Insights on metabolic connections and interplay between cancer and diabetes: role of multi-target drugs

Abstract

Cancer is recognized as a leading cause of death globally, imposing significant health burdens. Traditional cancer treatments encompass chemotherapy, surgery, and radiotherapy. Chemotherapy employs cytotoxic chemicals either alone or in combination. However, these therapies can adversely affect normal cells and are hindered by drug resistance. Exploration of alternative therapeutic approaches such as use of antidiabetic drugs for cancer treatment to rule out challenges in current therapy is much needed. Antidiabetic medications like sulfonylureas, biguanides, and thiazolidinediones have demonstrated beneficial effects and are being repurposed for cancer management. The review discusses mechanisms underlying their anticancer properties linked to metabolic factors common to both diseases, including hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity. Nevertheless, certain antidiabetic drugs may pose risks for developing cancer, particularly pancreatic cancer. Despite the concerns, the overall beneficial impact of these agents in cancer treatment outweighs their potential drawbacks. The review highlights the metabolic connections between cancer and diabetes, as well as the mechanistic actions of antidiabetic drugs on cancer.

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Discover Medicine
Review
Insights onmetabolic connections andinterplay betweencancer
anddiabetes: role ofmulti‑target drugs
AngelineJulius1· SureshMalakondaiah1· RaghuBabuPothireddy2
Received: 24 December 2024 / Accepted: 17 March 2025
© The Author(s) 2025 OPEN
Abstract
Cancer is recognized as a leading cause of death globally, imposing signicant health burdens. Traditional cancer treat-
ments encompass chemotherapy, surgery, and radiotherapy. Chemotherapy employs cytotoxic chemicals either alone or
in combination. However, these therapies can adversely aect normal cells and are hindered by drug resistance. Explora-
tion of alternative therapeutic approaches such as use of antidiabetic drugs for cancer treatment to rule out challenges
in current therapy is much needed. Antidiabetic medications like sulfonylureas, biguanides, and thiazolidinediones have
demonstrated benecial eects and are being repurposed for cancer management. The review discusses mechanisms
underlying their anticancer properties linked to metabolic factors common to both diseases, including hyperglycemia,
hyperinsulinemia, inammation, oxidative stress, and obesity. Nevertheless, certain antidiabetic drugs may pose risks
for developing cancer, particularly pancreatic cancer. Despite the concerns, the overall benecial impact of these agents
in cancer treatment outweighs their potential drawbacks. The review highlights the metabolic connections between
cancer and diabetes, as well as the mechanistic actions of antidiabetic drugs on cancer.
Keywords Hyperglycemia· Inammation· Oxidative stress· Multi-target drugs· Anti-diabetic drugs
1 Introduction
Cancer and diabetes are among the most prevalent and challenging diseases of the twenty-rst century, signicantly
contributing to global morbidity and mortality. Both conditions are multifaceted in nature, characterized by intricate
pathophysiological mechanisms involving metabolic dysfunction, chronic inammation, oxidative stress, and dysregu-
lated signaling pathways. The coexistence of these diseases in patients further complicates their management, as shared
risk factors and overlapping molecular pathways can exacerbate disease progression and treatment resistance [1].
Cancer represents a signicant global health challenge, contributing signicantly to mortality rates each year and
imposing substantial nancial burdens on patients. Conventional approaches to cancer treatment are either as stan-
dalone treatments or in combination. Radiotherapy is typically used for localized cancers following surgery, while chemo-
therapy is often the rst-line treatment for initial tumors, targeting rapidly dividing cells with cytotoxic drugs. However,
chemotherapy’s eectiveness is hindered by its cytotoxic eects on cells, such as those in the intestinal epithelium and
bone marrow, and the development of drug resistance [2].
* Angeline Julius, angeline.ibt@bharathuniv.ac.in | 1Centre forMaterials Engineering andRegenerative Medicine, Bharath Institute
ofHigher Education andResearch, Chennai, TamilNadu, India. 2AcaDiCell Innovations International Pvt. Ltd., Peerakankaranai,Vandalur,
TamilNadu, India.

