Diabetes mellitus and ovarian cancer: Intersecting pathways and clinical outcomes

Abstract

Diabetes mellitus (DM), particularly type 2 diabetes and ovarian cancer (OC) intersect through a complex network of metabolic, inflammatory, and hormonal disturbances that influence tumorigenesis, disease progression, and clinical outcomes. Epidemiologic evidence consistently associates pre-existing DM with higher OC incidence and poorer survival; however, the mechanistic underpinnings remain incompletely defined and substantive knowledge gaps persist. Central to this intersection is the diabetic metabolic milieu, characterized by chronic hyperglycemia, compensatory hyperinsulinemia, and low-grade inflammation, which promotes cellular proliferation, genomic instability, and metastatic potential. Mechanistically, dysregulated insulin and insulin-like growth factor-1 signaling activates the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin axis, driving anti-apoptotic signaling, angiogenesis, and metabolic reprogramming. In parallel, diabetes-associated oxidative stress contributes to DNA damage, defective repair mechanisms, and epigenetic alterations that may accelerate malignant transformation of ovarian or fallopian tube precursor lesions. Despite these insights, critical gaps also remain regarding the influence of contemporary antidiabetic pharmacotherapies - such as metformin, receptor agonist-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors - on tumor metabolism, chemoresponsiveness, and survival outcomes. The interplay between reproductive hormonal signaling, diabetic metabolic alterations, and immune-stromal remodeling in the ovarian tumor microenvironment is similarly understudied. This review integrates epidemiologic, molecular, and clinical evidence linking DM and OC, evaluates the potential modifying effects of antidiabetic treatments, and highlights priorities for future investigation. Clarifying these intersecting pathways is essential for advancing risk stratification, informing precision therapies, and improving outcomes in this vulnerable population.

Key Words: Hyperinsulinemia; Insulin resistance; Inflammation; Metformin; Oxidative stress

Core Tip: Epidemiologic data consistently demonstrate that women with pre-existing diabetes mellitus have higher ovarian cancer incidence and poorer survival, yet the mechanistic underpinnings remain incompletely defined, and substantive knowledge gaps persist. Some biologic linkages uncovered include hyperglycemia, compensatory hyperinsulinemia, and chronic low-grade inflammation, creating a pro-tumorigenic milieu that enhances cellular proliferation, genomic instability, and metastatic potential. And at the molecular level, dysregulated insulin and insulin-like growth factor-1 signaling amplifies phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways, fostering anti-apoptotic signaling, metabolic reprogramming, and angiogenesis.

INTRODUCTION

Ovarian cancer is a leading cause of gynecologic cancer-related mortality, with advanced-stage cases showing a dismal five-year survival rate of under 50%[1]. Despite advances in surgical and chemotherapeutic interventions, prognosis remains poor, underscoring the need to identify modifiable risk factors and novel therapeutic targets. Among the emerging associations in oncology, the link between diabetes mellitus (DM) and cancer has garnered significant attention. Epidemiological evidence suggests that DM is not only a risk factor for ovarian cancer but also adversely affects clinical outcomes in affected patients[2]. The global prevalence of DM, particularly type 2 diabetes (T2DM), has risen dramatically, with projections estimating over 552 million by 2030 and 1.3 billion cases by 2050[3]. This metabolic disorder is characterized by chronic hyperglycemia, insulin resistance, and hyperinsulinemia[4,5], which may contribute to carcinogenesis through multiple pathways. Meta-analyses of cohort and case-control studies indicate that women with DM have a 17%-22% increased risk of developing ovarian cancer compared to non-diabetic women[2]. Furthermore, diabetic patients with epithelial ovarian cancer exhibit significantly worse progression-free survival and overall survival, independent of obesity and other confounding factors[6]. The biological mechanisms underlying this association are complex and multifactorial. Hyperinsulinemia, a hallmark of T2DM, may promote tumor growth via activation of the insulin-like growth factor-1 (IGF-1) axis, stimulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and Ras-mitogen-activated protein kinase pathways, which are critical for cell proliferation and survival[7,8]. Additionally, chronic hyperglycemia fosters a pro-tumorigenic microenvironment by inducing oxidative stress, advanced glycation end-products (AGEs), and chronic inflammation, further actively exacerbating cancer progression[9]. Intriguingly, certain antidiabetic medications, such as metformin, have shown potential anticancer effects, suggesting a possible role for metabolic therapy in ovarian cancer management[10]. However, despite accumulating evidence, the biological and clinical links between diabetes and ovarian cancer remain insufficiently clarified. Most studies to date have focused on the general relationship between DM and overall cancer risk, while ovarian cancer-specific data remain limited and, in some cases, conflicting. Moreover, existing reviews have not comprehensively synthesized epidemiological evidence, mechanistic pathways, and clinical outcomes in the context of ovarian cancer. This integrated review addresses this gap by exploring the intersecting pathways between DM and ovarian cancer, synthesizing epidemiological, molecular, and clinical evidence. Specifically, we examine how metabolic dysregulation in DM influences ovarian cancer risk and prognosis, discuss the potential role of antidiabetic drugs as adjunct therapies, and highlight areas where further research is warranted. A deeper understanding of this relationship may pave the way for multidisciplinary and personalized treatment strategies, ultimately improving outcomes for diabetics diagnosed with ovarian cancer.

