New Onset Diabetes Vs Long-Standing Diabetes Pathogenesis About Pancreatic Cancer: A Narrative Review

Pancreatic cancer (PC) is a deadly malignancy with a 5-year survival rate of less than 10%. More than 85% of PC patients have impaired glucose tolerance, indicating a complex bidirectional relationship. Diabetes can be both a risk factor and a complication of PC: the link between these two diseases is now a high priority for research. T2DM-associated PC is caused by insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation. Furthermore, recent research suggests that anti-diabetic medications may influence the risk of pancreatic cancer in type 2 diabetes; specifically, metformin reduces the risk of PC, whereas insulin therapy increases the risk. Diabetes also improves after pancreatic resection, implying that diabetes is caused by pancreatic cancer. Compared to the general population, people with new-onset diabetes have a 6-to-8-fold increased risk of developing pancreatic cancer. Diabetes of new-onset is an important screening tool for asymptomatic pancreatic cancer patients, and it improves pancreatic cancer survival. A deeper comprehension of the underlying pathophysiological mechanisms that distinguish T2DM from new-onset diabetes can help distinguish the two conditions. Additionally, evaluating the clinical features that set the two apart can help identify high-risk individuals for targeted screenings of suspected PC, which may help detect a tumor at a potentially treatable stage.

Despite having a relatively low incidence of 12.9 per 100,000 person-years, pancreatic cancer (PC) is the seventh most common cause of cancer-related death worldwide, according to the World Health Organization (WHO) [1]. Most of these tumors are of the ductal adenocarcinoma histological subtype (PDAC), originating primarily from ductal epithelial cells of the exocrine pancreas [2]. Age, gender, and race/ethnicity all impact PC incidence and death rates. The disease is rare in young adults (45 years old), peaks in the seventh and eighth decades, and is slightly more common in men (M/F: 1.3/1) and Black individuals [3, 4]. With a 5-year survival rate of less than 10% and a high recurrence rate even after potentially curative resection, PC was associated with an extremely poor prognosis [5]. The 5-year survival rate for patients who had their entire tumor completely removed was only up to 25%. A number of risk factors have been found to contribute to the burden of PC, including smoking, genetic predisposition, and advanced age [6]. Diabetes is also regarded as a risk factor for PC, as patients with the condition have a risk of PC that is more than twice as high as that of people without the condition [7]. Actually, diabetes affects about half of patients with sporadic pancreatic cancer. Diabetes is thought to be secondary to malignancy, having developed 2-3 years prior to cancer diagnosis, and is diagnosed concurrently with or shortly after cancer diagnosis in nearly 50% of diabetic pancreatic cancer patients [8]. Numerous recent studies have demonstrated the complex and reciprocal nature of the relationship between PC and diabetes, and current efforts are being made to differentiate the relationship between PC and the various forms of diabetes that are involved [9]. According to the American Diabetes Association, there are several forms of diabetes; however, two of them—type 2 diabetes (T2DM) and type 3c diabetes—need to be addressed in relation to PC. Chronic non-communicable type 2 diabetes (T2DM) is typified by persistent insulin resistance (IR) combined with impaired insulin secretion as a result of beta cell dysfunction [10]. This leads to hyperglycemia. Type 3c diabetes is defined as diabetes that is linked to various exocrine pancreatic disorders, primarily chronic pancreatitis, and pancreatic cancer. In particular, new-onset diabetes (NODM), which appears in the context of PC between 2-3 years, is primarily linked to pancreatic cancer [11]. There is a significant correlation between the length of DM and the advancement of PC. Studies evaluating time-related factors consistently show a negative correlation between the length of diabetes and the risk of pancreatic cancer, with the risk rising to a peak soon after the diagnosis and then gradually declining but staying elevated for many years. These findings point to a bidirectional causal relationship, suggesting that diabetes raises the risk of pancreatic cancer, which may be the outcome of malignancy that is not yet manifest [12]. Regarding the field of early PDAC detection, the identification of NOD as a clinical manifestation of occult PDAC carries significant implications. Being able to differentiate between long-term T2DM and PC-caused NOD offers the chance to diagnose PC at an early stage, when treatment may be curative [13]. Recent research also indicates that anti-diabetic drugs may have a direct impact on the major mediators of the relationship between T2DM and PC, thereby affecting the course, outcome, and development of cancer [14]. In the context of long-term diabetes, this story will highlight the latest research on the pathophysiological mechanisms underlying PC development, the biological processes in PC that predispose PC patients to developing diabetes, and the importance of these associations for PC early diagnosis and anti-diabetic treatment selection.

