An analysis of the global burden of pancreatic cancer attributable to High fasting plasma glucose: 1990– 2021

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High fasting plasma glucose (HFPG), a key metabolic risk factor, significantly contributes to pancreatic cancer mortality and disability-adjusted life years (DALYs). This study aimed to quantify the global burden of pancreatic cancer attributable to HFPG from 1990 to 2021 and inform targeted prevention strategies. Methods: We extracted data on the burden of pancreatic cancer attributable to high fasting blood glucose from 1990 to 2021 from the Global Burden of Disease (GBD) 2021 database. We characterized this burden across different ages, sexes, age groups, Socio-demographic Index (SDI) regions, and countries. To illustrate temporal trends in the pancreatic cancer burden, we computed the estimated annual percentage change (EAPC) for the period 1990–2021. Decomposition analysis was used to identify drivers of changes in burden, while inequality analysis assessed disparities across SDI levels. Results: Globally, the ASMR and ASDR of PC related to HFPG showed an upward trend between 1990 and 2021, and the absolute number of deaths and DALYs cases increased more than threefold. High SDI regions exhibit a higher burden due to a higher number of HFPG patients, population growth, and aging, while low SDI regions face higher EAPCs due to limited resources. Moreover, this inequality has become even more pronounced. Men are more susceptible in all age groups. There are significant differences in burden management among countries, with some low SDI countries showing better performance than high SDI countries. Conclusion: It was found that PC attributable to HFPG was generally on the rise from 1990 to 2021 around the world. The age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) for PC linked to HFPG increased with higher SDI. Older and middle-aged populations bore the heaviest burden, with males carrying a greater PC burden than females. Population growth and epidemiological shifts drove this increase, while SDI-related inequalities are worsening. Targeted interventions addressing metabolic risks and healthcare access are warranted. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction The early stages of pancreatic cancer often go unnoticed due to nonspecific symptoms such as abdominal pain, weight loss, and jaundice, leading to delayed diagnosis and a high likelihood of advanced disease at the time of detection. Radical surgical resection, such as pancreaticoduodenectomy, remains the sole potentially curative treatment [1] . Unfortunately, it is estimated that only 15–20% of patients are eligible for curative surgical resection [2] , with a 5-year overall survival (OS) rate of less than 10% for all stages combined [3] . Furthermore, the epidemiology of pancreatic cancer is influenced by multiple factors, including geographic location, gender, and age. Regions such as North America, Europe, and high-income Asian countries exhibit higher incidence rates compared to African nations. Men and individuals over 60 years old demonstrate elevated susceptibility to this disease.The reasons for these disparities are multifaceted, involving differences in smoking prevalence, rates of chronic pancreatitis and diabetes, and socioeconomic determinants affecting healthcare access. Emerging evidence demonstrates that HFPG contributes to PC through insulin/IGF-1 signaling dysregulation [4] , Warburg effect potentiation [5] , and advanced glycation end-products (AGEs)-mediated cellular damage [6] . For instance, chronic hyperglycemia induces pathological overexpression of insulin-like growth factor 1 (IGF-1) in pancreatic β-cells, which activates downstream oncogenic pathways through receptor tyrosine kinases [4, 7] . This metabolic derangement creates a permissive microenvironment for neoplastic transformation, highlighting the imperative to elucidate the precise molecular crosstalk between glucose homeostasis disorders and pancreatic oncogenesis. Epidemiological studies consistently identify hyperglycemia as a modifiable risk determinant, accounting for approximately 25–35% of global pancreatic cancer burden [8, 9] . As the predominant metabolic risk factor, HFPG contributes substantially to pancreatic cancer-associated mortality and DALYs, representing 19.7% of total metabolic-related cancer DALYs worldwide [10] . These findings underscore the critical need for multinational cohorts to quantify the population-attributable fraction of pancreatic cancer cases linked to dysglycemic states, thereby enabling data-driven health policy formulation and precision prevention initiatives. The GBD 2021 Study provides a comprehensive framework for evaluating the metabolic oncology burden, with specific relevance to pancreatic cancer pathogenesis. While existing literature has extensively characterized the general epidemiology of pancreatic cancer, the precise disease burden attributable to hyperglycemic states remains inadequately quantified [11] . This investigation aims to delineate the spatiotemporal patterns of pancreatic cancer mortality and DALYs across 204 countries and territories, focusing on high fasting plasma glucose as an etiological driver. Through decomposition analysis of annual percentage changes (APCs), we will identify geographic hotspots demonstrating the most rapid escalation in glucose-related pancreatic cancer burden, critical intelligence for implementing metabolic surveillance programs. The study further incorporates multivariable regression models to decipher the tripartite relationship between pancreatic cancer burden, socioeconomic development, and national healthcare access metrics. A comparative risk assessment framework will be employed to partition the population-attributable fractions of hyperglycemia-related pancreatic cancer into three components: demographic aging effects, population growth dynamics and true epidemiological transition. By projecting disease trajectories through 2035 using Bayesian age-period-cohort modeling [12] , this analysis will provide evidence-based projections to guide the development of glucose-centric early detection protocols and therapeutic interventions. These multidimensional outputs are expected to revolutionize current paradigms in pancreatic cancer prevention, particularly for populations undergoing rapid nutritional transition. 