EPIDEMIOLOGICAL LINK BETWEEN DM AND OVARIAN CANCER

The associated between diabetes and cancer has been recognized for over a century. Both type 1 diabetes (T1DM) and T2DM are linked to an elevated cancer risk, with cancer identified as a leading cause of death in individuals with T1DM. Conversely, diabetes is present in approximately 8%-18% of cancer patients. Evidence also suggests that individuals with diabetes face an increased risk of mortality associated with cancer[11]. Despite the recognition of a connection between diabetes and malignancy as early as 1914, the origins and progression of both diseases remain complex and multifactorial. Because diabetes and cancer share risk factors including age, race, and obesity, it is exceedingly challenging to draw straightforward conclusions[12].

Prior large-scale meta-analyses have estimated that diabetes is associated with a 25% to 41% elevated risk of death from all cancer types[13]. A comprehensive meta-analysis encompassing 27 studies revealed that individuals with T2DM face a 10% increased likelihood of developing cancer and a 16% higher rate of cancer-related mortality[14]. According to numerous studies and meta-analyses, T2DM is linked to a lower risk of prostate cancer and a higher risk of cancer at various locations, such as the liver, pancreas, endometrial, colorectum, breast, and bladder. It is possible that the observed correlations between T2DM and cancer are due to confounding from common risk factors like obesity or are causal (for instance, brought on by hyperglycemia or hyperinsulinemia). Given the significant worldwide incidence of these illnesses, these relationships could have significant public health implications if they are causal[15]. Clinical observations indicate that diabetic women are more likely to develop tumors with lower levels of differentiation and experience less favorable outcomes than those without diabetes. A contributing factor may be the presence of elevated insulin and IGF-1 levels in the bloodstream, both of which have been implicated in promoting tumor growth and progression[16].

Notably, most epidemiological research exploring the association between T2DM and cancer has depended on self-reported diabetes status. Although this method demonstrates very high specificity (> 99%), its sensitivity is relatively low - approximately 66% when compared to data from medical records[17]. Given that nearly 46% of diabetes cases remain undiagnosed, many individuals with diabetes may have been misclassified as non-diabetic, particularly in cohort studies[15]. Since diabetes is often recorded at baseline, this misclassification tends to be non-differential but could be differential in case-control designs. To improve accuracy, future prospective studies should account for incident diabetes cases and incorporate time-varying variables such as disease duration, glycemic control, treatment regimens, and complications. Mendelian randomization can also help clarify causality in the absence of randomized trials. Large-scale consortia are needed to explore these associations, especially for rare cancers where data remain limited and inconsistent[18].

Long-term insulin therapy has been linked to an elevated risk of ovarian cancer[19], whereas prolonged use of metformin appears to confer a protective effect. Notably, this benefit does not extend to sulfonylurea use. Evidence suggests that metformin use is linked to significantly lower ovarian cancer incidence and mortality[20]. Supporting this, Zhang and Li[21] analyzed 28 studies and found that metformin use in diabetic cancer patients corresponded with reduced all-cause mortality, with particularly notable benefits observed in cases of ovarian cancer.