Long-standing PC T2DM risk factor

Diabetes is widely recognized as a risk factor for PC. Both men and women with DM have been found to have an elevated risk of PC [15], and people with type 2 diabetes have been found to have an increased mortality rate from PC [16]. Numerous data point to a low reported risk ratio—which ranges from 1.4 to 2.1—for long-term diabetes-related PDAC development [17]. While long-term T2DM and NODM present varying degrees of increased risk, with NODM posing a greater risk, both present an increase in risk [18]. The major impact of long-term diabetes on PC susceptibility has been explained by a number of mechanisms, the most significant of which are chronic hyperglycemia, insulin resistance, inflammation, and alterations in the tumor microenvironment.

Hyperglycemia and Advanced Glycation End Products

Chronic hyperglycemia, a hallmark of diabetes, in numerous ways, promotes the growth of cancer cells. The incidence of PDAC actually rises by 14% for every 0.56 mmol/l increase in fasting blood glucose levels [19]. The proliferation of cancer cells and the expansion of tumors are greatly aided by hyperglycemia [20]. Furthermore, greater phosphorylation of p38 MAPK (mitogen-activated protein kinase) in pancreatic cancer cells is caused by elevated blood sugar levels. It follows that this increases the cell's capacity to divide, evade apoptosis, infiltrate neighboring tissues, and migrate. It is possible to counteract the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) process that hyperglycemia induces in tumor cells by inhibiting p38 MAPK [21]. Hyperglycemia also promotes endothelial dysfunction, angiogenesis, and cell proliferation [22]. By activating EGFRs, the receptors for epidermal growth factors, and their corresponding factors [23]. Moreover, advanced glycation end products (AGEs) are produced in large quantities and accumulate in a hyperglycemic environment [24]. AGEs cause pancreatic cells' receptors (RAGEs) to become active, which in turn triggers a number of signaling pathways linked to inflammation, cancer progression, and cell survival [25].  For example, upon binding between AGEs and RAGEs, the MAPK and NF-κB signaling pathways are activated, leading to an increase in HIF-1α and NF-κB transcription. These molecular processes produce a hypoxic microenvironment and protect cells from oxidative stress-induced cell death [26]. Solid tumors frequently experience hypoxia, which is essential for a number of reasons, including promoting angiogenesis, strengthening the tumor's defenses against the immune system, stifling anti-tumor responses, and reducing the effectiveness of treatment [27]. Additionally, the interaction between AGE and RAGE raises inflammatory signaling molecules. More inflammation results from this, and myeloid-derived suppressor cells (MDSCs), which weaken the immune system, are drawn in. In cells, AGEs/RAGEs binding also triggers the PI3K-AKT and KRAS signaling pathways. As a result, the TP53 protein, which typically triggers apoptosis, is reduced. Moreover, it stimulates mTOR, which regulates autophagy and cell proliferation. These alterations work together to give cancer cells the ability to multiply, endure longer, and stimulate the growth of pancreatic cancer [26].

Insulin Resistance

Unlike hyperglycemia, insulin resistance shows a separate relationship with the chance of developing PC [28]. Moreover, elevated C-peptide levels show a relationship with a higher chance of the illness [29]. Studies have shown that PC tissue expresses more insulin receptors, and high levels of circulating insulin are often associated with a poor prognosis in PDAC cases [30, 31].Insulin mainly triggers two signaling pathways: the extracellular signal-regulated kinase (ERK) 1/2-MAPK pathway and the insulin receptor (IR)-insulin receptor substrates (IRS)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signal pathway. Through a variety of mechanisms, including mediating metabolic reprogramming, interacting with insulin-like growth factor 1 (IGF-1), bolstering drug resistance, and encouraging the formation of a tumor microenvironment marked by inflammation, fibrosis, and neo-angiogenesis, these two pathways play critical roles in enhancing the development of PDAC [32].

Inflammation

One important mediator of the relationship between diabetes and pancreatic carcinogenesis is chronic inflammation. There is evidence of both systemic and localized inflammation. Chronic low-grade inflammation is also caused by obesity, which is closely linked to type 2 diabetes. Proinflammatory cytokines such as TNF-alpha, IL-1, IL-6, IL-18, and IFN-gamma, as well as inflammatory markers like CRP, are elevated in the bloodstream as a result of diabetes [33]. In addition to decreasing immune surveillance, inflammatory stimuli activate oncogenic transcription factors like NF-kB, STAT3, and NFAT, which raise the expression of genes governing cell survival, proliferation, and oncogenic transformation [26]. Furthermore, TNF-alpha, particularly at low concentrations, is crucial for the promotion of tumors because it generates reactive oxygen species (ROS) and reactive nitrogen species (RNS), both of which have the ability to damage DNA [34]. ROS triggers signaling cascades that propel the development and progression of cancer, such as PI3K/Akt/mTOR and MAPK/ERK [35].

