association between type 2 diabetes and gynaecological malignancy, there is evidence that gestational diabetes increases a woman’s chance of developing a gynaecological malignancy. The incidence of gestational diabetes is rising, now complicating around seven per cent of pregnancies worldwide, and it is associated with both neonatal and maternal morbidity.32 One such maternal morbidity is its known association with the development of type 2 diabetes, with it heralding a seven-fold increase in the likelihood of developing the disease.33

Given that women with gestational diabetes are more likely to develop type 2 diabetes, they are also more at risk of gynaecological malignancies and a recent study has demonstrated this association.34 Fuchs et al (2017) conducted a population-based study looking at the incidence of female malignancies in women with and without gestational diabetes. They looked at 9893 patients with a follow-up period of 12 years. Authors found that gestational diabetes was an independent risk factor for ovarian, endometrium and breast cancer. There was no association between the number of times gestational diabetes was diagnosed and the RR for malignancies.35

Anti-diabetic agents and gynaecological cancer

There is now a growing body of evidence regarding the effects of anti-diabetic agents on the risk of cancer, with some being correlated with an elevated risk, while metformin seems to lower the risk.36 37 38

Metformin, a biguanide, inhibits insulin-dependent hepatic gluconeogenesis and promotes insulin uptake into surrounding cells via improving insulin resistance and reducing free fatty acids through the inhibition of lipolysis.39 Metformin is first-line therapy for type 2 diabetes and is inexpensive, with a proven safety profile.40 41 In addition to its well established anti-diabetic properties, there is growing evidence and interest regarding its anti-tumour properties.42 43 44 45 The mechanism of this involves the activation of adenosine monophosphate-activated protein kinase (AMPK) and the inhibition of mammalian target of rapamycin (mTOR), which in combination reduce cell growth.46

In relation to gynaecologic oncology, as the carcinogenesis of endometrial cancer can involve obesity, type 2 diabetes and hyper-oestrogenic states, metformin has been investigated and proven to be therapeutic regarding the prevention and improvement of prognosis.47,48 A recent review on metformin in gynaecological malignancies confirmed significant treatment efficacy.49

In addition to endometrial cancer, the review goes on to cite three studies that have shown a potential therapeutic effect on outcomes of women with ovarian cancer and its prevention, however, they are observational.50 The review discusses cervical cancer, noting there to be no statistically significant effect of metformin on its prognosis.51 The authors conclude by saying the reduction in cancer risk of women using metformin is apparent after more than five years of usage, however at this stage, evidence is not sufficient for its use in malignancies other than endometrial cancer, as more long-term randomised trials are needed.52

In terms of other anti-diabetic agents such as insulin, as noted, excessive insulin and IGF-1 signalling can cause the development and proliferation of cancer, and, as such, exogenous insulin is suspected to be a powerful carcinogenic factor in patients with diabetes mellitus.53 In support of this, a meta-analysis recently showed insulin to increase a person’s risk of cancer development with a RR of 1.39.54 In relation to women’s cancer, a number of studies have found that insulin glargine, a long-acting insulin analogue, increases the risk of breast cancer in women with type 2 diabetes who have been using it for more than five years.55

Globally, the rising levels of chronic diseases, in particular diabetes, pose significant challenges to the O&G practitioner. There is now a growing body of evidence showing that diabetes has significant implications for the development of gynaecological malignancies, increasing a woman’s lifetime risk of developing cancer. We can expect to see a continued growth in the incidence of gynaecological malignancies, in particular endometrial cancer. Further research into the effect of diabetes on gynaecological malignancies and determining how the risk of diabetes can be moderated by anti-diabetic agents will be an exciting space to watch in the future.