Why Diabetes Mellitus is a Risk Factor for Endometrial Cancer
Diabetes mellitus increases endometrial cancer risk primarily through its association with metabolic syndrome—particularly obesity, hyperinsulinemia, and chronic anovulation—rather than through hyperglycemia alone. 1
The Metabolic Syndrome Connection
Diabetes functions as part of a metabolic cluster that drives Type I endometrial cancer development. The mechanistic pathway operates as follows:
Type I endometrial cancers (70% of cases) are mediated primarily by the sequelae of obesity and are associated with excess endometrial cell proliferation. Patients with Type I endometrial cancer are frequently afflicted with hyperestrogenism, hyperlipidemia, diabetes, and anovulatory uterine bleeding—all conditions associated with metabolic syndrome, which has been identified as an independent risk factor for endometrial cancer development. 1
Diabetes confers approximately a 2-fold increased risk of endometrial cancer (RR 1.72-2.10). 2, 3 However, this association is substantially attenuated when adjusted for body mass index, suggesting that obesity is the primary driver. 4
Biological Mechanisms Linking Diabetes to Endometrial Cancer
Hyperinsulinemia and Insulin Resistance
In premenopausal women, obesity causes insulin resistance, elevated ovarian androgens, anovulation, and chronic progesterone deficiency, increasing the risk of endometrial cancer. 5 This creates unopposed estrogen stimulation of the endometrium without the protective effects of progesterone.
Hyperinsulinemia directly promotes endometrial cell proliferation and tumor growth through activation of the AKT/PKB/mTOR signaling pathway, which regulates cellular growth and proliferation. 6, 7
Unopposed Estrogen Exposure
In postmenopausal women, adipose tissue converts androstenedione to estrone, leading to higher circulating bioavailable estrogens without progesterone opposition. 5 This hormonal imbalance drives endometrial hyperplasia and subsequent malignant transformation.
Chronic anovulation and unopposed estrogen exposure are the primary mechanistic drivers linking metabolic conditions (including diabetes) to endometrial cancer. 5
Additional Pathways
A high-glucose environment contributes to the growth and invasiveness of endometrial cancer cells through enhanced glycolysis and metabolic reprogramming. 7
Chronic inflammation, adipokines, and hyperinsulinemia create a tumor-promoting microenvironment that facilitates cancer development and progression. 8, 7
The Confounding Role of Obesity
The relationship between diabetes and endometrial cancer is largely confounded by body weight:
When BMI is controlled in multivariate analyses, the association between diabetes and endometrial cancer becomes non-significant or substantially reduced. 4 In the Women's Health Initiative study of 88,107 postmenopausal women, diabetes showed a 44% increased risk (HR 1.44) before BMI adjustment, but this became non-significant after controlling for obesity. 4
Obesity independently increases endometrial cancer risk by 2.54-2.73 fold (BMI ≥30) and up to 4.7-fold in severe obesity (BMI ≥35-40). 5, 8 This magnitude exceeds the independent effect of diabetes alone.
However, some modest independent elevated risk remains even after BMI adjustment (HR 1.31 when considering time-dependent diabetes exposure), suggesting diabetes contributes through mechanisms beyond obesity alone. 4
Clinical Implications
Risk Stratification
Diabetic women, particularly those who are obese and postmenopausal, represent a high-risk population requiring heightened surveillance for abnormal uterine bleeding. 5
The combination of diabetes, obesity, hypertension, and hyperlipidemia—the metabolic syndrome constellation—confers the highest risk for Type I endometrial cancer. 1
Common Pitfalls
Do not attribute endometrial cancer risk to hyperglycemia control alone. The primary drivers are insulin resistance, hyperinsulinemia, and obesity-related hormonal changes rather than glucose levels per se. 4, 7
Recognize that diabetes treatment with metformin has not been definitively shown to reduce endometrial cancer risk in large epidemiological studies, despite promising mechanistic data showing anti-proliferative effects through AKT/mTOR pathway inhibition. 4, 6 Early treatment with metformin is expected to be an effective adjuvant alternative for endometrial cancer in the future, but this remains investigational. 7
Weight loss of 5-10% can restore ovulation, improve insulin sensitivity, and lower endometrial cancer risk in obese diabetic patients, making lifestyle intervention a critical component of cancer prevention. 5