Tumor Microenvironment Changes

Diabetes causes the pancreatic tumor microenvironment (TME) to significantly change, which accelerates the onset and spread of cancer. Initially, there is a correlation between diabetes and elevated adipose tissue accumulation and fatty infiltration in the pancreas. Diabetes patients had greater pancreatic fat content than controls, according to a meta-analysis [36]. It has been reported that intrapancreatic adipocyte accumulation increases the risk of developing pancreatic cancer through a variety of pathways, including the release of inflammatory cytokines and the activation of inflammatory pathways [37]. Diabetes also triggers the transformation of dormant pancreatic stellate cells (PSCs) into CAFs or cancer-associated fibroblasts. PSCs are the main progenitors of CAFs in the pancreas. In response to various stimuli, including obesity, hyperglycemia, and hyperinsulinemia, PSCs change from a quiescent state to activated myofibroblast-like cells (MFCs) [38]. Upon activation, they release cytokines that facilitate the growth, invasion, metastasis, EMT, and resistance to chemotherapy of tumor cells [24]. Above all, CAFs can prevent immune effector cells like CD8 + T cells from being recruited into tumor tissues by secreting different chemokines. Moreover, it has been shown that CAFs significantly contribute to immune suppression within the tumor by raising the quantity of immunosuppressive cells such as regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and M2-type macrophages within the tumor's immune microenvironment (TIME) [39].

New onset DM an early manifestation of PC

Long-term type 2 diabetes is thought to increase the risk of developing prostate cancer (PC), but new-onset diabetes is thought to be an early sign of the disease that appears two to three years before the cancer is diagnosed [13]. Within three years of first meeting the glycemic criteria for new-onset diabetes, patients with NOD have an 8–10-fold increased risk of developing pancreatic cancer compared to the general population; the 3-year incidence of pancreatic cancer is 1% [40]. Patients who have been diagnosed with impaired glucose homeostasis within the last 12 months have the highest relative probability of an undiagnosed SPC [41]. Although the exact mechanisms underlying the association between PC and NOD are still unknown, the fact that more than 50% of patients experience a resolution of their diabetes following tumor removal through surgery suggests that the two conditions are causally related [42]. Since NOD can exist even before PC is radiologically detectable and has been demonstrated to improve following surgery, the theory that it is solely the result of PDAC's destruction of the endocrine pancreas is not a tenable explanation [43]. It is thought that tumor-secreted products trigger insulin resistance and insufficient beta cell response to stimuli, ultimately resulting in beta cell failure and new-onset diabetes [44].

Insulin resistance

Insulin action is significantly impaired by PC-associated NOD, according to early groundbreaking research [43]. The disordered glucose regulation typically appears gradually and appears as early as the PanIN period (a period that precedes pancreatic cancer) [32]. Actually, between 15 and 20 percent of PC patients have a normal β-cell function but are normoglycemic due to increased insulin resistance [45]. It is not insulin overexpression at pancreatic islet beta cells that causes this insulin resistance, but rather an increase in synthesized products that cause insulin resistance in the human body [32]. Muscle, adipose, and liver tissue from pancreatic cancer patients showed reduced insulin sensitivity; this is thought to be the consequence of exosome microRNAs secreted by pancreatic cancer cells [46]. Skeletal muscle from PC patients exhibits decreased phosphatidylinositol 3-kinase activity and impaired glucose transport when compared to controls; however, the early stages of insulin signaling (insulin receptor binding, tyrosine kinase activity, and insulin receptor substrate 1 content) are unaffected. According to these findings, exosomes inhibit the PI3K/Akt/FoxO1 signaling pathways and glucose transport, which in turn affects Glut4 translocation and glucose transport [47]. In addition to miRNAs, pancreatic cancer cells also produce galectin-3 and S100A9, which inhibit myotube cells' capacity to absorb glucose [19]. Additionally, a study found that the diabetic pancreatic cancer group had a lower fractional velocity of glycogen synthase, indicating that the insulin resistance linked to PC may have originated from a post-IR defect in the skeletal muscles [48]. Furthermore, because pancreatic cancer also targets adipose tissue, interactions between the two conditions may account for the development of insulin resistance and paraneoplastic weight loss in pancreatic cancer [49]. One potential mediator of this resistance is adrenomedullin (AM). This 52-amino acid peptide is expressed by pancreatic F-cells and has a variety of functions, including modulating tumor growth and progression through autocrine stimulation [50]. Adrenomedullin is produced by pancreatic cancer cells and fibroblasts in the pancreatic cancer microenvironment. This inhibits the adipocyte response to insulin signals by preventing beta cells from secreting insulin and enhances the insulin-inhibitory effect of PC cells both in vitro and in vivo. In patients with PC, particularly those with DM, a recent study discovered significant AM up-regulation in their plasma, at the gene and protein levels [51, 52]. Furthermore, Javeed et al. demonstrated that AM enters β cells by caveolin-mediated endocytosis after being transported from PC to β cells as exosomal cargo. This leads to insulin resistance via ADMR-AM interactions, reduced insulin secretion, overexpression of ER stress genes, and elevated reactive oxygen/nitrogen species. Remarkably, the inhibitory effect of PC-derived AM-positive exosomes on insulin secretion is eliminated upon blocking the interaction between AM and its receptors [53]. Additionally, PDA causes hepatic cells to become less sensitive to insulin, a sign of a lower level of liver gluconeogenesis [54]. Elevated blood glucose levels then stimulate insulin synthesis and secretion in pancreatic islet beta cells, resulting in endogenous hyperinsulinemia when a delayed and blunted insulin response occurs in PDA patients. Furthermore, diabetic PDA patients who take insulin regularly to control blood sugar were found to have worsened glucose control due to the high rate of insulin resistance. As a result of PDA-induced increased insulin resistance, more insulin will be used, which will raise exogenous hyperinsulinemia [32]. Moreover, it was recently demonstrated that PC patients with new-onset diabetes produce noticeably less glucose-dependent insulinotropic peptide (GIP), which is primarily secreted by enteroendocrine cells [52]. These patients have shown reduced levels of GIP, which may be the result of an increase in dipeptidyl peptidase IV levels brought on by the tumor and which can be reversed by tumor resection. As a result, low GIP levels may both contribute to and serve as a biomarker for PDAC-DM [55]. Additionally, it has been discovered that islet amyloid polypeptide (IAPP), which is typically secreted alongside insulin by β cells, is also a hormone that contributes to insulin resistance in patients with pancreatic cancer. According to a study, patients with diabetes who have pancreatic cancer have higher plasma levels of IAPP. This is explained by the PC cells stimulating β cells to secrete IAPP selectively and by changing β cells' reactivity to other secretagogues [56].