2 Methods 2.1 Data source All data in this paper are from GBD 2021, which includes a series of indicators such as incidence rate, morbidity, mortality and DALYs of 204 countries and regions from 1990 to 2021. It is available for free worldwide through the official website of the Institute of Health Metrics and Evaluation at the University of Washington in the United States( http://ghdx.healthdata.org/ ). We selected “High fasting plasma glucosee” in the risk list and “pancreatic cancer” in the cause list [13] . We obtained the death rate of pancreatic cancer PC caused by high abdominal glucose from 21 regions and 204 countries DALYs、 ASMR and ASDR [14] . The data is downloaded for analysis at various levels, including gender, age, country, GBD region, and SDI. 2.2 Definitions According to the World Health Organization (WHO) standards, high fasting blood glucose is defined as follows: prediabetes: 6.1–6.9 mmol/L (110–125 mg/dL); diabetes: in adults aged ≥ 20 years, ≥ 7.0 mmol/L (≥ 126 mg/dL) [15] . The Global Burden of Disease (GBD) defines high fasting plasma glucose (HFPG) as fasting blood glucose levels ranging from 86.4 to 97.2 mg/dL. The Socio-demographic Index (SDI) is a composite indicator that incorporates three core metrics: the total fertility rate among individuals under 25 years, educational attainment among people aged 15 and older, and per capita income. SDI values categorize all countries and regions into five tiers: low SDI, low-middle SDI, middle SDI, middle-high SDI, and high SDI, ranging from 0 to 1. 2.3 Statistical analysis We present global temporal trends in mortality, DALYs, ASMR, and ASDR from 1990 to 2021, stratified by SDI level and region. To highlight the geographical disparities associated with High fasting plasma glucose in 2021, we constructed a map illustrating ASMR and ASDR linked to this risk factor. We performed descriptive analyses of mortality rates and DALYs stratified by SDI and region, and calculated the EAPC for the period 1990–2021. Next, we investigated the relationship between High fasting plasma glucose-related pancreatic cancer burden and SDI, accounting for geographic location (across 204 countries and 21 regions) and year. Additionally, we applied Das Gupta's decomposition method to examine the contributions of factors including age structure, epidemiological shifts, and population growth to overall changes in disability-adjusted life years (DALYs). Finally, we used the slope index of inequality (SII) and concentration index (CI) [16] to quantify cross-national inequalities in the burden of high fasting blood glucose-related pancreatic cancer across 204 countries and regions from 1990 to 2021. All data analyses and visualizations were performed using R statistical software (version 4.4.2). 3 Results 3.1 Global and Regional Burden of Pancreatic Cancer Pancreatic cancer imposes a substantial global health burden, with marked increases in both mortality and DALYs between 1990 and 2021. Globally, death cases surged from 39,731 to 132,753 (234% increase), while the ASMR rose from 1.08 to 1.56 per 100,000, reflecting an estimated annual percentage change (EAPC) of 1.34% (95% CI: 1.27–1.41). Similarly, DALYs escalated from 888,340 to 2,751,644 (209% increase), with the ASDR climbing from 22.64 to 31.70 per 100,000 (EAPC: 1.22%, 1.16–1.28).Regional disparities were pronounced. High SDI regions exhibited the highest ASMR (2.66 per 100,000 in 2021) and ASDR (53.80 per 100,000), driven by aging populations and lifestyle factors. Conversely, Low SDI regions showed the steepest relative increases in ASMR (EAPC: 1.75%, 1.59–1.90) and ASDR (EAPC: 1.61%, 1.45–1.76), likely due to limited healthcare access and delayed diagnoses. High-income North America had the highest absolute burden in 2021 (22,015 deaths; ASMR: 3.19), while Central Asia experienced the most rapid ASMR growth (EAPC: 3.57%, 3.30–3.84). Age-specific patterns revealed a disproportionate burden in older populations. Over 70% of deaths and DALYs occurred in individuals aged 60–89 years, with peak incidence in the 75–79 age group across all SDI strata. Notably, High SDI regions demonstrated a bimodal distribution, with secondary peaks in younger cohorts (50–54 years), potentially linked to rising obesity and metabolic syndrome. ( Fig. 1 , see Additional file 1–3 ) 3.2 PC burden attributable to HFPG by age and sex Both the absolute number and rate of disability-adjusted life years (DALYs) attributed to hyperglycemia-related pancreatic cancer were near zero in the 25–59 age group. After 60 years of age, they increased with age, peaking in the 80–84 age group. In the population aged 95 years and older, the absolute number of DALYs decreased due to a sharp reduction in the elderly population base, while the rate remained high. Across all SDI groups, males consistently exhibited higher absolute DALY numbers and rates than females, indicating more severe healthy life loss in males, with this gender disparity consistent across SDI strata. In high-SDI regions, longer life expectancy led to more pronounced cumulative effects of hyperglycemia-related pancreatic cancer in the elderly, resulting in the highest DALY rates and absolute numbers among all groups. Additionally, the light blue confidence intervals for the ≥ 75 age group widened significantly, reflecting high health heterogeneity in the elderly and indicating higher estimation error in DALY measurements for this subgroup.​ Mortality data, stratified by age, gender, and SDI, showed high consistency with DALYs: mortality numbers and rates were near zero in the 25–59 age group; after 60 years, they increased rapidly, peaking in the 80–84 age group; in the ≥ 95 age group, the absolute number of deaths declined markedly due to a reduced population base, though the rate remained elevated. In each SDI group, male mortality (both absolute number and rate) was consistently higher than that in females, aligning with the gender pattern of DALYs. This confirms that males experience both greater healthy life loss and higher mortality risk. In high-SDI regions, hyperglycemia-related pancreatic cancer is more likely to progress to fatal stages, resulting in the highest death counts and rates across all groups Furthermore, the confidence intervals for the ≥ 75 age group widened significantly, consistent with DALY patterns, reflecting heterogeneity in elderly mortality profiles. ( Fig. 2 , see Additional file 6 ) 3.3 PC burden attributable to HFPG was associated with SDI From 1990 to 2021, ASMR and ASDR of PC attributable to high fasting plasma glucose increased with higher SDI. Notably, Southern Latin America, Central Europe, sub-Saharan Africa, the Caribbean, high-income Asia Pacific, high-income North America, and Oceania exhibited ASMR and ASDR values that exceeded levels expected for their SDI development levels. At the national level, the correlations between HFPG- and SDI-driven ASMR and ASDR for PC aligned with regional patterns. However, a distinct divergence emerged for ASDR: when SDI reached approximately 0.75, the correlation with ASDR began to decline. Notably, countries such as the United Arab Emirates, Uruguay, Greenland, the