Growing evidence suggests a significant association between T2DM and increased cancer risk, with diabetic individuals nearly twice as likely to develop certain malignancies, including endometrial, pancreatic, and hepatocellular cancers. This heightened risk may, in part, be influenced by the pharmacologic management of diabetes[22]. These observations may be rooted in the metabolic disturbances characteristic of diabetes, particularly the role of insulin - a peptide hormone released by pancreatic β-cells in response to rising blood glucose levels. While insulin is essential for maintaining glycemic balance, it may also contribute to cancer-related signaling pathways. Moreover, the diabetic state alters the regulation of other metabolic hormones such as IGF-1, leptin, and adiponectin, all of which have been implicated in cancer biology[8]. After being stimulated by growth hormone, the liver mostly produces the peptide growth factor IGF-1. About half of its sequence is similar to that of insulin. It shares approximately 50% of its sequence with insulin. Many tissues’ growth and development are regulated by IGF-1, especially during pregnancy. Free IGF-1 in the circulation exerts its biological effects by binding to the IGF-1 receptor (IGF-1R), thereby activating signaling pathways involved in cell growth and survival. Under normal physiological conditions, most circulating IGF-1 is bound to IGF binding proteins (IGFBPs), which regulate its availability[23]. In metabolic syndrome, however, the levels of bioavailable IGF-1 may rise. This increase is potentially driven by two factors: Hyperglycemia, which may suppress IGFBP synthesis, and hyperinsulinemia, which can enhance hepatic growth hormone receptor expression and stimulate IGF-1 production. One known risk factor for numerous cancer types is elevated circulating IGF-1[22]. It is commonly recognized that IGF1 and IGF2 have mitogenic properties. IGFs can promote development and differentiation in a variety of tissues because nearly all cell types express IGF-1R. IGFs phosphorylate themselves and their primary substrate, insulin receptor substrate 1 (IRS-1), when they bind to IGF-1R and activate the receptor tyrosine kinase. Depending on the type of cell, phosphorylated IRS-1 can induce differentiation, proliferation, or both by activating the PI3K/Akt and Ras/Raf/mitogen-activated protein kinase cascades. Components of this system are commonly altered or amplified in malignancies, and PI3K activation can result in anti-apoptotic signals[7].

Findings from nested case-control studies and sensitivity analyses utilizing just cohorts were comparable. Studies that controlled for established risk variables like age, obesity, smoking, and alcohol consumption showed a stronger correlation[2]. Noto et al[24] reported that cancer incidence was approximately 7% in diabetic patients in 12 cohort studies. Nineteen cohort studies showed that the cancer mortality rate among diabetic individuals was about 3%. The risk ratio of death for all cancer types was similarly higher in those with diabetes. Another significant component could be hyperglycemia, although methodological problems, bias, and concealed malignant tumors cannot be totally ruled out[25].

Epidemiological studies have consistently linked higher concentrations of fasting insulin, postprandial insulin, and C-peptide with an elevated risk of developing multiple types of cancer, highlighting the potential role of hyperinsulinemia in cancer pathogenesis. Individuals with the highest insulin or C-peptide concentrations demonstrated a significantly higher incidence of colorectal, pancreatic, breast, and endometrial cancers[26]. A powerful growth factor, insulin can influence proliferation and cancer in a number of ways, either directly or indirectly IGF. Because hyperinsulinemia inhibits IGFBP1 in the liver, it increases the amount of bioavailable IGF and may also make cells more sensitive to this hormone. Studies conducted in vitro verified that insulin and IGF, at healthy amounts, promote growth and prevent apoptosis. Additionally, hyperinsulinemia may promote the migration of tumor cells. Furthermore, both cancer cells and normal tissue express insulin and IGF receptors widely. More often expressed is the infrared-A receptor, which has a more marked mitogenic effect than a metabolic one. Additionally, insulin resistance preserves downstream mutagenesis signaling effects while primarily impairing metabolic cell responsiveness. Phase III results were disappointing, despite early phase clinical trials showing that IGF-1R specific antibodies are making colon cancer stem cells more sensitive to treatment[27].

Based on studies above, DM has been consistently associated with adverse ovarian cancer outcomes, including more advanced stage at diagnosis, higher all-cause and cancer-specific mortality, and reduced progression-free survival. These associations appear strongest among women with long-standing diabetes, poor glycemic control, or concomitant obesity, suggesting a cumulative effect of metabolic dysregulation. Importantly, the studies have shown that the observed risk persists after adjustment for confounders such as body mass index (BMI), age, and reproductive factors, supporting an independent contribution of DM-related pathophysiology.