Beta cell dysfunction

Patients diagnosed with PDAC typically experience a reduction in both the quantity and size of β cells within their islets [57]. PDAC patients also showed impairments in the β cell response, which includes the response to an oral glucose load, hyperglycemic clamp, or glucagon stimulation [58]. The increased activation of the TGF beta pathway is one of the several mechanisms that have been proposed to explain the pathophysiological mechanisms behind the beta cell dysfunction observed in patients with pancreatic cancer. Parajuli et al. found that as PDAC progressed, the TGF-β signaling pathway was expressed more frequently, which in turn caused β-cell mass to be lost through apoptosis.According to this study [59], there is a correlation between increased TGF-β signaling activation and increased caspase 3 cleavage within islets, which ultimately results in apoptotic β-cell death during PDAC progression and causes new-onset diabetes. Furthermore, it was discovered that necrotic stellate cells, a major collagen-producing cell type in PDAC, cause β-cell apoptosis and dysfunction by causing islet fibrosis and reducing β-cell insulin production, potentially contributing to the development of diabetes mellitus [60]. Macrophage migration inhibitory factor is another potential contender (MIF). Pro-inflammatory cytokine MIF influences glucose homeostasis as well as inflammation. It has been noted that pancreatic cancer cells overproduce it, and studies have shown how it regulates Ca2+ channels to inhibit glucose-stimulated insulin release from both isolated islets and β-cells. Furthermore, elevated serum MIF levels have been observed in patients with pancreatic cancer who also have diabetes, whereas no such rise has been observed in patients with pancreatic cancer who do not have diabetes or in newly diagnosed Type 2 diabetics who do not have cancer [61]. Adrenomedullin, a strong inhibitor of insulin secretion and an inducer of endoplasmic reticulum (ER) stress increased β-cell dysfunction, and death has also been demonstrated to be upregulated in cancer cells [62]. Every one of the physio-pathological scenarios listed above causes β-cells to be selectively depleted, which may eventually lead to reduced insulin secretion and the ensuing hyperglycemia and diabetes. Indeed, this may worsen the diabetes phenotype by further causing an imbalance in the ratio between β-cells and other endocrine cells that are not sensitive to PDAC [63]. Relevantly, recent research has revealed that a significant increase in the systemic glucagon/insulin ratio is experienced by the majority of PDAC patients diagnosed with diabetes. This phenomenon is thought to facilitate gluconeogenesis and the release of glucose into the circulatory system [64]. Apart from glucagon, another study found that PDAC and/or PanINs have no effect on δ- and PP cells, two other types of islet cells [65].