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To overcome these limitations, alternative interventions are being explored. Some studies have investigated the poten-
tial of non-traditional therapeutic agents to address challenges like multidrug resistance and toxicity associated with
conventional anticancer drugs [3]. Epidemiological research has established metabolic links between cancer and type
2 diabetes, characterized by insulin resistance and pancreatic β-cell dysfunction, which increase the risk of cancers [4].
Although the exact mechanisms underlying the relationship between diabetes and cancer are still unknown, hyper-
glycemia, the production of AGEs and oxidative stress, hyperinsulinemia from exogenous insulin use or insulin resistance,
inammation, and obesity are common risk factors for both diseases. Even while diabetes is known to increase the risk
of cancer, several antidiabetic medications have been demonstrated to help prevent cancer [5].
Exogenous insulin therapy is the mainstay of treatment for type 1 diabetes, which is dened as complete insulin insuf-
ciency. Conversely, type 2 diabetes treatment typically involves antidiabetic drugs and lifestyle adjustments. By increas-
ing insulin secretion from pancreatic β-cells, improving insulin sensitivity in peripheral tissues, facilitating glucose uptake
into cells, and reducing glucose reabsorption in the kidneys and intestines, these medications help normalize blood
glucose levels and mitigate associated complications [6]. Remarkably, some of these drugs have demonstrated activity
against cancer cells, potentially inhibiting disease progression. Although some studies suggest that antidiabetic drugs
might pose a cancer risk or accelerate cancer progression, their anti-cancer eects generally outweigh these risks [7].
Traditional approaches to treating cancer and diabetes often focus on targeting single pathways or symptoms. How-
ever, such strategies may fail to address the complex interplay of biological processes underlying these diseases. Multi-
target drugs, designed to simultaneously modulate multiple pathways, represent a paradigm shift in the treatment of
cancer and diabetes. By oering a holistic approach, these drugs hold the potential to improve therapeutic ecacy,
minimize side eects, and address the shared mechanisms that link cancer and diabetes.
Furthermore, the article explores the signicance of multi-target drugs in addressing cancer and diabetes, outlining
challenges and future directions for their development. The objective is to underscore the potential of multi-target
therapies to transform the management of these interlinked diseases, providing insights for researchers and clinicians.
2 Diabetes andcancer
Multi-target drugs represent a transformative approach to managing cancer and diabetes, addressing the shared molecu-
lar and clinical complexities of these diseases. By targeting multiple pathways simultaneously, these therapies oer the
potential to improve ecacy, reduce side eects, and mitigate treatment resistance. Despite challenges in their devel-
opment, advancements in drug design, systems biology, and clinical trial methodologies are paving the way for their
successful implementation. As cancer and diabetes continue to pose signicant global health challenges, multi-target
drugs oer a promising avenue for improving patient outcomes and advancing the eld of medicine [8].
The research landscape exploring the connection between diabetes and cancer has predominantly focused on type
2 diabetes, given its higher prevalence compared to type 1 diabetes. Consequently, there is a signicant gap in under-
standing how type 1 diabetes relates to cancer risk and outcomes. Diabetes type 1 and type 2 have dierent hormonal
and metabolic traits. The autoimmune death of pancreatic beta cells causes type 1 diabetes, which is characterized by
complete insulin insuciency. On the other hand, type 2 diabetes is characterized by relative insulin insuciency and
insulin resistance, frequently combined with hyperglycemia and hyperinsulinemia [9].
Studies investigating diabetes and cancer risk typically include predominantly type 2 diabetes patients, making it chal-
lenging to generalize ndings to type 1 diabetes individuals. This limitation arises because the underlying mechanisms
linking diabetes to cancer can vary signicantly between these two types [10]. For instance, in type 1 diabetes, where
endogenous insulin secretion is decient and exogenous insulin is commonly administered, the dynamics inuencing
cancer development may dier from those in type 2 diabetes, where insulin resistance and higher insulin levels are
prevalent [11].
Several factors inuence the relationship between diabetes and cancer, including obesity, duration of diabetes, and
specic antidiabetic treatments such as insulin therapy. These factors can modify cancer risk through various mechanisms,
aecting cellular processes involved in carcinogenesis. Despite the growing body of research, studies often face limita-
tions such as small sample sizes, ambiguity in dening type 1 diabetes cohorts, short follow-up durations, and inconsist-
ent assessments of diabetes duration [12]. These challenges contribute to varied ndings across dierent cancer types
and hinder precise conclusions about the impact of diabetes, especially type 1 diabetes, on cancer risk and outcomes.
Understanding the mechanistic actions of antidiabetic drugs in the context of cancer management is crucial. Some
medications used in diabetes treatment, such as metformin, have shown potential anticancer eects through pathways

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independent of their glucose-lowering eects (Table1). However, the specic impacts of these drugs in individuals with
type 1 diabetes and their potential role in modifying cancer risk warrant further investigation.
Metformin activates AMPK (AMP-activated protein kinase), a critical energy sensor that regulates metabolic homeo-
stasis. Metformin inhibits hepatic gluconeogenesis, and directly inhibits the mTOR pathway, limiting tumor growth and
proliferation [19]. In cancer, metformin indirectly reduces insulin and IGF-1 levels, depriving tumors of growth signals.
Retrospective and prospective studies show lower cancer incidence and mortality in diabetic patients on metformin,
particularly for colorectal, breast, and pancreatic cancers [20]. Trials are investigating its ecacy in cancer therapy in
non-diabetic patients. However, ecacy appears to vary by cancer type and patient population. Higher doses required
for direct anti-cancer eects may not be well-tolerated due to gastrointestinal side eects [21, 22].
Pioglitazone activates PPAR-γ, improving insulin sensitivity by modulating gene expression involved in glucose and
lipid metabolism [23]. In cancer, PPAR-γ activation induces tumor dierentiation, inhibits proliferation, and promotes
apoptosis. Pioglitazone reduces systemic inammation and angiogenesis by downregulating pro-inammatory cytokines
[24]. Preclinical studies demonstrate anti-cancer eects in models of bladder and breast cancer. Observational studies
show mixed results, with some linking pioglitazone to reduced cancer risk, while others raise concerns about bladder
cancer. Associated with cardiovascular risks its clinical adoption is still under query and lack of randomized trials speci-
cally targeting its use in cancer prevention or therapy [25].
Aspirin irreversibly inhibits COX-1 and COX-2 (Cyclooxygenase enzymes), reducing prostaglandin production, chronic
inammation, and cancer-promoting signaling pathways such as NF-κB [26]. Reduction of platelet aggregation by aspi-
rin, limit metastatic spread by impairing tumor cell-platelet interactions. Studies like CAPP2 conrm its eectiveness in
Lynch syndrome patients depending on dose and duration, with risks outweighing benets in certain populations [27].
Statins inhibit HMG-CoA reductase, reducing cholesterol synthesis. In cancer, statins disrupt the mevalonate pathway,
which is critical to produce intermediates like isoprenoids that promote tumor cell proliferation. Induces apoptosis and
inhibits angiogenesis and metastasis. Observational studies show a reduction in breast, prostate, and colorectal cancer
incidence in diabetic patients, also in preclinical models [28].
Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors (Empagliozin, Dapagliozin) inhibit SGLT2 in the proximal renal
tubules, promoting glucose excretion and reducing blood glucose levels thereby limiting glucose availability for rapidly
proliferating tumor cells [29]. Preclinical studies suggest additional eects on metabolic reprogramming and reduction
in oxidative stress. Emerging evidence suggests reduced cancer-related mortality in patients using SGLT2 inhibitors,
though direct anti-cancer eects remain under investigation. Ongoing trials are exploring their potential synergistic
use with chemotherapy [30].
Liraglutide, Semaglutidem (Glucagon-Like Peptide-1 receptor agonists) mimic GLP-1, enhancing glucose-dependent
insulin secretion, suppressing glucagon release, reduces hyperinsulinemia and systemic inammation. These agonists
may directly target GLP-1 receptors expressed in certain tumors, inhibiting proliferation and inducing apoptosis. Evi-
dence suggests reduced risk of colorectal, pancreatic, and liver cancers in diabetic patients using GLP-1 agonists. Rare
but severe side eects include pancreatitis and possible associations with thyroid cancer.
While diabetes, particularly type 2 diabetes, has been extensively studied about cancer, the evidence regarding type
1 diabetes remains limited. Future research eorts should prioritize delineating the unique interplay between type 1
diabetes and cancer, considering the distinct metabolic and hormonal proles and the implications of diabetes manage-
ment strategies on cancer outcomes [31, 32].
3 Diabetes‑cancer link‑factors thatcontribute
Diabetes may promote cancer initiation or progression through systemic alterations aecting all tissues and localized
mechanisms specic to certain organs. The key factors involved include hyperglycemia, insulin resistance, chronic inam-
mation, and changes in cellular environments that alter growth signaling, apoptosis, and tissue repair [33]. Chronic
hyperglycemia can lead to the formation of advanced glycation end products (AGEs), which are harmful compounds
that accumulate in tissues. AGEs bind to receptors for advanced glycation end products (RAGE), triggering inamma-
tory pathways, oxidative stress, and cellular dysfunction. This can increase the likelihood of cancerous transformation
and metastasis [34].
Furthermore, insulin can stimulate insulin-like growth factor (IGF)-1, which in turn activates various signaling
pathways such as the PI3K/Akt pathway that promote cell proliferation, survival, and resistance to apoptosis [35].