United States, Montenegro, and Hungary exhibited burdens exceeding expected levels based on their SDI regions. (Fig. 3 , Additional file 5) 3.4 Decomposition analysis of PC burden attributable to HFPG We conducted a decomposition analysis to further explore the impact of aging, population, and epidemiological changes on Deaths and DALYs of PC attributable to HFPG. Globally, DALYs increased by 2,470,741.64 cases between 1990 and 2021, with contributions from: Aging: 422,559.48 cases (17.10%), Population growth: 1,282,176.36 cases (51.90%), Epidemiological changes: 766,005.80 cases (31.00%). For mortality, total deaths rose by 134,847.76 cases during the same period, driven by:Aging: 26,461.92 cases (19.63%), Population growth: 65,420.46 cases (48.53%), Epidemiological changes: 42,965.38 cases (31.84%). For DALYs, in the High middle SDI region, aging and population contribute the most, with aging contributing 122172.56 (24.42%) and population contributing 210404.77 (42.06%), accounting for a total of 66.48% (24.42%+42.06%), significantly higher than other SDI regions. The region with the highest contribution to epidemiological change is High SDI, with a contribution of 763187.41 (60.21%). For Deaths, the regions with the greatest contributions from aging and population, as well as epidemiological changes, are both High SDI regions, accounting for (35689.82) 55.25% and (28889.59) 44.75%, respectively. The contribution of epidemiological changes in low SDI regions to DALYs and Deaths is relatively low (DALYs 38.92%, Deaths 40.21%), and the impact of aging in low SDI regions is weak (-0.48%). (Fig. 4 ) 3.5 Cross-country inequality analysis of PC burden attributable to HFPG There were significant relative and absolute SDI-related inequalities in the burden of PC attributable to HFPG, with an increasing trend in SII from 1990 to 2021. Disproportionately higher burdens of PC attributable to HFPG were observed in the higher SDI regions. The SII was 37.708 (95%CI, 23.961–37.453) in 1990 and increased to 81.762 (95%CI, 73.376–90.147) in 2021, indicating a larger gap in the DALYs rate between regions with the highest and lowest SDI. Furthermore, the CI was 0.420 (95%CI, 0.191,0.634) in 1990 and decreased to 0.439 (95%CI, 0.185–0.624) in 2021, suggesting persistent inequalities between low and high SDI regions, though the relative concentration of the burden had increased. (Fig. 5 ) 4 Discussion Previous research has demonstrated that a HFPG is a leading risk factor for PC [17] ; Although some studies have pointed out the trend of mortality of PC related to HFPG and the description of disease burden in some regions [18, 19] , there is an urgent need to understand the burden of PC attributable to HFPG in global and regions. The study presents a comprehensive summary of the burdens of PC attributable to HFPG at global, regional, and national levels, and projects burden trends for the next 14 years with no intervention using the latest GBD 2021 data. This analysis aims to provide policymakers with insights for effective resource allocation and the design of targeted prevention strategies. The results showed that from 1990 to 2021, the ASMR and ASDR of PC related to HFPG showed an upward trend, with EAPC of 1.340 and 1.219, respectively. However, globally, the absolute number of deaths and DALYs in 2021 exceeded three times that of 1990. The observed ASMR aligns with recent reports of PC overtaking breast cancer as the third-leading cause of cancer death in high-income nations [20] , but our decomposition analysis reveals novel drivers: population growth contributes 48.5% to mortality increases, surpassing aging and epidemiological changes. This challenges the prevailing view that demographic shifts dominate PC epidemiology, underscoring the multiplicative effect of HFPG proliferation in expanding populations. The 81.762 SII value for DALYs inequality (2021) quantifies how SDI stratification exacerbates HFPG-PC burdens. While high SDI regions exhibit 2.66-fold higher ASMR than global averages, the steepest EAPC growth in low SDI regions mirrors diabetes pandemic patterns in Africa and South Asia. This study profoundly elucidates the synergistic pathogenic effects of chronic injury induced by HFPG and the aging process in pancreatic cancer. At the molecular level, long-term HFPG induces persistent pancreatic cell damage through oxidative stress and the accumulation of AGEs [5, 21] . Concurrently, aging impairs cellular repair capacities—characterized by telomere shortening and diminished DNA damage repair function—thereby accelerating the initiation and progression of pancreatic cancer [22] . Epidemiologically, HFPG potentiates the likelihood of pancreatic cells surpassing malignant transformation thresholds, thereby increasing the risk of pancreatic cancer development [23] . These findings suggest that in clinical practice, it is imperative to strengthen early screening strategies for pancreatic cancer in individuals aged over 45 years with a long history of hyperglycemia, while actively controlling blood glucose levels to mitigate the cumulative effects of pancreatic injury. Men exhibit a persistently higher disease burden, which arises from the interplay of physiological, behavioral, and sociocultural factors. Physiologically, the protective role of estrogen in pancreatic homeostasis is well-established: animal studies have demonstrated that estrogen inhibits pancreatic cancer cell proliferation, whereas male androgens may indirectly exacerbate HFPG-induced damage by promoting insulin resistance [24, 25] . Behaviorally and socially, men are more frequently exposed to risk factors such as smoking and alcohol abuse [26, 27] . Both smoking and alcohol abuse are recognized as significant risk factors for pancreatic cancer pathogenesis: smoking significantly elevates risk, with smoking cessation effectively reducing risk to baseline levels—particularly in individuals with shorter smoking histories. Alcohol abuse exhibits a positive dose-response relationship with pancreatic cancer risk, with beer and spirits posing particular harm [28] . Their synergistic effects may exacerbate cellular damage and elevate risk in high-risk populations. Intervention strategies should therefore emphasize smoking cessation and alcohol reduction or abstinence to alleviate the global disease burden [29, 30] . In high-SDI regions, longer life expectancy allows sufficient time for HFPG-induced chronic damage to accumulate and progress to pancreatic cancer [31] . Simultaneously, robust medical resources facilitate earlier disease diagnosis, comprehensive tracking, and reduced underreporting, resulting in a substantial pancreatic cancer burden attributable to HFPG [32] . In contrast, low-SDI regions are characterized by shorter