New-onset diabetes vs. long-standing diabetes

There is consistent evidence linking diabetes to pancreatic cancer [66]. Depending on how long it has been since the cancer diagnosis, diabetes mellitus linked to pancreatic cancer is classified into two main groups: long-standing diabetes mellitus (diagnosed more than three years ago) and new-onset diabetes mellitus (diagnosed less than three years ago) [67]. PC and diabetes have a reciprocal relationship. New-onset diabetes is an early symptom and a pathogenetic feature of PC, whereas long-term diabetes is thought to be an etiologic/risk factor of SPC [68]. Making the correct distinction between these two forms of diabetes is crucial to establishing an early PC diagnosis [69]. First, the risk of developing PC varies between diabetes with a long history and diabetes with a recent onset. Since PDA is not well documented in DM2, and PDA risk is comparable to other common cancers in these patients, DM2 is thought to be a relatively low PDA risk group [70]. Though more than 50% of PDA-related diabetic cases developed diabetes in the 36 months prior to the PDA diagnosis, NOD is thought to be a high-risk signal of PDA. In addition, this cohort study showed that NOD had a 2.3-fold higher risk of pancreatic cancer than did long-term diabetes mellitus [71]. Similarly, the relative risk of PDAC in patients with diabetes mellitus increased with a shorter duration of the disease: 6.69 for less than a year, 1.86 for 1-4 years, 1.72 for 5-9 years, and 1.36 for more than 10 years, according to a meta-analysis of 88 studies [72]. Remarkably, a different study found that although the relative risk of pancreatic cancer decreased with age at the onset of type 2 diabetes, the absolute risk of the disease increased with age [73]. Second, as previously mentioned, there are differences in the pathophysiological mechanisms underlying the development of each type of diabetes and how it relates to pancreatic cancer. Third, following the onset of diabetes, subjects with T2DM vs. T3cDM experience different changes in body weight [74, 75]. Patients with T3cDM are substantially more likely than those with T2DM to have a decrease in body weight at the diagnosis of prediabetes or diabetes, most likely as a result of the tumor-induced loss of subcutaneous fat tissue [76]. Body weight loss typically occurs before other systemic and local symptoms in PC. In fact, a study found that the mean time between the onset of diabetes in pancreatic cancer and the onset of symptoms was two months and thirteen months, respectively, before the cancer was diagnosed. According to these data, weight loss may be linked to the development of diabetes and may occur several months before the onset of diabetes and cancer-specific symptoms in pancreatic cancer [77]. Consequently, a patient with newly diagnosed prediabetes or diabetes should have suspicions about a paraneoplastic origin if their body weight decreases by more than 2 kg [68]. Conversely, compared to T3cDM, T2DM typically starts with a higher BMI and increased body weight linked to insulin resistance and hyperinsulinemia [14]. It's also crucial to note that, even in cases where DM2 patients do experience weight loss, this weight loss is typically linked to a gradual improvement in glycaemic control, as opposed to what is seen in people with NO diabetes, where weight loss is associated with worsening glycemia [78]. There have been mixed findings from earlier research on the effect of diabetes mellitus (DM) on PDAC patients' prognoses. According to research by Mizuno et al., patients with new-onset diabetes mellitus alone had a median survival time for pancreatic cancer that was about 10 months longer than that of patients without diabetes [79]. This better prognosis could be linked to early detection and treatment of diabetes-related pancreatic cancer. This study found that patients with pancreatic cancer had a poor prognosis when they had long-term diabetes [10]. Conversely, other research revealed that patients with DM who received chemotherapy for PDAC had smaller tumor sizes, a higher risk of dying from the treatment, and a worse prognosis than those with long-standing or recently developed diabetes [80, 81]. Furthermore, a recent study discovered that significant weight loss and long-term diabetes are risk factors for distant metastases. This implies that cancer cells may spread to distant locations more easily if they are exposed to diabetes-related metabolic abnormalities over an extended period of time [82]. Lastly, the finding that more than 50% of patients with new-onset DM who had their PaC resected experienced an improvement in their DM, whereas patients with long-standing DM did not show a discernible improvement in their hyperglycemic status after surgery, suggesting a causal relationship between PC and NO diabetes [8].

Early detection of pancreatic cancer in patients with new onset diabetes mellitus 

The majority of the time, pancreatic cancer is discovered in an advanced stage. The depressing 5-year survival rate of 3–15% is a result of such late detection, which also limits treatment options [83]. Only 15-20% of cases are currently diagnosed at a level where curative surgery is a possibility [84]. As a result, early detection of pancreatic cancer is critical. The majority of patients with pancreatic intraepithelial neoplasia (PanIN), stage I, are either asymptomatic or exhibit non-specific symptoms like pyrosis, abdominal pain, and weight loss in the early stages of the disease. When PC-related symptoms appear, the illness has already progressed [85]. Given the rarity of PC, it is strongly advised against doing a generalized screening of asymptomatic adults. Moreover, none of the primary imaging technologies for PC identification are affordable or easily applied to a larger scale of screening. In order to identify high-risk individuals for focused screenings, numerous attempts have been made recently [5,86]. In order to choose which population should be screened, Chari suggests using two "sieves": the first is for high-risk individuals (hereditary PC, NOD), and the second is for particular traits of these high-risk groups (known risk factors, suggestive symptoms, serum biomarkers, non-invasive imaging) [87].