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Table 1 Multi-target drugs used for both cancer and diabetes, emphasizing their mechanisms and clinical signicance
Drug Primary use (diabetes) Mechanism in diabetes Mechanism in cancer Evidence
Metformin First-line treatment for Type 2 Diabetes Activates AMPK, reduces hepatic
gluconeogenesis, improves insulin
sensitivity
Activates AMPK to inhibit mTOR,
reduces insulin/IGF-1, induces cell
cycle arrest and apoptosis
Reduced cancer incidence (breast, colo-
rectal, pancreatic); widely supported
by epidemiological studies [13]
Pioglitazone (TZDs) Improves insulin sensitivity via Peroxi-
some Proliferator-Activated Receptor
Gamma (PPAR-γ)activation
Activates PPAR-γ, reduces inamma-
tion, and enhances glucose uptake PPAR-γ activation inhibits tumor pro-
liferation, promotes apoptosis, and
reduces angiogenesis
Some evidence in bladder and breast
cancer; limited use due to side eects
like cardiovascular risks [14]
Aspirin Anti-inammatory and anti-thrombotic
agent Reduces inammation, indirectly
improving insulin sensitivity Inhibits COX-2, reduces prostaglandins,
inammation, and tumor angiogen-
esis
Associated with lower colorectal and
other cancer risks in diabetic popula-
tions [15]
Statins Lowers cholesterol by inhibiting HMG-
CoA reductase Reduces systemic inammation,
improves endothelial function Inhibits the mevalonate pathway, sup-
presses tumor growth, angiogenesis,
and metastasis
Linked to reduced cancer risk (breast,
prostate, colorectal) in diabetic
patients [16]
SGLT2 Inhibitors Promotes glucose excretion via kidney
ltration Lowers blood glucose and insulin levels Limits glucose availability to cancer
cells, may disrupt tumor metabolic
pathways
Emerging evidence suggests reduced
cancer mortality in diabetic patients
[17]
GLP-1 Agonists Enhances glucose-dependent insulin
secretion Activates GLP-1 receptors, reduces
hyperinsulinemia and systemic
inammation
Reduces proliferation in GLP-1
receptor-positive tumors, lowers can-
cer risk indirectly through metabolic
improvement
Shown to reduce risks of colorectal and
pancreatic cancers in clinical studies
[18]

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Chronic activation of these pathways in cells can lead to uncontrolled growth, a hallmark of cancer. In the colon,
increased insulin and IGF-1 levels contribute to enhanced epithelial cell proliferation and decreased apoptosis that
accelerates the development of colorectal cancer [36]. High levels of estrogen during hyperinsulinemia particularly
in postmenopausal women, has been linked to the initiation and progression of breast cancer. Locally, specific organs
are affected by altered insulin signaling, changes in the tumor microenvironment, and dysregulated metabolic pro-
cesses. These factors increase the risk of developing a variety of cancers, including those of the pancreas, liver, colon,
breast, and endometrium. Understanding these mechanisms is crucial for developing strategies to reduce cancer
risk in people with diabetes [37].
Chronic systemic inflammation in diabetes causes elevated levels of inflammatory cytokines (TNF-α, IL-6, and CRP)
in the blood and have been linked to cancer development and progression by causing DNA damage, mutations,
and genomic instability, all of which are critical for cancer initiation. Inflammation can create a tumor-promoting
microenvironment by modifying the extracellular matrix, increasing the availability of growth factors, and enhancing
angiogenesis. Inflammatory signaling pathways such as the NF-κB and JAK/STAT pathways contribute to both insulin
resistance and tumorigenesis by promoting DNA damage, angiogenesis, and metastasis [38].
Diabetes not only affects cancer incidence but also impacts cancer prognosis and mortality [39, 40]. This increased
risk of mortality applies to various cancers, including colorectal cancer, where diabetes is associated with higher
cancer-specific case fatality [41]. In terms of mortality outcomes, diabetes plays a more significant role downstream,
affecting cancer-specific case fatality and overall mortality rates more than it does in influencing the initial incidence
of cancer. This trend is particularly notable in pancreatic cancer, where diabetes is strongly linked to both incidence
and poorer survival outcomes [42]. Probable population-based investigations and top-notch datasets are crucial
for comprehending these correlations. Potential confounding variables like age, body weight, physical activity lev-
els, food preferences, and other medical issues should all be carefully taken into account and adjusted for in these
investigations [43].
While diabetes clearly associated with increased risks of specific cancers and poorer outcomes in cancer patients,
further research is needed to elucidate the precise mechanisms and to comprehensively assess the impact across
different cancer types and populations [44]. It’s important to note that specific regions or populations may exhibit
unique associations between diabetes and certain cancers. Studies analyzing type 1 diabetes cohorts have indicated
elevated risks for some cancers compared to the general population, although findings have not been consistent
across all studies [45]. Recommendations have been made to focus studies on specific cancer types rather than overall
cancer incidences when exploring the relationship between type 2 diabetes and cancer, considering variations in
site-specific cancer patterns influenced by biological, clinical, or socioeconomic factors [46]. Figure1 illustrates the
linkage between diabetes and cancer.
Fig. 1 Linkage between dia-
betes and cancer