PATHOPHYSIOLOGICAL MECHANISMS LINKING DIABETES TO OVARIAN CARCINOGENESIS

There is a complicated relationship between diabetes and cancer. From a molecular perspective, evidence indicates that hyperinsulinemia, adipokine imbalances, raised IGF-1, and elevated cytokine and estrogen levels probably all contribute to both a higher risk of cancer and worse cancer outcomes[12]. The idea that diabetes raises the incidence of colorectal, breast, and endometrial cancers, among other malignancies, and may be linked to a lower survival rate for colon, pancreatic, and breast cancers is supported by data from several epidemiologic investigations and meta-analyses. Obesity, a well-known risk factor for cancer development and death, appears to have no bearing on this effect[12]. It is theoretically conceivable that T2DM-induced hyperglycemia and hyperinsulinemia encourage tumorigenesis. Through the activation of IGF-1 and the reduction of IGFBP, insulin promotes the development of cancer cells[28].

Oxidative stress and hyperglycemia are key factors in the production of AGEs. AGEs and reactive oxygen species contribute significantly to cellular and molecular damage associated with aging. Beyond inducing DNA adducts and strand breaks, these reactive molecules promote mutagenesis and genomic instability, thereby playing a central role in age-related pathological processes. Glycation increases oxidative stress and inflammation, which intensifies biomolecular damages linked to aging[29]. According to Krisanits et al[30], AGEs leave a permanent mark on healthy breast tissues. Through the molecular start of receptor for advanced glycation end-products, the metabolic imprint of AGEs might progress into potentially hyperplastic lesions. The AGE-induced metabolic memory in otherwise healthy tissue micro-milieu is essential for the imminent initiation of malignancies. This is summarized in Figure 1.

Figure 1 Mechanistic pathways linking diabetes mellitus to ovarian carcinogenesis. IGF: Insulin-like growth factor; ROS: Reactive oxygen species; AGE: Advanced glycation end-products.

The existence of complications or comorbidities, the duration of diabetes, the profiles of antidiabetic medication and different degrees of metabolic controls are some of the confounding factors that are directly linked to the clinical diversities of diabetes. As a result, accurately assessing cancer risk in individuals with diabetes presents challenges. The interplay between diabetes and cancer is further obscured by a range of shared risk factors, such as age, sex, ethnicity, lifestyle behaviors (including alcohol and tobacco use), dietary patterns, physical inactivity, obesity, and elevated BMI[31]. Even though the majority of research controlled for this and other factors, it is still important to consider the specific roles that food, physical activity, and obesity play in the higher incidence of cancer. Diabetes is frequently caused by several factors, which have also been demonstrated to independently affect cancer risk. Most diabetes individuals are overweight or obese[27]. Rising BMI has been consistently linked to an elevated risk of cancer. In particular, individuals classified as obese (BMI ≥ 30 kg/m²) face a greater likelihood of developing malignancies compared to those who are overweight (BMI 25-29.9 kg/m²)[32]. This increased risk is thought to stem, in part, from obesity-induced insulin resistance and elevated estrogen levels - both of which are implicated in the pathogenesis of estrogen-sensitive cancers. Notably, significant weight gain has been linked to a higher incidence of malignancies in sites such as the cervix, breast, and endometrium[27].

Some cancer cells contain more insulin receptors (IRs), and some tumors may show more activation of IR signaling pathways when hyperinsulinemia is present. Additionally, extensive research has explored the roles of IGF-I and IGF-II, along with their receptor interactions, in cancer development. Insulin indirectly stimulates hepatic production of IGF-I, further influencing tumorigenesis[33]. Furthermore, hyperinsulinemia may decrease levels of IGFBP-1 and IGFBP-3 directly or indirectly, increasing the amount of bioavailable IGF-1. There is more unbound IGF-I available to interact with the IGF-1R when these binding proteins are present in lower amounts. Furthermore, a lot of cancers overexpress IGF-II, which also communicates via IGF-1R and infrared-A, one of the IR isoforms[34]. While increased local IGF-1 synthesis by the tumor and IGF-1R expression negatively affect disease prognosis, several investigations have shown that circulating IGF-1 levels do not correlate with tumor growth[34].