life expectancies, where HFPG is more likely to cause fatal outcomes during early acute complications [32] ; pancreatic cancer may also be underdiagnosed due to limited diagnostic capacity, leading to underestimation of the true burden. Additionally, inadequate primary healthcare infrastructure in low-SDI regions contributes to unrecognized hyperglycemia, indirectly exacerbating pancreatic injury risk [26] . Thus, low-SDI regions should prioritize strengthening primary healthcare systems—including popularizing blood glucose monitoring devices, training community physicians, and establishing rapid referral pathways for tumor diagnostics. Although the burdens of PC associated with HFPG are closely related to population growth and aging, other factors must also be considered. The increasing prevalence of metabolic disorders, particularly elevated HFPG in recent decades, is an undeniable contributor [33] . Chronic hyperglycemia is linked to systemic comorbidities and oncogenic mechanisms across multiple organ systems [34] . For cancers, HFPG drives carcinogenesis through pathways such as insulin resistance, chronic inflammation, and oxidative stress, which promote cellular proliferation and inhibit apoptosis [35, 36] . Epidemiological studies have demonstrated a strong association between HFPG levels and heightened risks of pancreatic ductal adenocarcinoma [37] , the most common histological subtype. Lifestyle and dietary patterns play pivotal roles in modulating HFPG. As socioeconomic conditions improve, populations increasingly adopt diets rich in refined carbohydrates and saturated fats, coupled with reduced physical activity and sedentary behaviors—factors that exacerbate hyperglycemia and metabolic dysfunction. For instance, excessive sugar intake directly impairs pancreatic β-cell function and exacerbates insulin resistance, creating a microenvironment conducive to malignant transformation [38] . Furthermore, prolonged hyperglycemia accelerates the formation of AGEs [39] , which interact with pancreatic stellate cells to induce fibrosis and stromal remodeling, hallmarks of pancreatic cancer progression. This multilevel analysis establishes HFPG as a modifiable driver of pancreatic cancer's shifting epidemiology, with inequalities entrenched in both development gradients and biological susceptibilities. While population aging imposes unavoidable burdens, most of ASMR increases stem from preventable factors—a clarion call for precision prevention tailored to SDI contexts and sex-age vulnerabilities. However, there are several limitations in using GBD data to analyze global pancreatic cancer attributable to HFPG. Firstly, GBD 2021 estimates rely on aggregated global data rather than primary sources, introducing potential biases in extrapolation across diverse populations. Secondly, the study focuses on global and regional trends without examining within-country disparities. Additionally, the analysis assumes HFPG acts as an independent risk factor, whereas in reality, HFPG often coexists and interacts synergistically with other metabolic and lifestyle factors worldwide—this may compromise the accuracy of attribution. Finally, variations in data quality and reporting standard. 5 Conclusion This study reveals the substantial global burden of PC and its association with HFPG from 1990 to 2021. Globally, PC mortality and DALYs increased markedly, with pronounced regional disparities: high SDI regions bear the heaviest burden, while low SDI regions show steeper growth. The burden is disproportionately concentrated in older populations (60–89 years), with high SDI regions exhibiting a bimodal age distribution, including secondary peaks in younger groups. HFPG-related PC burden, negligible before 60, rises with age thereafter, with males experiencing greater losses across all SDI strata. Decomposition analysis identifies population growth and epidemiological changes as key drivers of increased deaths and DALYs. Additionally, cross-country inequalities persist and widen, with higher burdens in high SDI regions. These findings highlight the need for targeted interventions addressing aging, lifestyle factors, and healthcare disparities to mitigate PC burden, particularly in high-risk groups and regions. Declarations 1.Ethics approval and consent to participate This manuscript is for public database research and does not involve any ethical issues,Not applicable 2.Consent for publication Not applicable 3.Availability of data and materials The manuscript data are all from GBD2021, a public database, and the website is http://ghdx.healthdata.org/. 4.Competing interests The authors declare that they have no competing interests. 5.Funding This article is supported by the National Natural Science Foundation of China (Project Code: 82460507) . 6.Authors' contributions Siyuan Li is mainly responsible for data visualization and article writing, Xizhuang Pan is mainly responsible for topic selection and data visualization, Song Chen is mainly responsible for organizing data, and Wang Xing and Pan Yaozhen are responsible for reviewing and modifying manuscripts. 7.Acknowledgements Thanks to the Institute for Health Metrics and Evaluation (IHME), and the Global Burden of Disease study collaborations. 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Cheruiyot A, Hollister-Lock J, Sullivan B, Pan H, Dreyfuss JM, Bonner-Weir S, et al. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion. J Clin Invest, 2023, 134:. Wang W, Hapach LA, Griggs L, Smart K, Wu Y, Taufalele PV, et al. Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening. Sci Adv, 2022, 8:eabo1673. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.xlsx Additionalfile2.xlsx Additionalfile3.docx Additionalfile4.docx Additionalfile5.docx AdditionalFile6.