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3.1 Hyperglycaemia
Patients with cancer frequently exhibit glucose intolerance, which raises concerns regarding a possible connection
between type 2 diabetes and cancer, especially in light of the effects of elevated blood glucose levels [47]. Divergent
theories exist today on how increased blood glucose levels affect the development of cancerous cells. However, it
has been shown that hyperglycemia can enhance the generation of reactive molecules and free radicals, which can
cause oxidative damage to DNA, a crucial stage in the development of cancer. Proto-oncogenes and tumor suppres-
sor genes may experience alterations because of this oxidative stress. Glycated hemoglobin levels, which indicate
non-enzymatic and irreversible hemoglobin glycation and may also contribute to oxidative stress and cancer, can
also be used to evaluate persistent hyperglycemia [48]. This is corroborated by a study conducted in the general
Korean population, which discovered a correlation between a 3.03-fold increase in the risk of all cancer types and a
39.4% increase in glycated hemoglobin, indicating glycated hemoglobin as a causative risk factor. However, evidence
from large randomized controlled trials indicates that improving glycemic control in type 2 diabetes does not reduce
cancer risk, challenging the direct link between hyperglycemia and increased cancer risk. Furthermore, the complex
interaction of hyperglycemia with insulin resistance and obesity complicates the analysis of its independent impact
on cancer risk [49].
Furthermore, elevated glucose levels cause the glycation of proteins to increase and the production of AGEs, which
have been linked to the development of cancer and long-term consequences from diabetes. AGEs damage proteins
and modify the extracellular matrix directly, and they bind to the receptor for advanced glycation end products
(RAGE), triggering oxidative stress and inflammation[50]. The AGE-RAGE interaction is implicated in various path-
ways that promote cancer progression, such as inducing platelet-derived growth factor-B in pancreatic cancer and
promoting thrombogenesis, angiogenesis, and inflammation via specific signaling pathways[51].
Furthermore, cancer cells often rely on anaerobic glucose metabolism, leading to increased glycolysis and sub-
sequent AGE formation as a by-product. This dual effect of diabetes and cancer results in heightened AGE-RAGE-
dependent stress responses, fostering oxidative stress and chronic inflammation, which create a conducive environ-
ment for both diseases’ progression [1].
Excessive glucose levels under hyperglycemic circumstances also affect immune function by reducing ascorbic
acid delivery into immune cells in a competitive manner, which hinders immune cells’ capacity to carry out essential
tasks for fighting cancer cells. This phenomenon underscores how hyperglycemia can promote anabolic metabolism
in cancerous cells, fueling their growth and increasing the cancer risk associated with diabetes [52].
Pathways such as Wnt signaling link metabolic diseases like hyperglycemia and obesity with increased cancer risk
[33]. These connections highlight the intricate interplay between diabetes, cancer, and metabolic dysregulation,
emphasizing the need for further research into their shared mechanisms and potential therapeutic targets. Mecha-
nisms involved in linking hyperglycemia and cancer are listed in Table2.
3.2 Hyperinsulinemia
Hyperinsulinemia plays a significant role in cancer development by promoting anabolic and anti-apoptotic processes.
Experimental studies on animals have shown that models lacking insulin or with hyperglycemia exhibit fewer tumors
that progress slowly. Conversely, administering insulin reverses these effects, highlighting its mitogenic properties
[67].
Insulin binds to insulin receptors (IR), hybrid receptors (IR-IGF-IR), or insulin-like growth factor-insulin receptors
(IGF-IR) to produce its effects. IGF-IR is more extensively distributed in all tissue types [68]. A bad prognosis is linked
to the overexpression of IR in breast and prostate cancer cells, indicating that both receptors are involved in promot-
ing tumour growth. Insulin binding to its receptors initiates downstream signaling pathways like RAS/RAF/MEK/ERK
and Akt/protein kinase B, promoting cell proliferation and inhibiting apoptosis. The homology between insulin and
IGF-1 allows them to interact with either IR or IGF-IR, potentially forming hybrid receptors in tissues where both are
co-expressed [69]. These hybrid receptors, particularly in malignant breast and thyroid tissues, contribute to enhanced
cellular proliferation in response to insulin and IGF-1.
Moreover, insulin decreases the liver’s synthesis of IGFBP-1/2, proteins that typically block the effects of IGF-1.
Increased amounts of free circulating IGF-1, a powerful mitogen that stimulates the development of pre-cancerous

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Table 2 Factors linking hyperglycemia and cancer
Factor Mechanism Examples of associated cancers
Insulin Resistance Increases insulin and IGF-1 levels, promoting cell proliferation and reducing apoptosis Breast [53], Colorectal [54]
Oxidative Stress Elevated glucose leads to excessive ROS production, causing DNA damage and mutations Lung [55], Pancreatic [56]
Chronic Inammation Persistent hyperglycemia activates inammatory pathways (e.g., NF-κB), enhancing tumor growth Liver [57], Prostate [58]
Epigenetic Alterations Hyperglycemia induces histone modications and altered gene expression, fostering malignancy Gastric [59], Colon [60]
Angiogenesis Promotion High glucose increases VEGF levels, supporting new blood vessel formation for tumors Renal Cell Carcinoma [61],
Glioblastoma [62]
Altered Metabolism Provides excess glucose as fuel for cancer cell glycolysis (Warburg eect) Cervical [63], Liver [64]
Immune Evasion Impairs immune surveillance by reducing T-cell activity in a hyperglycemic environment Melanoma [65], Ovarian [66]