Diabetes is believed to influence tumor development through several mechanisms, including persistent inflammation, elevated insulin levels, and hyperglycemia. In particular, hyperinsulinemia can increase circulating levels of bioavailable IGF-1, which may play a critical role in cancer progression[2]. The impact of hormonal pathways in response to hyperinsulinemia on ovarian cancer seems to be complex. Hyperinsulinemia is linked to ovarian androgen, and ovarian cancer may be influenced by excess androgen. However, irregular menstruation and chronic anovulation are caused by insulin resistance and persistent hyperinsulinemia[35] and these benefits may be predicted to lower the chance for ovarian cancer, since continuous ovulation is a known risk factor for the disease. According to earlier research, alcohol use may contribute to the development of ovarian cancer by increasing levels of circulating estrogens and other hormones, and obesity may increase the risk of ovarian cancer through a hormonal mechanism[36]. Additionally, research in genetics indicates that individuals with a genetic tendency to begin smoking are at an increased risk of developing ovarian cancer[37]. This is summarized in Table 1.

Table 1 Key molecular pathways and mediators through which diabetes mellitus and its metabolic features promote ovarian cancer development and progression.

Mechanism	Key mediators	Proposed pro-tumorigenic effects in ovarian cancer
Hyperinsulinemia	Insulin, infrared-A isoform	Activates PI3K/AKT/mTOR and Ras-mitogen-activated protein kinase pathways, promoting cell proliferation and inhibiting apoptosis
IGF-1 axis activation	IGF-1, IGF-1R	Similar to insulin, stimulates growth and survival pathways. Hyperinsulinemia reduces IGFBPs, increasing bioavailable IGF-1
Chronic hyperglycemia	AGEs, reactive oxygen species	Induces oxidative stress, DNA damage, genomic instability, and chronic inflammation, shaping a pro-tumor microenvironment
Hormonal imbalance	Androgens, estrogens	Hyperinsulinemia may increase ovarian androgen production; altered estrogen metabolism may provide additional growth signals
Chronic inflammation	Adipokines, cytokines	Expanded adipose tissue secretes pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6), promoting tumor growth and progression

PI3K/AKT/mTOR: Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin; IGF-1: Insulin-like growth factor-1; IGF-1R: Insulin-like growth factor-1 receptor; IGFBP: Insulin-like growth factor binding proteins; AGE: Advanced glycation end-product.

It is uncertain what mechanism specifically raises estrogenic stimulation in diabetes. There is evidence that the pituitary-gonadal axis may be altered in diabetics due to aberrant amounts of luteinizing hormone, follicle-stimulating hormone and estrogen. This idea is supported by the discovery made by Distiller et al[38] that DM reduces the pituitary’s sensitivity to luteinizing hormone-releasing hormone. A different theory is put out by Deutsch and Benjamin[39], who speculate that a lower metabolic clearance rate could be the cause of elevated circulating levels of estrone in individuals with overt diabetes. Individuals with diabetes show significantly reduced urinary excretion of steroids such as androstenetriol and pregnenetriol when compared to non-diabetic counterparts. The underlying cause of this alteration remains unclear, with possible explanations including impaired hepatic or renal function, or fluctuations in sex hormone-binding globulin levels[40].

IMPACT OF DIABETES ON OVARIAN CANCER OUTCOMES

DM not only significantly increases the risk of developing various cancers but also negatively influences cancer prognosis. Both conditions are complex and heterogeneous, with a multifactorial interplay potentially driving their association. Beyond hyperglycemia and insulin resistance, diabetes is often accompanied by several metabolic and inflammatory disturbances - including expanded adipose tissue with a detrimental cytokine profile, chronic low-grade inflammation, oxidative stress, dyslipidemia, hypertension, prothrombotic tendencies, and hormonal imbalances[27].

Diabetes has a negative impact on the prognosis of many tumors in addition to dramatically raising the risk of malignancy. First of all, individuals with diabetes appear to receive a cancer diagnosis later than the general population (either because they do not use screening tests or because their caregivers do not give them the attention they need); additionally, they appear to receive less aggressive cancer treatments (e.g., because of neuropathic or renal complications), which would expose them to worse treatment outcomes. Experts list a number of reasons, including a higher incidence of infections, a higher death rate following surgery, increased treatment toxicity, or heightened neoplastic cell aggression while growing in a chronic hyperglycemia/hyperinsulinemia milieu. Regardless of gender, patients with long-term diabetes receiving insulin therapy have a particularly poor cumulative survival rate for several cancer types[41,42].