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7063506","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":489617159,"identity":"d6cd5b7f-7a4e-4aef-ace8-1c287fdb7ab7","order_by":0,"name":"Siyuan Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIie3RMQrCMBSA4VcC6RLtmmLRKwQEz5NQ6KYILh0cIogdrLvH6OgYl04R1471BjrpotjSUWnq5pBvzk9e8gAs6w/h0fn+uMbLoecmx5LHS3PSp8D8vc7HfqpDVurcnAyrZNDbIMEKPvEva9RhsIHkjGDM/VRFsZAYvGTL25NAKU5JMPPcVV6IQwBUn7L2BIRUjOJFfUshNAZGp6YkdKrRkMiqt8zFBnVIaIRA8SaBbgnR2JGq+WTKdU6MbxklKUbPV7PK26PeabJrTz6Q345blmVZX70BnOZLZz60Sw4AAAAASUVORK5CYII=","orcid":"","institution":"Clinical Medicine School of Guizhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Siyuan","middleName":"","lastName":"Li","suffix":""},{"id":489617160,"identity":"7feb7cbc-f133-40ec-8829-8397ea3392ea","order_by":1,"name":"Xizhuang Pan","email":"","orcid":"","institution":"Clinical Medicine School of Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xizhuang","middleName":"","lastName":"Pan","suffix":""},{"id":489617161,"identity":"51fe4405-71fe-4874-80ea-4e559b38c10c","order_by":2,"name":"Song Chen","email":"","orcid":"","institution":"Clinical Medicine School of Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Chen","suffix":""},{"id":489617162,"identity":"d64a91be-e254-4b81-8fbe-c7c2c68040cb","order_by":3,"name":"Xing Wang","email":"","orcid":"","institution":"The Affiliated Cancer Hospital of Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Wang","suffix":""},{"id":489617163,"identity":"d196119b-8cc3-4afe-a8cd-fc9633b896df","order_by":4,"name":"Yaozhen Pan","email":"","orcid":"","institution":"The Affiliated Cancer Hospital of Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yaozhen","middleName":"","lastName":"Pan","suffix":""}],"badges":[],"createdAt":"2025-07-07 09:08:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7063506/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7063506/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87575491,"identity":"9d761b71-28e0-4f3d-9f23-4f8da25097f2","added_by":"auto","created_at":"2025-07-25 11:38:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1172686,"visible":true,"origin":"","legend":"\u003cp\u003eAge-standardized DALY rate (ASDR) of PC attributable to HFPG per 100,000 population in 2021, by country\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/cecd5fa3b21a0177e22ec4d7.png"},{"id":87575488,"identity":"07e35c1c-48b8-405f-9856-182a0b53e59b","added_by":"auto","created_at":"2025-07-25 11:38:10","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":522840,"visible":true,"origin":"","legend":"\u003cp\u003eAge-specific numbers and rates of DALYs and deaths of PC attributable to HFPG by age and sex, in 2021.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/3d4f700e3f98c5543077e1bf.jpeg"},{"id":87576884,"identity":"2b5bb606-cd14-4fbb-8d8d-314c1da2e82a","added_by":"auto","created_at":"2025-07-25 11:46:11","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":565689,"visible":true,"origin":"","legend":"\u003cp\u003eAge-standardized DALY rate and ASMR of PC attributable to HFPG in 21 GBD regions by the SDI, 1990–2021.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/e7d848ac7a9ba3bb51401d82.jpeg"},{"id":87575498,"identity":"91730a7b-7aa3-4d9c-9e2f-bea2399c03b2","added_by":"auto","created_at":"2025-07-25 11:38:10","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":282986,"visible":true,"origin":"","legend":"\u003cp\u003eDecomposition analysis of changes in the DALYs and deaths of PC attributable to HFPG between 1990 and 2021 across SDI regions.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/5af53dca910a9154d91f37a2.jpeg"},{"id":87575504,"identity":"b016707e-2098-477b-b84c-b92888db8874","added_by":"auto","created_at":"2025-07-25 11:38:11","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":579763,"visible":true,"origin":"","legend":"\u003cp\u003eInequality analysis of DALYs in PC attributable to HFPG in 1990 and 2021 across the world.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/cd9d132da43d89bd6fdd510f.jpeg"},{"id":105575657,"identity":"8709aef9-5332-4d1e-a5bb-b297693be619","added_by":"auto","created_at":"2026-03-27 13:40:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3431560,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/1c31a713-b031-47c3-ae1e-01d620cabd8c.pdf"},{"id":87575490,"identity":"b6db7c42-263b-4c7b-a042-0148be76ea28","added_by":"auto","created_at":"2025-07-25 11:38:10","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":13892,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/ab70c89698ba91104e368375.xlsx"},{"id":87575497,"identity":"e2eb4cb2-1132-493d-b20d-ad8943c68934","added_by":"auto","created_at":"2025-07-25 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11:38:11","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":3333780,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile6.docx","url":"https://assets-eu.researchsquare.com/files/rs-7063506/v1/d8965829f6d1ac60f33bc639.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"An analysis of the global burden of pancreatic cancer attributable to High fasting plasma glucose: 1990– 2021","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eThe early stages of pancreatic cancer often go unnoticed due to nonspecific symptoms such as abdominal pain, weight loss, and jaundice, leading to delayed diagnosis and a high likelihood of advanced disease at the time of detection. Radical surgical resection, such as pancreaticoduodenectomy, remains the sole potentially curative treatment\u003csup\u003e[1]\u003c/sup\u003e. Unfortunately, it is estimated that only 15\u0026ndash;20% of patients are eligible for curative surgical resection\u003csup\u003e[2]\u003c/sup\u003e, with a 5-year overall survival (OS) rate of less than 10% for all stages combined\u003csup\u003e[3]\u003c/sup\u003e. Furthermore, the epidemiology of pancreatic cancer is influenced by multiple factors, including geographic location, gender, and age. Regions such as North America, Europe, and high-income Asian countries exhibit higher incidence rates compared to African nations. Men and individuals over 60 years old demonstrate elevated susceptibility to this disease.The reasons for these disparities are multifaceted, involving differences in smoking prevalence, rates of chronic pancreatitis and diabetes, and socioeconomic determinants affecting healthcare access.\u003c/p\u003e\u003cp\u003eEmerging evidence demonstrates that HFPG contributes to PC through insulin/IGF-1 signaling dysregulation\u003csup\u003e[4]\u003c/sup\u003e, Warburg effect potentiation\u003csup\u003e[5]\u003c/sup\u003e, and advanced glycation end-products (AGEs)-mediated cellular damage\u003csup\u003e[6]\u003c/sup\u003e. For instance, chronic hyperglycemia induces pathological overexpression of insulin-like growth factor 1 (IGF-1) in pancreatic β-cells, which activates downstream oncogenic pathways through receptor tyrosine kinases\u003csup\u003e[4, 7]\u003c/sup\u003e. This metabolic derangement creates a permissive microenvironment for neoplastic transformation, highlighting the imperative to elucidate the precise molecular crosstalk between glucose homeostasis disorders and pancreatic oncogenesis. Epidemiological studies consistently identify hyperglycemia as a modifiable risk determinant, accounting for approximately 25\u0026ndash;35% of global pancreatic cancer burden\u003csup\u003e[8, 9]\u003c/sup\u003e. As the predominant metabolic risk factor, HFPG contributes substantially to pancreatic cancer-associated mortality and DALYs, representing 19.7% of total metabolic-related cancer DALYs worldwide\u003csup\u003e[10]\u003c/sup\u003e. These findings underscore the critical need for multinational cohorts to quantify the population-attributable fraction of pancreatic cancer cases linked to dysglycemic states, thereby enabling data-driven health policy formulation and precision prevention initiatives.