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cells expressing insulin, IGF-1, and hybrid receptors, are the result of this reduction. Proinflammatory cytokines are
released as a result of hyperinsulinemia, which promotes carcinogenesis even more [54]. In summary, hyperinsuline-
mia fosters tumor development through multiple mechanisms involving insulin and IGF-1 signaling, highlighting
its potential role in promoting cancer progression, especially in conditions like obesity and diabetes where insulin
levels are elevated.
3.3 Wnt/β‑catenin signaling pathway
The Wnt/β-catenin and mammalian target of rapamycin (mTOR) signaling pathways are critical in regulating cell processes
and have signicant implications in both cancer and type 2 diabetes [70]. Essential for several physiological processes,
including stem cell maintenance, epithelial-mesenchymal transition, and embryonic development, is the Wnt/β-catenin
pathway. Birth abnormalities and the emergence of cancers such as hepatocellular carcinoma, colon cancer, leukemia, and
metabolic illnesses like type 2 diabetes are linked to modications in this system caused by mutations in its constituent
parts [70]. The two main pathways that drive this process are the non-canonical pathway and the canonical Wnt signal-
ing dependent on β-catenin [71]. Hyperglycemia, characteristic of conditions like obesity and diabetes, enhances Wnt
signaling by promoting nuclear accumulation of β-catenin, thereby stimulating continuous expression of genes crucial
for cell proliferation and survival [72].
High glucose levels promote the formation of the lymphoid enhancer factor/β-catenin complex, leading to increased
acetyltransferase activity of p300 and reduced deacetylase activity of SIRT1. This results in the acetylation of β-catenin
at lysine 354, facilitating its nuclear translocation and activation of Wnt target genes. Dysregulation or mutations in
components such as adenomatous polyposis coli (APC), Axin, and β-catenin can lead to constitutive activation of the
pathway, contributing to malignancies like colorectal and hepatocellular carcinomas (Fig.2) [72].
Dysregulation of mTOR signaling is associated with insulin resistance, tumor formation, angiogenesis, and immune cell
activation. mTOR exists in two complexes: mTORC1, which regulates anabolic processes and cell growth, and mTORC2,
which inuences cell survival and cytoskeletal organization [73].
Activation of mTORC1 promotes cell growth and proliferation by enhancing protein synthesis and inhibiting
autophagy. This pathway is often constitutively activated in cancers due to mutations or alterations in upstream regula-
tors such as PI3K, AKT, and PTEN. Mutations in these components lead to persistent mTORC1 activation, driving tumori-
genesis in various cancers including breast, colorectal, and prostate cancers [74].
Both the Wnt/β-catenin and mTOR signaling pathways play crucial roles in regulating cell growth, proliferation, and
metabolism, and their dysregulation is implicated in the pathogenesis of cancer and type 2 diabetes. Understanding
these pathways’ intricate mechanisms and their interactions with other cellular processes is essential for developing
Fig. 2 Hyperglycemia induced
dysregulation of components
such as adenomatous polypo-
sis coli (APC), Axin, Dishev-
elled (DVL), Casein kinase 1
alpha (CK1α), GSK-3 beta and
formation of β-catenin-LEF
complex, activates Wnt target
genes

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targeted therapies and improving outcomes for patients aected by these diseases. The mTOR pathway controls basic
physiological functions such as cell survival, growth, proliferation, and metabolism. Dysregulation of mTOR signaling
has profound implications in both cancer and type 2 diabetes. Listed are the mTOR Complexes and Functions and their
implications in diseases [75].
3.4 mTOR complexes andfunctions
3.4.1 mTOR complex 1 (mTORC1)
mTORC1 inhibits catabolic processes like autophagy while controlling anabolic activities including the creation of lipids,
proteins, and organelles [76]. Growth factors such as insulin and insulin-like growth factor (IGF) can activate mTORC1 by
sending signals through the PI3K/AKT signaling pathway [77]. When AKT inhibits the Tuberous Sclerosis Complex (TSC)
1/2, mTORC1 is activated, which promotes cell division and growth [78].
Dysregulation or mutations in elements upstream or downstream of mTORC1, such as Ras, Raf, PI3K, AKT, PTEN, and
TSC genes, can result in constitutive activation of mTORC1 that causes cancers, including glioblastoma, melanoma, and
lymphoid malignancies [78].
3.4.2 mTOR complex 2 (mTORC2)
Dysregulation or mutations in elements upstream or downstream of mTORC1, such as Ras, Raf, PI3K, AKT, PTEN, and
TSC genes, can result in constitutive activation of mTORC1 that causes cancers, including glioblastoma, melanoma, and
lymphoid malignancies [79].
3.4.3 Role incancer
Component mutations of the mTOR pathway, particularly in upstream regulators and downstream eectors, lead to
aberrant activation of mTOR signaling, a hallmark of many cancers. Activation of mTORC1 angiogenesis, resulting in
tumour progression both invitro cell lines and invivo models. Activation mutations in oncogenes (Ras, Raf, PI3K, AKT)
and loss-of-function mutations in tumor suppressor genes (PTEN, TSC1/2) contribute to mTOR pathway dysregulation [80].
3.4.4 Role intype 2 diabetes
mTORC1 signaling inuences the function and mass of pancreatic β cells, crucial for glucose homeostasis. Dysregulated
mTORC2 signaling is implicated in insulin resistance, a key feature of type 2 diabetes. Enhanced mTORC1 activity initially
supports β-cell function (increased mass and insulin secretion), but prolonged activation can lead to β-cell dysfunction
and contribute to diabetes progression [81].
3.4.5 Therapeutic implications
mTOR inhibitors, such as rapamycin (sirolimus) and its derivatives, are actively studied for their potential in cancer therapy
due to their ability to inhibit mTORC1 activity and suppress tumor growth [82].
Targeting mTOR signaling remains a promising strategy in both cancer treatment and management of metabolic
disorders like type 2 diabetes. mTOR signaling plays a pivotal role in coordinating cellular responses to environmental
cues, and its dysregulation contributes signicantly to the pathogenesis of cancer and type 2 diabetes. Understanding
the complex interactions within this pathway is essential for developing targeted therapies aimed at mitigating these
diseases [74].
3.5 Role ofsevere inflammation
Severe inammation plays a pivotal role in the complex interplay between diabetes, inammation, and the develop-
ment of liver and pancreatic cancers. Here’s a detailed breakdown of how inammation inuences these processes [83].