In recent studies, the influence on the frequency and outcomes of patients with endometrial cancer has been evaluated by considering medical conditions such as diabetes, alongside prognostic factors like tumor characteristics (including grade and histology), patient attributes (such as age and performance status), and treatment variables (like chemotherapy and surgical cytoreduction)[6]. Lee et al[43] reported that prostate cancer patients with pre-existing DM faced a 29% higher risk of cancer-specific mortality and a 37% increase in overall mortality. In contrast, the link between DM and mortality in ovarian cancer remains uncertain, as available epidemiological data are limited and yield conflicting conclusions. Nevertheless, our synthesis of the evidence suggests that ovarian cancer patients with DM experience significantly higher long-term mortality compared to those without DM. Since 90% of adult DM is T2D, and none of the included studies particularly addressed T1DM, our findings are largely applicable to T2D[44].

The chemotherapy for advanced ovarian cancer now requires both cisplatin and paclitaxel. A randomized trial comparing treatments for patients with bulky ovarian cancer found that the combination of cisplatin and paclitaxel outperformed cisplatin/cyclophosphamide. Additionally, each treatment demonstrated a high response rate when used as a single agent[45]. Gogas et al[45] evaluated how diabetes affected the toxicity of treatment for ovarian cancer. They discovered that three diabetic individuals out of 21 who received cisplatin developed grade III neuropathy while, six patients had documented nephropathy, and two of them needed their dosages reduced. Two patients had their therapy stopped. Woopen et al[46] were unable to demonstrate that diabetes is a separate cause of neuropathy and neurologic damage in their trial, which included four times as many diabetic individuals as the Gogas et al’s group[45]. They found that kidney grade III/IV toxicities were more common in insulin-using patients. A previous therapeutic termination was not linked to the existence of diabetes per se. On the other hand, early therapy discontinuation was more common among diabetics receiving insulin[46].

Patients with DM and cancer are more susceptible to both hyperglycemia and hypoglycemia. Acute DM consequences, including surgical and medical treatments, can be brought on by conditions like tiredness, dehydration, vomiting and diarrhea, cachexia, and infections. Hyperglycemic hyperosmolar state and diabetic ketoacidosis are potentially fatal diseases that contribute to a number of DM-related deaths (up to 20% for hyperglycemic hyperosmolar state, 2% in patients over 65, and approximately 0.4% for diabetic ketoacidosis)[47].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Metformin in cancer therapy

It is theoretically conceivable that T2DM-induced hyperglycemia and hyperinsulinemia encourage tumorigenesis. It is interesting to note that metformin, a medication used to treat diabetes, lowers insulin and glucose levels and may have anticancer properties. According to epidemiologic research, metformin users have higher cancer survival rates and lower cancer incidences. Additionally, preclinical research supports the drug’s antitumorigenic activity against colon, prostate, and breast cancer. Metformin reduces the growth of cancer cell lines in ovarian cancer in a dose-dependent and time-dependent way, according to two preclinical investigations[28].

Specifically, the reduction of the mTOR signaling pathway has been suggested as one of metformin’s main effects. Metformin reduces circulating insulin and IGF-1 levels while activating the AMP-activated protein kinase/Liver kinase B1 signaling pathway. This activation suppresses the mTOR pathway, ultimately leading to decreased insulin signaling, protein synthesis, and cellular proliferation[48]. Nonetheless, the potential function of metformin as a cancer prevention medication for patients is still debatable and is currently the subject of many research. In individuals with diabetes, metformin treatment was not substantially linked to a lower risk of cancer[49]. To better understand metformin’s influence on cancer development, there is a need for extensive population-based cohort studies alongside forward-looking mechanistic investigations. Given the complexity of DM, effective management requires coordinated care and self-management strategies to reduce complications[50]. Diabetes treatment in cancer patients necessitates an all-encompassing and cooperative strategy. To provide proper care and lower the risk of complications, oncologists and diabetologists must work together and communicate[47].

Potential role for glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitors

Emerging antidiabetic drug classes such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer mechanisms that may attenuate pathways linking diabetes to ovarian cancer. GLP-1 RAs improve glycemic control and mitigate hyperinsulinemia, thereby reducing activation of insulin/IGF-1 signaling that drives tumorigenic PI3K/AKT/mTOR pathways - key mediators implicated in diabetes-associated oncogenesis. Epidemiologic evidence suggests that GLP-1 RA use in adults with overweight or obesity is associated with a lower overall cancer incidence, including a statistically significant reduction in ovarian cancer risk compared with non-use (hazard ratio approximately 0.53), supporting the hypothesis that metabolic modulation can influence cancer outcomes in high-risk populations[51]. Beyond metabolic control, GLP-1 RAs demonstrate anti-inflammatory and antioxidative properties, including reductions in circulating interleukin-6, tumor necrosis factor-α, and C-reactive protein, which may mitigate the chronic inflammatory milieu implicated in ovarian tumorigenesis[52] as seen in Figure 2.