\u003c/p\u003e\u003cp\u003eThe GBD 2021 Study provides a comprehensive framework for evaluating the metabolic oncology burden, with specific relevance to pancreatic cancer pathogenesis. While existing literature has extensively characterized the general epidemiology of pancreatic cancer, the precise disease burden attributable to hyperglycemic states remains inadequately quantified\u003csup\u003e[11]\u003c/sup\u003e. This investigation aims to delineate the spatiotemporal patterns of pancreatic cancer mortality and DALYs across 204 countries and territories, focusing on high fasting plasma glucose as an etiological driver. Through decomposition analysis of annual percentage changes (APCs), we will identify geographic hotspots demonstrating the most rapid escalation in glucose-related pancreatic cancer burden, critical intelligence for implementing metabolic surveillance programs. The study further incorporates multivariable regression models to decipher the tripartite relationship between pancreatic cancer burden, socioeconomic development, and national healthcare access metrics. A comparative risk assessment framework will be employed to partition the population-attributable fractions of hyperglycemia-related pancreatic cancer into three components: demographic aging effects, population growth dynamics and true epidemiological transition. By projecting disease trajectories through 2035 using Bayesian age-period-cohort modeling\u003csup\u003e[12]\u003c/sup\u003e, this analysis will provide evidence-based projections to guide the development of glucose-centric early detection protocols and therapeutic interventions. These multidimensional outputs are expected to revolutionize current paradigms in pancreatic cancer prevention, particularly for populations undergoing rapid nutritional transition.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data source\u003c/h2\u003e\u003cp\u003eAll data in this paper are from GBD 2021, which includes a series of indicators such as incidence rate, morbidity, mortality and DALYs of 204 countries and regions from 1990 to 2021. It is available for free worldwide through the official website of the Institute of Health Metrics and Evaluation at the University of Washington in the United States(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ghdx.healthdata.org/\u003c/span\u003e\u003cspan address=\"http://ghdx.healthdata.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e ). We selected \u0026ldquo;High fasting plasma glucosee\u0026rdquo; in the risk list and \u0026ldquo;pancreatic cancer\u0026rdquo; in the cause list\u003csup\u003e[13]\u003c/sup\u003e. We obtained the death rate of pancreatic cancer PC caused by high abdominal glucose from 21 regions and 204 countries DALYs、 ASMR and ASDR\u003csup\u003e[14]\u003c/sup\u003e. The data is downloaded for analysis at various levels, including gender, age, country, GBD region, and SDI.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Definitions\u003c/h2\u003e\u003cp\u003eAccording to the World Health Organization (WHO) standards, high fasting blood glucose is defined as follows: prediabetes: 6.1\u0026ndash;6.9 mmol/L (110\u0026ndash;125 mg/dL); diabetes: in adults aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years, \u0026ge;\u0026thinsp;7.0 mmol/L (\u0026ge;\u0026thinsp;126 mg/dL)\u003csup\u003e[15]\u003c/sup\u003e. The Global Burden of Disease (GBD) defines high fasting plasma glucose (HFPG) as fasting blood glucose levels ranging from 86.4 to 97.2 mg/dL. The Socio-demographic Index (SDI) is a composite indicator that incorporates three core metrics: the total fertility rate among individuals under 25 years, educational attainment among people aged 15 and older, and per capita income. SDI values categorize all countries and regions into five tiers: low SDI, low-middle SDI, middle SDI, middle-high SDI, and high SDI, ranging from 0 to 1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e\u003cp\u003eWe present global temporal trends in mortality, DALYs, ASMR, and ASDR from 1990 to 2021, stratified by SDI level and region. To highlight the geographical disparities associated with High fasting plasma glucose in 2021, we constructed a map illustrating ASMR and ASDR linked to this risk factor. We performed descriptive analyses of mortality rates and DALYs stratified by SDI and region, and calculated the EAPC for the period 1990\u0026ndash;2021. Next, we investigated the relationship between High fasting plasma glucose-related pancreatic cancer burden and SDI, accounting for geographic location (across 204 countries and 21 regions) and year. Additionally, we applied Das Gupta's decomposition method to examine the contributions of factors including age structure, epidemiological shifts, and population growth to overall changes in disability-adjusted life years (DALYs). Finally, we used the slope index of inequality (SII) and concentration index (CI)\u003csup\u003e[16]\u003c/sup\u003e to quantify cross-national inequalities in the burden of high fasting blood glucose-related pancreatic cancer across 204 countries and regions from 1990 to 2021. All data analyses and visualizations were performed using R statistical software (version 4.4.2).\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Global and Regional Burden of Pancreatic Cancer\u003c/h2\u003e\u003cp\u003ePancreatic cancer imposes a substantial global health burden, with marked increases in both mortality and DALYs between 1990 and 2021. Globally, death cases surged from 39,731 to 132,753 (234% increase), while the ASMR rose from 1.08 to 1.56 per 100,000, reflecting an estimated annual percentage change (EAPC) of 1.34% (95% CI: 1.27\u0026ndash;1.41). Similarly, DALYs escalated from 888,340 to 2,751,644 (209% increase), with the ASDR climbing from 22.64 to 31.70 per 100,000 (EAPC: 1.22%, 1.16\u0026ndash;1.28).Regional disparities were pronounced. High SDI regions exhibited the highest ASMR (2.66 per 100,000 in 2021) and ASDR (53.80 per 100,000), driven by aging populations and lifestyle factors. Conversely, Low SDI regions showed the steepest relative increases in ASMR (EAPC: 1.75%, 1.59\u0026ndash;1.90) and ASDR (EAPC: 1.61%, 1.45\u0026ndash;1.76), likely due to limited healthcare access and delayed diagnoses. High-income North America had the highest absolute burden in 2021 (22,015 deaths; ASMR: 3.19), while Central Asia experienced the most rapid ASMR growth (EAPC: 3.57%, 3.30\u0026ndash;3.84). Age-specific patterns revealed a disproportionate burden in older populations. Over 70% of deaths and DALYs occurred in individuals aged 60\u0026ndash;89 years, with peak incidence in the 75\u0026ndash;79 age group across all SDI