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3.5.1 Inflammation anddiabetes
Poorly controlled diabetes is associated with chronic inammation with increased levels of inammatory cytokines
such as IL-6, TNF-α, and others. These inammatory markers contribute to insulin resistance and systemic inammation,
which are key factors in the pathogenesis of diabetes [84]. Diabetes, especially type 2 diabetes, signicantly increases
the risk of developing liver and pancreatic cancers. Factors contributing to this increased risk include hyperinsulinemia,
hyperglycemia, and chronic inammation [35].
3.5.2 Inflammation inliver cancer (HCC)
Inammatory cytokines such as IL-6, TNF-α, IL-1α, IL-1β, and IL-8 play critical roles in promoting chronic hepatic inam-
mation. They are upregulated in liver diseases like hepatitis and non-alcoholic fatty liver disease (NAFLD), creating an
inammatory microenvironment conducive to carcinogenesis [85].
IL-6 activates the gp130 receptor on hepatocytes, initiating signaling pathways like JAK/STAT3, PI3K/Akt, and Ras/Raf/
MAPK. These pathways not only support liver regeneration but also promote survival and proliferation of hepatocytes,
contributing to the development of HCC [86]. Activation of NF-κB due to inammation further exacerbates the pro-
tumorigenic environment in the liver, enhancing the progression of liver diseases towards cancer.
3.5.3 Inflammation inpancreatic cancer (PDAC)
Similarly, IL-6 is implicated in pancreatic cancer by activating the STAT3 signaling pathway, which stimulates cancer cell
proliferation and survival. This cytokine also modulates other pathways like ERK2, contributing to the aggressive nature
of PDAC. IL-4 and IL-8 also play roles in promoting pancreatic cancer cell growth and metastasis, highlighting the multi-
faceted role of inammation in disease progression [87]. NF-κB Activation: In pancreatic diseases like pancreatitis, NF-κB
activation leads to the production of inammatory cytokines, fostering an inammatory environment that can initiate
and promote tumor formation [88].
3.6 Role ofoxidative stress
Oxidative stress plays a critical role in the interplay between diabetes and cancer, linking these two conditions through
shared metabolic pathways and cellular mechanisms. Here’s a detailed breakdown of how oxidative stress contributes
to both diabetes and cancer and their association.
3.6.1 Oxidative stress indiabetes
Elevated blood glucose levels in diabetes contribute signicantly to oxidative stress. Several pathways amplify oxida-
tive stress in hyperglycemic conditions. Increased oxidative glucose metabolism in mitochondria leads to excessive
production of reactive oxygen species (ROS) such as O2·‾, OH·, and H2O2 [89]. Overactivation of uncoupling proteins
in mitochondria and NADPH oxidase contributes to the generation of superoxides, exacerbating oxidative stress. These
pathways increase ROS production and contribute to cellular damage. Antioxidant systems in the body are overwhelmed,
leading to inadequate protection against oxidative damage. These cells, responsible for insulin production, have limited
antioxidant enzyme expression, making them vulnerable to oxidative stress and contributing to diabetic complications
[90]. Prolonged oxidative stress damages biomolecules such as lipids, proteins, carbohydrates, and DNA, leading to cel-
lular dysfunction and tissue damage characteristic of diabetes complications [91].
3.6.2 Oxidative stress incancer
ROS-induced DNA damage can lead to mutations, replication errors, and genomic instability, all of which contribute to
the initiation and progression of cancer. Persistent oxidative stress induces chronic inammation, which plays a crucial
role in cancer development. Inammatory cells like neutrophils and mast cells release ROS during inammation, further
exacerbating oxidative stress [92]. Soluble mediators such as cytokines (TNF-α, IL-1, IL-6) and chemokines perpetuate
inammation and oxidative stress. Activation of transcription factors (NF-κB, HIF-1α, Nrf2, STAT3, AP-1, NFAT) by these
mediators promotes cell proliferation, survival, and angiogenesis, crucial for tumor growth [93]. Diabetes, characterized

