Interlinked Epidemics: Unraveling the Association Between Diabetes and Cancer

Over the past two decades, a growing body of epidemiological studies has provided compelling evidence that diabetes, particularly type 2 diabetes mellitus (T2DM), is associated with an increased risk of developing several malignancies [9]. Large-scale cohort and case–control studies have consistently reported higher incidence and mortality rates for certain cancers among individuals with diabetes compared to non-diabetic populations [9,10]. The most robust associations have been observed for cancers of the liver, pancreas, endometrium, colon, breast, and bladder. Meta-analyses have estimated that T2DM confers approximately a 20–30% higher overall cancer risk, with site-specific risk varying widely depending on cancer type and study population [3-4].

 

Several factors contribute to this observed association. The long duration of diabetes and poor glycemic control appear to magnify cancer risk, suggesting a dose–response relationship. Additionally, the age-related rise in both diabetes and cancer prevalence amplifies their co- occurrence, as older adults are disproportionately affected by both conditions [10,11]. Gender differences have also been reported; for example, women with diabetes show a relatively higher risk for endometrial and postmenopausal breast cancers, while men exhibit stronger associations with liver and pancreatic cancers [1-3,11]. Importantly, some studies have demonstrated that the increased risk persists even after adjusting for shared risk factors such as obesity, physical inactivity, and smoking, indicating that diabetes itself contributes independently to carcinogenesis.

 

While observational studies cannot establish direct causality, the consistent associations across diverse populations, combined with biological plausibility, strongly support diabetes as a significant risk factor for cancer [2]. This epidemiological link underscores the urgency to explore the mechanistic pathways underlying this relationship, which may provide novel avenues for cancer prevention and management in diabetic patients.

 

Etiology and Pathogenesis

The etiology of diabetes-associated cancer is rooted in a convergence of metabolic, hormonal, and inflammatory disturbances that arise from chronic diabetic states [10,11]. Type 2 diabetes mellitus (T2DM), which accounts for the majority of diabetes cases, is primarily driven by insulin resistance, compensatory hyperinsulinemia, and persistent hyperglycemia—all of which play pivotal roles in promoting oncogenesis [7]. Hyperinsulinemia stimulates insulin and insulin-like growth factor-1 (IGF-1) receptors on various tissues, activating proliferative signaling cascades such as the PI3K/Akt/mTOR and MAPK/ERK pathways, thereby fostering uncontrolled cell growth and inhibiting apoptosis [12,13]. Concurrently, chronic hyperglycemia induces oxidative stress through the overproduction of reactive oxygen species (ROS), resulting in DNA damage, mutagenesis, and genomic instability—key initiators of malignant transformation [8].

 

Figure 1: Pathological factors which create pre-tumorigenic environment

 

Moreover, both T2DM and obesity are associated with a state of chronic low-grade inflammation, marked by increased levels of pro-inflammatory cytokines (TNF-α, IL-6, CRP) that activate nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways, enhancing tumor-promoting processes such as angiogenesis, invasion, and metastasis [14,15]. Dysregulated adipokines, such as reduced adiponectin and elevated leptin, further contribute to cancer development by promoting cellular proliferation and inflammatory signaling. Epigenetic alterations triggered by hyperglycemia—such as aberrant DNA methylation, histone modification, and microRNA dysregulation—can silence tumor suppressor genes or activate oncogenes, establishing a molecular environment conducive to cancer initiation and progression [16-18]. Collectively, these interlinked pathophysiological mechanisms create a pro-tumorigenic milieu that explains the elevated cancer risk observed in individuals with diabetes.

 

Pathophysiological Factors Involved in Diabetes-Induced Cancer

A.          Hyperinsulinemia and Insulin Resistance

v  Excess insulin (due to insulin resistance) acts as a growth factor.

v  Activates insulin receptors (IR) and IGF-1 receptors, promoting:

o   PI3K/Akt/mTOR signaling

o   Cell proliferation

o   Anti-apoptotic effects

v  Increases risk especially for breast, colorectal, and endometrial cancers.

v  Drives both hyperglycemia and hyperinsulinemia.

v  Results in increased free fatty acids (FFAs), which:

o   Contribute to lipotoxicity, inflammation, and cancer-promoting environments [7,19,20].