Screening models

New-onset diabetes (NOD) is one of the most promising high-risk factors for pancreatic cancer because elderly patients with NOD have a higher risk of sporadic PC than the general population [40]. A score to evaluate the risk of PC in patients with NOD has been developed in recent years. To assess the risk of pancreatic cancer in patients with new-onset diabetes, Sharma et al. created a model known as enriching new-onset diabetes for pancreatic cancer (END-PAC). The blood glucose, weight, and age changes at glycemically defined new-onset diabetes are measured by the model. Patients with new-onset diabetes are more likely to develop PC if they have more significant changes in blood glucose, less significant weight changes, and higher ages [88]. The END-PAC model has been verified by multiple investigations. At the 3+ threshold, for instance, the sensitivity and specificity of the END-PAC model were 62.6% and 78.5%, respectively, according to a study conducted on 13,947 NOD patients in a healthcare setting [89]. The Health Improvement Network (THIN) model from the United Kingdom is another model that should be brought up. The population with a 5% 3-year predicted risk of ductal PC among individuals with NOD can be identified using this Boursi et al. model with 11% sensitivity and 99.7% specificity. To identify the population with a 5% 3-year predicted risk of ductal PC among people with NOD, this model takes into account factors such as age, changes in body mass index (BMI), smoking, diabetes medications, proton pump inhibitors, changes in hemoglobin A1c, total cholesterol, creatinine, and alkaline phosphatase [90].

Biomarkers associated with PC and new-onset diabetes

No single biomarker currently seems appropriate for clinical use for the early detection of pancreatic ductal cancer, despite multiple attempts. In patients with NOD, the amount of carbohydrate antigen 19-9 (CA19-9) secreted by cancer cells may be a good predictor of PC [91]. Higher CA19-9) levels above the upper normal limit were associated with a 5.5 times greater risk of developing PC within 2 years of diagnosis in asymptomatic NOD patients, according to a study by Choe et al [92]. Another study suggested that patients with diabetes with or without PC could be distinguished using a cut-off serum CA19-9 level of 75 U/mL. The CA19-9 for PC had a sensitivity of 69.5% and a specificity of 98.2% at this cut-off [93]. It is crucial to note, though, that other benign diseases affecting the pancreas, biliary tract, and other organs can also cause an increase in CA19-9 levels. However, some data suggests that its levels are much higher in malignant than in benign diseases [94].Osteoprotegerin is another potential biomarker (OPG). OPG is a member of the TNF receptor superfamily (TNFRSF) and a soluble decoy receptor for TNF-related apoptosis-inducing ligand (TRAIL) [95]. In a meta-analysis of gene expression microarray datasets, Shi W et al. discovered that patients with PC-related DM had elevated serum OPG levels. Serum OPG showed a sensitivity of 68%, specificity of 73.9%, and area under the curve (AUC) of 73.7% in identifying PC in patients with NOD [96]. Furthermore, the systemic inflammatory response to the tumor raises C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) is an upregulating factor of CRP in PCa patients. Higher levels of sTNF-R2 were found to tend to increase PC risk, and this association was stronger in people with diabetes, according to Grote VA et al. [97]. Promising biomarkers for identifying PC in NOD patients include other pancreatic metabolites like docosahexaenoic acid, LysoPC and histidyl-lysine46, and changes in microRNA blood levels like miR-20b-5p, miR-29a, and miR-18a-5p [98].

Biomarkers that help differentiate between NOD and long-standing T2DM in PC patients

In clinical practice, it can be difficult to distinguish PC-induced NOD from the more prevalent T2DM based on clinical and biochemical factors. As a result, a number of biomarkers are proposed to help PC patients distinguish between the two types. One of these is islet amyloid polypeptide (IAPP), a hormone released by pancreatic beta cells that has been shown to have diabetogenic effects both in vivo and in vitro and is thought to be the root cause of insulin resistance in diabetes mellitus associated with PCa. While it was found to be normal or low in patients with type 2 DM, it was found to be elevated in patients with PCa-associated DM [99]. Other biomarkers include the protein S100A9, which is connected to inflammation through toll-like receptor-4, and Galectin-3, a β-galactoside-binding lectin involved in PC cell proliferation, migration, and invasion [42]. According to Liao et al., PDAC-related DM had higher levels of galectin-3 and S100A9 than T2DM. Additionally, they discovered that PDAC-related DM and T2DM can be distinguished from one another by serum levels of the proteins galectin-3 and S100A9 [100]. Thrombospondin-1 (TSP-1), a multimeric protein with anti-angiogenic characteristics, is another intriguing biomarker. TSP-1 levels were observed to be lower in PDAC patients than in non-diabetic individuals, especially in those with diabetes. Significantly, whereas lower TSP-1 levels were not observed in long-term T2DM, they were in PDAC-associated diabetes [101]. Furthermore, it was discovered that the enzyme vascular non-inflammatory molecule-1, or vanin 1, was linked to paraneoplastic islet cell dysfunction and may be a useful biomarker for identifying PC in patients with diabetes [102]. According to Huang et al., PDAC was found to have significantly higher Vanin-1 gene levels, and PDAC-associated diabetes could be distinguished from type 2 diabetes by measuring serum levels of Vanin-1 and matrix metalloproteinase 9 (MMP9) using quantitative real-time polymerase chain reaction [103].Additionally, a microRNA panel consisting of miR-483-5p, miR-19a, miR-29a, miR-20a, miR-24, and miR-25 was reported by Dai et al. to have an AUC of 0.887 in differentiating PC-related diabetes from T2DM [104].