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by chronic hyperglycemia and oxidative stress, increases the risk of DNA damage and promotes conditions favorable for
carcinogenesis. This association is complex and multifaceted, involving not only direct cellular damage but also systemic
eects on inammation and immune response [89].
4 Implications andResearch Challenges
Given the increasing prevalence of diabetes and its association with cancer, there is a pressing need for preventive strate-
gies targeting oxidative stress. Enhancing antioxidant defenses, reducing hyperglycemia through lifestyle changes or
pharmacotherapy, and targeting inammatory pathways are potential approaches [89].
Antioxidants and drugs that mitigate oxidative stress (like metformin) show promise in both diabetes management
and potentially cancer prevention or treatment. However, careful consideration of their dual eects on metabolism and
cancer risk is crucial. Oxidative stress serves as a common thread linking diabetes and cancer through shared metabolic
pathways and cellular responses [94]. Understanding these interconnected mechanisms oers insights into potential
preventive and therapeutic strategies that could mitigate the risk of cancer in diabetic patients and improve overall health
outcomes. Continued research into oxidative stress management holds promise for addressing the complex relationship
between these two prevalent and challenging diseases [95].
5 Use ofantidiabetic drugs andcancer risk
The relationship between antidiabetic medications and their potential impact on cancer risk is complex and has been
the subject of extensive research. Listed are the cancer risk of Here’s a breakdown of how dierent classes of antidiabetic
drugs, such as biguanides (metformin), sulfonylureas (SUs), and thiazolidinediones (TZDs), are implicated in cancer risk:
5.1 Metformin
Metformin is widely recognized for its potential anticancer eects. Several studies have suggested that metformin may
reduce the risk of cancer development and progression.
It exerts its eects through various mechanisms, including:
(i) AMPK Activation: Metformin activates AMP-activated protein kinase (AMPK), which regulates cellular energy
metabolism and inhibits cancer cell growth [96].
(ii) Insulin Sensitivity: By improving insulin sensitivity and reducing hyperinsulinemia, metformin indirectly mitigates
the growth-promoting eects of insulin and insulin-like growth factor 1 (IGF-1) [96].
(iii) Anti-inammatory Eects: Metformin has anti-inammatory properties that may contribute to its anticancer
eects [97].
Research have shown mixed results regarding metformin’s protective role against cancer. Some research supports
its use as a safe antidiabetic medication with potential benets in reducing cancer risk, particularly in gastrointestinal
cancers and possibly breast cancer.
5.2 Sulfonylureas (SUs)
Unlike metformin, SUs has been associated with an increased risk of certain cancers, particularly when used as mono-
therapy. SUs may stimulate carcinogenesis through mechanisms such as increasing insulin secretion and subsequent
hyperinsulinemia, which can promote cancer cell proliferation. They may also aect IGF-1 levels, which are linked to cell
growth and survival [98].
Population-based studies have shown that long-term use of SUs, especially in higher doses or as monotherapy, may
elevate the risk of pancreatic cancer and potentially other cancers.

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5.3 Thiazolidinediones (TZDs)
TZDs like pioglitazone have shown conicting results regarding their association with cancer risk. Some studies have
linked pioglitazone to an increased risk of pancreatic cancer. TZDs have also been associated with hepatic and pulmonary
cancers in certain populations, indicating a need for cautious use [99].
TZDs exert their eects through peroxisome proliferator-activated receptor gamma (PPARγ) activation, which regulates
insulin sensitivity and inammation. However, the long-term implications of PPARγ activation in cancer development are
still under investigation [100]. The choice of antidiabetic medication can inuence the risk of cancer in diabetic patients.
Metformin appears to be a favorable option due to its potential anticancer properties and overall safety prole in relation
to cancer risk. In contrast, SUs and TZDs, particularly pioglitazone, may pose a higher risk of certain cancers, especially
with prolonged use or in specic patient populations [33].
Clinicians should carefully consider the balance between glycemic control and potential cancer risks when selecting
antidiabetic therapies for their patients. Further research is needed to elucidate the precise mechanisms linking antidia-
betic medications to cancer risk and to rene treatment strategies accordingly [101].
5.4 Dipeptidyl peptidase‑4 (DPP‑4) inhibitors
DPP-4 inhibitors are a class of medications commonly used to manage type 2 diabetes mellitus. The relationship between
DPP-4 inhibitors and cancer risk has been the subject of various studies [102], yielding mixed results. Concerns have been
raised about a potential association between DPP-4 inhibitors and pancreatic cancer [103]. The association between
DPP-4 inhibitors and colorectal cancer appears to be dose-dependent [102]. A study found that low cumulative doses
of DPP-4 inhibitors were associated with a reduced risk of colorectal cancer, while high cumulative doses were linked
to an increased risk [102]. Research indicates that DPP-4 inhibitors may be associated with a reduced risk of melanoma
but not non-melanoma skin cancer. A study published in 2023 reported a 23% decreased risk of melanoma in patients
using DPP-4 inhibitors compared to those using sulfonylureas [104]. However, these ndings are not consistent across
all studies, and further research is needed to establish denitive conclusions.
5.5 Insulin
While insulin therapy is a cornerstone of diabetes management, concerns have been raised about its potential role in
cancer development mainly based on dose–response relationship and duration of the therapy. Hyperinsulinemia and
insulin therapy have been linked to cancer risk in some studies, particularly with certain cancers including colorectal and
breast cancers [105]. Long-acting insulin analogs, like glargine, have been scrutinized for potential risks, based on struc-
tural similarities to IGF-1, raising concerns about their potential mitogenic eects [106]. Hyperinsulinemia may promote
carcinogenesis through several biological pathways. Insulin acts as a growth factor by binding to insulin receptors (IR)
and insulin-like growth factor-1 receptors (IGF-1R) [54]. Overactivation of these receptors may enhance cell proliferation
and inhibit apoptosis, contributing to tumor development. Additionally high insulin levels suppress the production of
insulin-like growth factor binding proteins (IGFBPs), increasing free IGF-1 levels, which can stimulate tumor growth [53].
6 Conclusion
The repurposing of antidiabetic drugs for cancer management represents a promising avenue for targeted therapy, lev-
eraging shared metabolic pathways such as hyperglycemia, inammation, and oxidative stress. Drugs like sulfonylureas,
biguanides, TZDs, have demonstrated potential anticancer eects, yet challenges remain in fully integrating them into
oncology treatment protocols.
To establish the ecacy and safety of antidiabetic drugs in cancer treatment, large-scale, randomized controlled trials
are essential.
Future research should focus on identifying:
(i) Optimal dosing strategies for cancer patients, which may dier from those used for diabetes management.