 

Type 2 diabetes is characterized by insulin resistance, which leads to compensatory hyperinsulinemia. Elevated circulating insulin can activate the insulin receptor (IR) and insulin- like growth factor-1 receptor (IGF-1R) signaling pathways, both of which promote cellular proliferation, inhibit apoptosis, and enhance survival of pre-malignant and malignant cells [19,21]. Activation of the PI3K/Akt/mTOR and MAPK/ERK pathways downstream of IR and IGF-1R contributes to uncontrolled cell cycle progression and tumor growth [22].

 

B.           Chronic Hyperglycemia and Oxidative Stress

v  High glucose levels directly:

o   Fuel aerobic glycolysis (Warburg effect) in cancer cells [18].

o   Promote advanced glycation end products (AGEs) → bind to RAGE → trigger inflammation and oxidative stress [23].

o   Enhance Wnt/β-catenin signaling, increasing oncogene expression [24].

v  Persistent hyperglycemia causes excess reactive oxygen species (ROS).

v  ROS damage DNA, proteins, and lipids:

o   Leads to mutations and genomic instability.

o   Triggers pro-survival pathways (PKC, MAPK) [8,25].

 

Persistent hyperglycemia drives the overproduction of reactive oxygen species (ROS), causing oxidative stress, DNA damage, and genomic instability—hallmarks of cancer initiation. High glucose levels can also lead to the formation of advanced glycation end products (AGEs) that interact with their receptor (RAGE), triggering inflammatory and pro-survival signaling cascades [8,23]. In addition, hyperglycemia alters cellular metabolism by promoting glycolytic flux, which supports the metabolic demands of rapidly dividing cancer cells.

 

C.          Chronic Inflammation and Cytokine Signaling

v  Diabetes is a low-grade inflammatory state.

v  Elevated cytokines (e.g., IL-6, TNF-α) and C-reactive protein (CRP) activate: o NF-κB and JAK/STAT3 pathways → promote tumor initiation and progression.

·  Induce epithelial-to-mesenchymal transition (EMT) and angiogenesis [15, 26].

 

Diabetes is associated with low-grade systemic inflammation characterized by elevated levels of pro-inflammatory cytokines such as TNF-α, IL-6, and CRP. These inflammatory mediators can induce activation of transcription factors like NF-κB and STAT3, which regulate genes involved in proliferation, angiogenesis, invasion, and metastasis [15, 26]. The chronic inflammatory milieu also contributes to immune evasion by tumor cells and fosters a tumor-supportive microenvironment.

 

D.          Adipokine Dysregulation and Obesity-Linked Pathways

v    Leptin is increased: promotes angiogenesis, cell proliferation.

v    Adiponectin is decreased: removes its protective anti-inflammatory effect.

v    Elevated cholesterol and triglycerides alter membrane fluidity, hormone synthesis, and activate pro-carcinogenic signaling [14, 27].

 

Obesity, which frequently coexists with type 2 diabetes, further amplifies cancer risk through dysregulation of adipokines [20, 28]. Decreased adiponectin and elevated leptin levels promote cell proliferation, angiogenesis, and inflammatory signaling. Increased circulating free fatty acids and lipid metabolites can also activate oncogenic pathways and induce insulin resistance, creating a feed-forward loop that enhances tumorigenesis.

 

E.           Epigenetic Alterations and Genetic Susceptibility

v  Diabetes induces epigenetic alterations (e.g., DNA methylation, histone acetylation) in oncogenes and tumor suppressor genes [29].

v  T2DM compromises T-cell and NK cell function, allowing immune evasion by tumors [30].

 

Table: Etiological Factors in Clinical Trials for Diabetes-Induced Cancer

 

Hyperglycemic and hyperinsulinemic conditions can influence gene expression through epigenetic mechanisms such as DNA methylation, histone modifications, and altered microRNA profiles [31]. These changes may disrupt tumor suppressor gene function or enhance oncogene activation, thereby predisposing diabetic individuals to malignant transformation. Genetic polymorphisms in insulin signaling or glucose metabolism pathways may further modulate individual susceptibility to both diabetes and cancer.