Shared genetic predisposition between PC and DM 

Significant advancements in our knowledge of complex diseases, such as cancer and type 2 diabetes, have been made since the introduction of genome-wide association studies (GWAS) in 2005 [105]. According to GWAS, patients with type 2 diabetes may be at increased risk of developing pancreatic cancer if they have mutations in genes related to embryonic development and the control of pancreas-specific genes like Nr5a3, HNF1A (hepatocyte nuclear factor 1), and PDX1 (pancreatic and duodenal homeobox 1) [106,107]. For instance, normal pancreatic development, appropriate β-cell function, and insulin secretion all depend on the HFN1A and HNF1B genes [18]. It has been observed that mutations in these genes, which are linked to type 2 diabetes, also contribute to the development of pancreatic cancer [22]. Two (in FTO and MTNR1B) and one (in BCL11A) of the 37 type 2 diabetes risk alleles were found to have nominally positive associations with pancreatic cancer risk, according to a different study [108]. Furthermore, et al found that test cohorts for PC and T2DM shared 44 genes primarily enriched in the regulation of endodermal cell fate specification, suggesting a potential shared mechanism between the two conditions. A particularly noteworthy finding in validation cohorts was the identification of a hub-shared gene, S100A6, which is important for the progression of both PC and T2DM and may be used as a predictive biomarker to identify covert PC in T2DM patients [109]. S100A6 is a member of the S100 family and a calcium-binding protein with an EF-hand. According to earlier research, S100A16 primarily contributes to lipid metabolism and stimulates the release of insulin in response to calcium, a condition linked to hyperglycemia [110,111]. Furthermore, it has been discovered to have a role in a number of cancers, including pancreatic cancer [112]. S100A6 was found to be significantly more expressed in PC tissues than in non-tumor tissues in the study. Because S100A6 is involved in stimulating PC cell proliferation and migration, PC patients with high expression levels of the protein had a lower overall survival (OS) than those with low expression levels [109].Moreover, the major C-allele of the diabetes-related SNP GCKR rs780094 may raise the risk of pancreatic cancer. GCKR controls glucokinase (GCK) activity in pancreatic islet cells and liver cells, respectively.High levels of insulin and fasting glucose may be caused by a high degree of glucokinase inhibition in CC carriers, which may have a mitogenic effect on the exocrine pancreatic cells. Therefore, through increased insulin levels and/or diabetes, GCKR may influence the development of pancreatic cancer [113].The promoter genes of CDH1 AND CDKN2A are other variants that are important to note. According to a study, PDC frequently experienced both CDH1 and CDKN2A promoter gene methylation, and the frequency of positive cases was higher in long-DM patients than in non-DM and short-DM patients. Promoter methylation of CDH1 was more prevalent in pancreatic cancer with long-term diabetes mellitus and was positively connected with decreased expression of E-cadherin. Therefore, it is highly likely that diabetes itself will cause promoter methylation [114]. Last but not least, reverse causation should also be taken into account because type 2 diabetes can both cause and be preceded by pancreatic cancer [115]. Only the correlation between LINC-PINT rs6971499 and T2DM risk was validated among the 14 known PC susceptibility variants, albeit at a weak significance level that vanished upon multiple comparison adjustments [116].

Table 1: Compares new-onset diabetes to late-onset diabetes and its association with pancreatic cancer in terms of signs and symptoms, pathology, and treatment.

Effect of Anti-Diabetic Medication on Pancreatic Cancer

Insulin therapy

Insulin is safe for the majority of diabetic patients because pancreatic cancer is not common in the general population. On the other hand, individuals with high risk of PDA, such as those with NODM, and PDA patients, should use insulin with greater caution [32]. Numerous studies have demonstrated that insulin therapy may raise the incidence of PC [117, 118]. In fact, a retrospective cohort analysis of the UK GP database (The Health Information Network; THIN) [119] supported the yearly incremental risk of cancer in individuals receiving insulin treatment. Bosetti et al. examined the risk association between PC and insulin therapy by examining 15 case-control studies, comprising 13,987 controls and 8,305 patient cases. Research findings revealed that while long-term insulin use (≥15 years) was not linked to an increased risk of PC, short-term insulin use (<5>