strata. Notably, High SDI regions demonstrated a bimodal distribution, with secondary peaks in younger cohorts (50\u0026ndash;54 years), potentially linked to rising obesity and metabolic syndrome. ( Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, see Additional file 1\u0026ndash;3 )\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.2 PC burden attributable to HFPG by age and sex\u003c/h2\u003e\u003cp\u003eBoth the absolute number and rate of disability-adjusted life years (DALYs) attributed to hyperglycemia-related pancreatic cancer were near zero in the 25\u0026ndash;59 age group. After 60 years of age, they increased with age, peaking in the 80\u0026ndash;84 age group. In the population aged 95 years and older, the absolute number of DALYs decreased due to a sharp reduction in the elderly population base, while the rate remained high. Across all SDI groups, males consistently exhibited higher absolute DALY numbers and rates than females, indicating more severe healthy life loss in males, with this gender disparity consistent across SDI strata. In high-SDI regions, longer life expectancy led to more pronounced cumulative effects of hyperglycemia-related pancreatic cancer in the elderly, resulting in the highest DALY rates and absolute numbers among all groups. Additionally, the light blue confidence intervals for the \u0026ge;\u0026thinsp;75 age group widened significantly, reflecting high health heterogeneity in the elderly and indicating higher estimation error in DALY measurements for this subgroup.​\u003c/p\u003e\u003cp\u003eMortality data, stratified by age, gender, and SDI, showed high consistency with DALYs: mortality numbers and rates were near zero in the 25\u0026ndash;59 age group; after 60 years, they increased rapidly, peaking in the 80\u0026ndash;84 age group; in the \u0026ge;\u0026thinsp;95 age group, the absolute number of deaths declined markedly due to a reduced population base, though the rate remained elevated. In each SDI group, male mortality (both absolute number and rate) was consistently higher than that in females, aligning with the gender pattern of DALYs. This confirms that males experience both greater healthy life loss and higher mortality risk. In high-SDI regions, hyperglycemia-related pancreatic cancer is more likely to progress to fatal stages, resulting in the highest death counts and rates across all groups Furthermore, the confidence intervals for the \u0026ge;\u0026thinsp;75 age group widened significantly, consistent with DALY patterns, reflecting heterogeneity in elderly mortality profiles. ( Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, see Additional file 6 )\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.3 PC burden attributable to HFPG was associated with SDI\u003c/h2\u003e\u003cp\u003eFrom 1990 to 2021, ASMR and ASDR of PC attributable to high fasting plasma glucose increased with higher SDI. Notably, Southern Latin America, Central Europe, sub-Saharan Africa, the Caribbean, high-income Asia Pacific, high-income North America, and Oceania exhibited ASMR and ASDR values that exceeded levels expected for their SDI development levels. At the national level, the correlations between HFPG- and SDI-driven ASMR and ASDR for PC aligned with regional patterns. However, a distinct divergence emerged for ASDR: when SDI reached approximately 0.75, the correlation with ASDR began to decline. Notably, countries such as the United Arab Emirates, Uruguay, Greenland, the United States, Montenegro, and Hungary exhibited burdens exceeding expected levels based on their SDI regions. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Additional file 5)\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Decomposition analysis of PC burden attributable to HFPG\u003c/h2\u003e\u003cp\u003eWe conducted a decomposition analysis to further explore the impact of aging, population, and epidemiological changes on Deaths and DALYs of PC attributable to HFPG. Globally, DALYs increased by 2,470,741.64 cases between 1990 and 2021, with contributions from: Aging: 422,559.48 cases (17.10%), Population growth: 1,282,176.36 cases (51.90%), Epidemiological changes: 766,005.80 cases (31.00%). For mortality, total deaths rose by 134,847.76 cases during the same period, driven by:Aging: 26,461.92 cases (19.63%), Population growth: 65,420.46 cases (48.53%), Epidemiological changes: 42,965.38 cases (31.84%). For DALYs, in the High middle SDI region, aging and population contribute the most, with aging contributing 122172.56 (24.42%) and population contributing 210404.77 (42.06%), accounting for a total of 66.48% (24.42%+42.06%), significantly higher than other SDI regions. The region with the highest contribution to epidemiological change is High SDI, with a contribution of 763187.41 (60.21%). For Deaths, the regions with the greatest contributions from aging and population, as well as epidemiological changes, are both High SDI regions, accounting for (35689.82) 55.25% and (28889.59) 44.75%, respectively. The contribution of epidemiological changes in low SDI regions to DALYs and Deaths is relatively low (DALYs 38.92%, Deaths 40.21%), and the impact of aging in low SDI regions is weak (-0.48%). (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Cross-country inequality analysis of PC burden attributable to HFPG\u003c/h2\u003e\u003cp\u003eThere were significant relative and absolute SDI-related inequalities in the burden of PC attributable to HFPG, with an increasing trend in SII from 1990 to 2021. Disproportionately higher burdens of PC\u003c/p\u003e\u003cp\u003eattributable to HFPG were observed in the higher SDI regions. The SII was 37.708 (95%CI, 23.961\u0026ndash;37.453) in 1990 and increased to 81.762 (95%CI, 73.376\u0026ndash;90.147) in 2021, indicating a larger gap in the DALYs rate between regions with the highest and lowest SDI. Furthermore, the CI was 0.420 (95%CI, 0.191,0.634) in 1990 and decreased to 0.439 (95%CI, 0.185\u0026ndash;0.624) in 2021, suggesting persistent inequalities between low and high SDI regions, though the relative concentration of the burden had increased. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003ePrevious research has demonstrated that a HFPG is a leading risk factor for PC\u003csup\u003e[17]\u003c/sup\u003e; Although some studies have pointed out the trend of mortality of PC related to HFPG and the description of disease burden in some regions\u003csup\u003e[18, 19]\u003c/sup\u003e, there is an urgent need to understand the burden of PC attributable to HFPG in global and regions. The study presents a comprehensive summary of the burdens of PC attributable to HFPG at global, regional, and national levels, and projects burden trends for the next 14 years with no intervention using the latest GBD 2021 data. This analysis aims to provide policymakers with insights for effective resource allocation and the design of targeted prevention strategies.