 

MOLECULAR AND CELLULAR MECHANISMS LINKING DIABETES TO CANCER

Figure 2: Role of Signalings in Diabetes and Cancer

 

The molecular crosstalk between diabetes and cancer involves a complex interplay of metabolic and growth-signaling networks. Chronic hyperglycemia and hyperinsulinemia dysregulate:

v    PI3K/Akt/mTOR and MAPK/ERK for growth and survival

v    Wnt/β-catenin for proliferation and EMT

v    AMPK suppression removing growth brakes

v    ROS/NF-κB to drive inflammation and mutation

v    RAGE/TGF-β pathways fostering immunosuppression and angiogenesis [7,23,24].

 

These signaling axes not only explain higher cancer risks in diabetic patients but also suggest actionable drug targets (e.g., metformin, pathway inhibitors) [32].

 

The biological interplay between diabetes and cancer is multifaceted, involving a complex network of metabolic, hormonal, inflammatory, and genetic pathways that collectively create a pro-tumorigenic environment. Several key mechanisms have been identified that may explain how chronic diabetic states contribute to the initiation and progression of malignancies.

 

The molecular interplay between diabetes and cancer involves a complex network of signaling pathways and cellular processes that synergistically promote oncogenesis. Central to this link is insulin resistance, which drives chronic hyperinsulinemia—a hallmark of type 2 diabetes. Excess insulin activates the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) on epithelial and stromal cells, triggering downstream PI3K/Akt/mTOR and RAS/RAF/MEK/ERK (MAPK) signaling cascades [12,19,33]. These pathways enhance cellular proliferation, protein synthesis, and survival while suppressing apoptosis, thereby creating a proliferative advantage for premalignant cells. Concurrently, hyperglycemia increases intracellular glucose uptake, fueling the Warburg effect (aerobic glycolysis) which supports rapid tumor growth by providing biosynthetic precursors and ATP. Excess glucose also enhances the formation of advanced glycation end products (AGEs), which bind to their receptor RAGE and activate NF-κB signaling, leading to transcription of genes involved in inflammation, angiogenesis, and metastasis [13,23,34].

 

Additionally, chronic high glucose induces mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, resulting in oxidative DNA damage, double-strand breaks, and genomic instability—critical drivers of mutagenesis and malignant transformation. The diabetic state is also characterized by chronic low-grade inflammation, with elevated IL-6, TNF- α, and CRP promoting activation of STAT3, NF-κB, and COX-2 pathways, which stimulate angiogenesis, immune evasion, and epithelial-to-mesenchymal transition (EMT) [35, 36]. Adipokine dysregulation further contributes to tumorigenesis: leptin activates JAK/STAT and MAPK pathways to promote proliferation and angiogenesis, while reduced adiponectin removes inhibitory signals on AMPK, allowing unchecked mTOR activation. Finally, epigenetic reprogramming induced by hyperglycemia—including aberrant DNA methylati, histone acetylation, and altered microRNA expression—can silence tumor suppressors and activate oncogenes, cementing the malignant phenotype [27,37,38]. Together, these interwoven molecular events explain how the diabetic milieu acts as a potent driver of cancer initiation, progression, and metastasis.

 

A.          Hyperglycemia-driven signaling bridges diabetes and cancer

Chronic hyperglycemia activates key oncogenic signaling pathways, including PI3K/Akt/mTOR, Wnt/β-catenin, and O-GlcNAcylation, leading to enhanced cell proliferation and survival. Persistent high glucose also promotes metabolic reprogramming, oxidative stress, and pro- inflammatory cytokine production, creating a tumor-promoting microenvironment [39,40]. Collectively, these molecular alterations establish a mechanistic link between diabetes and increased cancer risk, progression, and therapeutic resistance.