Metformin therapy

Worldwide, metformin is frequently prescribed as the first-line treatment for type 2 diabetes. Traditionally, metformin lowers hepatic gluconeogenesis in order to act as an antidiabetic [122]. Numerous epidemiologic studies conducted in the last few years have suggested that metformin may be associated with a lower risk of PDAC [59]. Metformin-using diabetics have a lower risk of PC than non-users, according to a meta-analysis of 29 papers involving over 2 million participants [123]. In a similar vein, a different study found that taking metformin reduced the risk of PC by 37% when compared to other diabetes treatments [124]. Metformin's anti-cancer mechanism is not entirely understood, but it is primarily thought to be through activating liver kinase B1 (LKB1) and adenosine monophosphate protein-activated kinase (AMPK), which can reduce hepatic tissue insulin resistance and prolong survival in cancerous metformin [125]. In pancreatic cancer, metformin induces LKB1 activation to break the crosstalk between IR and GPCR, which reduces cancer growth and fibrosis. Additionally, research showed that metformin could trigger ferroptosis and apoptosis in pancreatic cancer by activating the AMPK signal pathway, which is inhibited by high glucose status [1]. Furthermore, metformin may stimulate the STING/IRF3/IFN-β pathway by blocking AKT signaling in PDAC cells, which would facilitate the infiltration of immune cells into the tumor microenvironment (TME), according to research by Ren et al. [126]. In addition, through the MTOR signaling pathway, metformin can suppress PDAC by promoting the expression of pro-apoptosis proteins caspase-3 and Bax and reducing the expression of anti-apoptosis protein Bcl-2 [127]. Remarkably, metformin was only found to prolong survival in diabetic PDA patients; no effect was observed in the overall PDA population. This suggests that metformin primarily reduces insulin resistance rather than having an anticancer effect [128].

Incretin-based therapy

Incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are another class of frequently used anti-diabetic medications. Data regarding the risk for PC were inconsistent, despite the initial preclinical and adverse database review studies raising concerns about acute pancreatitis and PC associated with their chronic use [129]. It was previously hypothesized that incretin-based treatments would cause the GLP-1 receptor to become overstimulated, which would raise the risk of PC [130]. However, Nreu et al. found in 2020 [131, 132] that there was no relationship between GLP1-RA use and PC.  It is noteworthy to note that certain research has linked GLP-1RAs to an antitumor effect on pancreatic cancers in humans [133]. It was proposed that GLP-RAs may help reverse insulin resistance caused by pancreatic cancer cells, resulting in a lower blood insulin level. This is because they lower blood glucose by encouraging energy storage in adipose tissue and inhibiting glucagon secretion [134]. However, there may not be enough information to make such a determination regarding the connection between PC and this incretin-based drug. A serine protease called dipeptidyl peptidase-4 (DPP4) facilitates the breakdown of GLP-1.52 Consequently, DPP4-inhibitor (DDP4i) can be employed as a type of hypoglycemic agent by inhibiting the degradation of GLP-1 [135, 136, 137].

Sodium-Glucose Cotransporter 2 Inhibitors

By reducing the reabsorption of glucose and raising the excretion of urine glucose, sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, another type of oral antidiabetic medication, contribute to the maintenance of glycaemic control [138]. Apart from their significant cardiovascular advantages, they exhibit the capacity to impede the advancement of Parkinson's disease. In cells of pancreatic cancer, SGLT-2 was found to be highly expressed. In preclinical pancreatic cancer models, SGLT-2 inhibitor treatment was found to reduce cancer proliferation and lower PDA risk in SGLT-2 inhibitor users. According to these results, SGLT2 inhibitors might be helpful in the treatment of cancer [139].

Diabetes has a broad spectrum of morbidity, while PC is a highly aggressive and deadly malignancy. The complex relationships between PC and diabetes are demonstrated by epidemiological studies. The mechanisms underlying the correlation between PC and DM include chronic inflammation, hyperglycemia, hyperinsulinemia, and insulin resistance. Metformin and insulin are the two main medical treatments for type 2 diabetes. Studies have shown that metformin lowers the risk of PC, but insulin therapy raises the risk of PC; for this reason, metformin has the potential to act as an anticancer drug and can be used to stop the growth of malignant lesions. Surgical resection is the only potentially curative treatment for PC; however, evidence suggests that T2DM is a significant comorbidity that predicts worse outcomes in patients undergoing PC resection and is associated with decreased survival.Consequently, research has been concentrating on novel screening models and biomarkers to identify PC risk in individuals with recently developed diabetes and encourage early detection of PC while it is still treatable.

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Conflicts of interest: The authors declare no conflict of interest. 

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Acknowledgment: The authors thank Dr. Hiba Hamdar (hiba.hamdar@live.com), who supervised us reviewed our article, and gave us her valuable comments.

Authors' contributions: Each author has contributed in the same manner to this manuscript.