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(ii) Patient selection criteria based on biomarkers or genetic predisposition to maximize therapeutic benets.
(iii) Combination therapies that integrate antidiabetic drugs with conventional or targeted cancer treatments to
enhance ecacy and reduce drug resistance.
Challenges in drug repurposing and development despite their potential, several barriers must be addressed. The
approval of antidiabetic drugs for oncological indications requires extensive preclinical and clinical validation, as their
mechanisms of action in cancer dier from their primary use. Long term safety concerns have to be addressed since
some antidiabetic drugs, particularly sulfonylureas and TZDs, have been linked to an increased risk of certain cancers,
necessitating further investigation into long-term eects and patient-specic risk factors.Pharmacokinetic considera-
tions must be taken into account since drug interactions and metabolic dierences between diabetic and non-diabetic
cancer patients may inuence ecacy and toxicity proles.
While antidiabetic drugs like metformin, sulfonylureas, and TZDs oer exciting possibilities for cancer management,
further clinical trials, mechanistic studies, and regulatory advancements are needed to optimize their use. Overcoming
these challenges could pave the way for more eective, safer, and cost-ecient therapeutic strategies, ultimately improv-
ing outcomes for patients with both diabetes and cancer.
7 Challenges andlimitations ofmulti‑target drug development
Developing multi-target drugs that simultaneously act on multiple pathways involved in diabetes and cancer presents
several challenges, including scientic, nancial, regulatory, and safety-related issues.
7.1 Scientific anddevelopment challenges
(i) Complex Disease Mechanisms
(ii) Both diabetes and cancer are heterogeneous diseases with diverse subtypes and underlying mechanisms.
(iii) Designing a drug that eectively targets multiple pathways without unintended interactions is challenging.
(iv) A multi-target drug must balance ecacy across dierent pathways without over-activating or inhibiting key
biological processes.
7.2 Off‑target effects andtoxicity
Multi-target drugs may lead to unintended interactions with other cellular pathways, increasing the risk of side eects.
For example, PPAR-γ agonists used in diabetes can have potential cardiovascular risks, and targeting metabolic pathways
in cancer can impact normal cell function.
7.3 Pharmacokinetic andpharmacodynamic optimization
A drug acting on multiple targets must have an optimized absorption, distribution, metabolism, and excretion (ADME)
prole to ensure eective bioavailability. Achieving the right balance between dierent targets requires extensive pre-
clinical studies to determine the optimal dosing regimen.
7.4 Drug resistance development
Cancer cells, in particular, are highly adaptable and can develop resistance mechanisms even against multi-target thera-
pies. Metabolic adaptation in diabetes (insulin resistance) can also counteract the eects of a drug over time.
7.5 Financial andcost challenges
Multi-target drug development requires extensive screening and optimization, increasing the cost of discovery and
preclinical research. The complexity of multi-target mechanisms often necessitates advanced computational modeling,
high-throughput screening, and invivo validation, adding to expenses.

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Because multi-target drugs interact with multiple pathways, the need for more extensive preclinical and clinical test-
ing extends the overall development time. Unexpected side eects or ecacy issues may lead to trial redesigns, further
increasing costs.
7.6 Regulatory andapproval challenges
Regulatory agencies like the FDA and EMA have well-dened guidelines for single-target drugs, but multi-target drugs
require more complex evaluation. The mechanism of action (MOA) for multi-target drugs may not be fully understood,
leading to diculties in dening ecacy endpoints.
7.7 Stringent safety requirements
Regulatory bodies require extensive toxicology studies and clinical trials to ensure that multi-target drugs do not cause
severe adverse eects. Drug interactions and metabolic eects need thorough investigation to avoid long-term risks,
particularly in chronic conditions like diabetes and cancer.
7.8 Complicated clinical trial designs
Clinical trials must evaluate ecacy across multiple targets and disease pathways, requiring larger and more diverse
patient groups. Since multi-target drugs aect multiple biological pathways, they may cause unintended systemic eects
(immune suppression, metabolic imbalances, organ toxicity). Patient-specic variations in genetics, metabolism, and
disease progression may aect drug ecacy and safety. A one-size-ts-all approach is unlikely to work, requiring addi-
tional biomarker-based patient stratication.
While multi-target drug development oers exciting potential for treating complex diseases like diabetes and cancer,
it faces signicant scientic, nancial, regulatory, and safety challenges. Overcoming these obstacles requires innova-
tive trial designs, personalized medicine approaches, and advanced computational modeling to predict and optimize
drug interactions. Despite the hurdles, advancements in AI-driven drug discovery, biomarker research, and combination
therapies may improve the success rate of multi-target drugs in the future.
8 Future directions
The interconnected molecular pathways between diabetes and cancer have led to the repurposing of several drugs
that target shared mechanisms such as inammation, hyperinsulinemia, and metabolic dysregulation. Among these,
metformin remains the most well-supported by evidence, showing broad potential in reducing cancer incidence and
progression. Drugs like SGLT2 inhibitors and GLP-1 receptor agonists represent newer classes with emerging evidence,
particularly for their dual role in improving metabolic health and potentially limiting cancer progression.
Signicant challenges that remain in translating these drugs into broader oncological practice are:
(i) Long-term safety concerns: Pioglitazone’s association with cardiovascular events and bladder cancer, or statins’
potential myopathies.
(ii) Drug-specic cancer eects: The impact of these drugs can vary based on cancer type, patient comorbidities, and
tumor biology.
(iii) Need for targeted trials: While many ndings stem from observational studies, more randomized controlled trials
are necessary to establish causality and dosing regimens for cancer prevention or adjunctive therapy.
Future directions include conducting well-designed clinical trials to validate the anti-cancer eects of these drugs in
diverse populations and exploring biomarker-based patient stratication to identify individuals most likely to benet.
Additionally, combining these agents with standard cancer therapies may provide synergistic benets while reducing
toxicities.
Emphasizing the clinical potential of these drugs, careful integration into therapeutic guidelines could signicantly
enhance outcomes for patients with diabetes and cancer, though overcoming translational barriers remains key.

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Author contributions A J conceived the idea, designed the gures and tables, performed formal analysis, supervised, and wrote the rst draft.
SM & RBP performed formal analysis and wrote the rst draft. AJ, SM & RBP made nal revisions, read and approved the nal manuscript.
Data availability No datasets were generated or analysed during the current study.
Declarations
Competing interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which
permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to
the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modied the licensed material. You
do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party
material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If
material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco
mmons. org/ licen ses/ by- nc- nd/4. 0/.
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