 

B.           Insulin–PI3K signalling: a metabolic driver of cancer

Chronic hyperinsulinemia enhances activation of the insulin receptor–PI3K/Akt pathway, stimulating downstream mTOR signaling and promoting cell growth and survival. This persistent signaling accelerates anabolic metabolism, increases glucose uptake, and supports biosynthetic   processes   essential   for   tumor   development   [7,12,41]. Sustained insulin–PI3K activation therefore acts as a metabolic driver linking type 2 diabetes with cancer progression and reduced therapeutic responsiveness.

 

C.          Integrating metabolic and molecular circuits in diabetes, obesity and cancer

Diabetes and obesity disrupt systemic metabolic homeostasis, leading to chronic hyperglycemia, hyperinsulinemia, and      altered   adipokine            signaling. These metabolic disturbances converge on shared molecular circuits such as PI3K/Akt/mTOR, AMPK, and inflammatory pathways that regulate cell growth, survival, and energy balance [42,43].

 

The integration of these metabolic and oncogenic networks establishes a mechanistic framework linking metabolic disorders with cancer initiation, progression, and therapeutic outcomes.

 

D.          Molecular basis of carcinogenesis in diabetic patients

Chronic hyperglycemia and hyperinsulinemia activate oncogenic signaling pathways such as PI3K/Akt/mTOR and MAPK, promoting uncontrolled cell proliferation and survival. Increased oxidative stress, advanced glycation end products (AGEs), and persistent low-grade inflammation further induce DNA damage and genomic instability [12,20]. Together, these metabolic and molecular alterations create a pro-tumorigenic environment that enhances cancer initiation, progression, and resistance to therapy in diabetic patients.

 

E.           Metabolic and hormonal remodeling of colorectal cancer signaling by diabetes

Diabetes-associated hyperglycemia and hyperinsulinemia reshape colorectal cancer signaling by persistently   activating   PI3K/Akt/mTOR   and   Wnt/β-catenin   pathways. Altered insulin, IGF-1, and adipokine profiles further enhance proliferative, anti-apoptotic, and pro-angiogenic               signaling              within    the          tumor    microenvironment. This metabolic and hormonal reprogramming promotes tumor growth, invasion, and therapeutic resistance in colorectal cancer patients with diabetes [44,45].

 

F.           mTOR complexes in diabetes-cancer interplay

mTOR exists as two functionally distinct complexes, mTORC1 and mTORC2, which integrate nutrient, insulin, and growth factor signals to regulate cell growth and metabolism. In diabetes, chronic hyperinsulinemia and nutrient excess lead to sustained activation of mTOR signaling, promoting anabolic processes and inhibiting autophagy [12,13]. This persistent mTOR dysregulation fosters tumor initiation, progression, and metabolic reprogramming, thereby linking diabetic metabolic imbalance with cancer development.

 

Table 2: Major Signaling Pathways in Diabetes-Induced Cancer

 

5.           Drugs in Clinical Trials for Diabetes-Induced Cancer

Emerging evidence highlighting the interplay between diabetes and cancer has prompted several clinical trials investigating pharmacological interventions that may simultaneously target metabolic dysregulation and tumor progression.

 

Table 3: Drugs in Clinical Trials for Diabetes-Induced Cancer

 

Metformin, a first-line antidiabetic agent, is one of the most extensively studied drugs, with numerous trials evaluating its potential to reduce cancer incidence and improve survival outcomes by activating AMPK, inhibiting mTOR signaling, and suppressing cancer cell proliferation. Thiazolidinediones, such as pioglitazone, are also under investigation for their ability to modulate PPAR-γ activity, thereby exerting anti-inflammatory and antiproliferative effects in certain malignancies. Additionally, newer classes of antidiabetic drugs, including GLP-1 receptor agonists and SGLT2 inhibitors [46-51], are being evaluated in clinical settings to determine their impact on tumor metabolism, angiogenesis, and metastatic behavior. Combination therapies involving conventional chemotherapeutics with metabolic modulators are another focus, aiming to improve treatment efficacy and minimize cancer recurrence in diabetic populations [52,53]. These ongoing trials could provide crucial insights into repurposing existing antidiabetic medications or developing novel agents for preventing and managing diabetes-associated cancers.

 

Table 4: Registered Clinical Trials Investigating the Interplay Between Diabetes, Antidiabetic Therapies, and Cancer Outcomes