Figure 2 Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors: Disrupting diabetes-ovarian cancer link. GLP-1: Glucagon-like peptide-1; IGF: Insulin-like growth factor; SGLT2: Sodium-glucose cotransporter-2.

Similarly, sodium-glucose cotransporter-2 (SGLT2) inhibitors may interrupt diabetes-driven carcinogenic processes by reducing systemic glucose levels independently of insulin, thereby limiting substrate availability for tumor glycolysis and metabolic reprogramming. Additionally, SGLT2 inhibitors have been shown to decrease oxidative stress, improve mitochondrial efficiency, and lower circulating insulin levels, collectively counteracting pro-oncogenic signaling cascades[53]. Early observational studies suggest neutral to favorable cancer outcomes with SGLT2 inhibitor use, but robust data specific to ovarian cancer are lacking. Together, GLP-1 RAs and SGLT2 inhibitors represent promising therapeutic strategies that may interrupt metabolic, inflammatory, and growth factor-mediated pathways linking DM to ovarian cancer, warranting focused mechanistic and clinical investigation.

Integrated care models

The Diabetes Oncology Program serves as a coordinated care initiative established within a major community cancer center, aiming to improve outcomes for patients managing both cancer and diabetes. Studies evaluating integrated care models indicate that coordinated, multidisciplinary management confers significant clinical benefits for patients with co-existing DM and ovarian cancer by addressing the bidirectional interactions between metabolic disease and malignancy[50]. These models typically integrate gynecologic oncology, endocrinology, primary care, nutrition, nursing, and supportive services within a structured care pathway, enabling concurrent optimization of glycemic control, cancer treatment, and symptom management. Evidence from oncology populations with diabetes demonstrates that proactive glucose monitoring, individualized antihyperglycemic regimens, and early endocrinology involvement reduce chemotherapy-related hyperglycemia, infection rates, and treatment interruptions, thereby improving treatment tolerance and adherence. Integrated models also facilitate perioperative metabolic optimization, which has been associated with lower surgical morbidity, shorter hospital stays, and improved recovery in patients undergoing cytoreductive surgery. Importantly, coordinated care supports individualized decision-making regarding antidiabetic therapies with potential anticancer benefits, while minimizing drug-drug interactions and hypoglycemia risk during chemotherapy. From a systems perspective, integrated care enhances communication across specialties, reduces fragmented care, and improves patient-reported outcomes, including quality of life and treatment satisfaction. Collectively, available evidence suggests that integrated care models not only mitigate the adverse prognostic impact of DM on ovarian cancer outcomes but also provide a scalable framework for delivering patient-centered, metabolically informed oncologic care in this high-risk population[50].

CONCLUSION

The intersection of DM and ovarian cancer represents a clinically significant and biologically complex relationship. Diabetes, particularly T2DM, not only increases the risk of ovarian cancer but also worsens its prognosis through metabolic dysregulation, hyperinsulinemia, chronic inflammation, and hormonal imbalance. Epidemiological evidence demonstrates poorer survival and increased treatment-related complications among diabetic women with ovarian cancer. Meanwhile, preclinical and clinical studies suggest that antidiabetic agents - especially metformin - may confer protective effects, though findings remain inconsistent. Given the rising global burden of both diabetes and ovarian cancer, it is essential to adopt integrated and multidisciplinary approaches to patient care. Future research should prioritize mechanistic studies, prospective cohort analyses, and randomized clinical trials to clarify causal pathways, therapeutic opportunities, and to evaluate the efficacy of GLP-1 RA in ovarian cancer patients may be beneficial. Ultimately, a deeper understanding of these intersecting conditions may guide precision medicine strategies, improve treatment outcomes, and reduce mortality in women affected by both diabetes and ovarian cancer. Given that this is a review article, it has inherent limitations, including the absence of a formal systematic review or meta-analytic framework. Consequently, study selection may be susceptible to selection and publication bias, and the available evidence is constrained by the limited number of randomized controlled trials.