\u003c/p\u003e\u003cp\u003eThe results showed that from 1990 to 2021, the ASMR and ASDR of PC related to HFPG showed an upward trend, with EAPC of 1.340 and 1.219, respectively. However, globally, the absolute number of deaths and DALYs in 2021 exceeded three times that of 1990. The observed ASMR aligns with recent reports of PC overtaking breast cancer as the third-leading cause of cancer death in high-income nations\u003csup\u003e[20]\u003c/sup\u003e, but our decomposition analysis reveals novel drivers: population growth contributes 48.5% to mortality increases, surpassing aging and epidemiological changes. This challenges the prevailing view that demographic shifts dominate PC epidemiology, underscoring the multiplicative effect of HFPG proliferation in expanding populations. The 81.762 SII value for DALYs inequality (2021) quantifies how SDI stratification exacerbates HFPG-PC burdens. While high SDI regions exhibit 2.66-fold higher ASMR than global averages, the steepest EAPC growth in low SDI regions mirrors diabetes pandemic patterns in Africa and South Asia.\u003c/p\u003e\u003cp\u003eThis study profoundly elucidates the synergistic pathogenic effects of chronic injury induced by HFPG and the aging process in pancreatic cancer. At the molecular level, long-term HFPG induces persistent pancreatic cell damage through oxidative stress and the accumulation of AGEs\u003csup\u003e[5, 21]\u003c/sup\u003e. Concurrently, aging impairs cellular repair capacities\u0026mdash;characterized by telomere shortening and diminished DNA damage repair function\u0026mdash;thereby accelerating the initiation and progression of pancreatic cancer\u003csup\u003e[22]\u003c/sup\u003e. Epidemiologically, HFPG potentiates the likelihood of pancreatic cells surpassing malignant transformation thresholds, thereby increasing the risk of pancreatic cancer development\u003csup\u003e[23]\u003c/sup\u003e. These findings suggest that in clinical practice, it is imperative to strengthen early screening strategies for pancreatic cancer in individuals aged over 45 years with a long history of hyperglycemia, while actively controlling blood glucose levels to mitigate the cumulative effects of pancreatic injury.\u003c/p\u003e\u003cp\u003eMen exhibit a persistently higher disease burden, which arises from the interplay of physiological, behavioral, and sociocultural factors. Physiologically, the protective role of estrogen in pancreatic homeostasis is well-established: animal studies have demonstrated that estrogen inhibits pancreatic cancer cell proliferation, whereas male androgens may indirectly exacerbate HFPG-induced damage by promoting insulin resistance\u003csup\u003e[24, 25]\u003c/sup\u003e. Behaviorally and socially, men are more frequently exposed to risk factors such as smoking and alcohol abuse\u003csup\u003e[26, 27]\u003c/sup\u003e. Both smoking and alcohol abuse are recognized as significant risk factors for pancreatic cancer pathogenesis: smoking significantly elevates risk, with smoking cessation effectively reducing risk to baseline levels\u0026mdash;particularly in individuals with shorter smoking histories. Alcohol abuse exhibits a positive dose-response relationship with pancreatic cancer risk, with beer and spirits posing particular harm\u003csup\u003e[28]\u003c/sup\u003e. Their synergistic effects may exacerbate cellular damage and elevate risk in high-risk populations. Intervention strategies should therefore emphasize smoking cessation and alcohol reduction or abstinence to alleviate the global disease burden\u003csup\u003e[29, 30]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn high-SDI regions, longer life expectancy allows sufficient time for HFPG-induced chronic damage to accumulate and progress to pancreatic cancer\u003csup\u003e[31]\u003c/sup\u003e. Simultaneously, robust medical resources facilitate earlier disease diagnosis, comprehensive tracking, and reduced underreporting, resulting in a substantial pancreatic cancer burden attributable to HFPG\u003csup\u003e[32]\u003c/sup\u003e. In contrast, low-SDI regions are characterized by shorter life expectancies, where HFPG is more likely to cause fatal outcomes during early acute complications\u003csup\u003e[32]\u003c/sup\u003e; pancreatic cancer may also be underdiagnosed due to limited diagnostic capacity, leading to underestimation of the true burden. Additionally, inadequate primary healthcare infrastructure in low-SDI regions contributes to unrecognized hyperglycemia, indirectly exacerbating pancreatic injury risk\u003csup\u003e[26]\u003c/sup\u003e. Thus, low-SDI regions should prioritize strengthening primary healthcare systems\u0026mdash;including popularizing blood glucose monitoring devices, training community physicians, and establishing rapid referral pathways for tumor diagnostics.\u003c/p\u003e\u003cp\u003eAlthough the burdens of PC associated with HFPG are closely related to population growth and aging, other factors must also be considered. The increasing prevalence of metabolic disorders, particularly elevated HFPG in recent decades, is an undeniable contributor\u003csup\u003e[33]\u003c/sup\u003e. Chronic hyperglycemia is linked to systemic comorbidities and oncogenic mechanisms across multiple organ systems\u003csup\u003e[34]\u003c/sup\u003e. For cancers, HFPG drives carcinogenesis through pathways such as insulin resistance, chronic inflammation, and oxidative stress, which promote cellular proliferation and inhibit apoptosis\u003csup\u003e[35, 36]\u003c/sup\u003e. Epidemiological studies have demonstrated a strong association between HFPG levels and heightened risks of pancreatic ductal adenocarcinoma\u003csup\u003e[37]\u003c/sup\u003e, the most common histological subtype. Lifestyle and dietary patterns play pivotal roles in modulating HFPG. As socioeconomic conditions improve, populations increasingly adopt diets rich in refined carbohydrates and saturated fats, coupled with reduced physical activity and sedentary behaviors\u0026mdash;factors that exacerbate hyperglycemia and metabolic dysfunction. For instance, excessive sugar intake directly impairs pancreatic β-cell function and exacerbates insulin resistance, creating a microenvironment conducive to malignant transformation\u003csup\u003e[38]\u003c/sup\u003e. Furthermore, prolonged hyperglycemia accelerates the formation of AGEs\u003csup\u003e[39]\u003c/sup\u003e, which interact with pancreatic stellate cells to induce fibrosis and stromal remodeling, hallmarks of pancreatic cancer progression.\u003c/p\u003e\u003cp\u003eThis multilevel analysis establishes HFPG as a modifiable driver of pancreatic cancer's shifting epidemiology, with inequalities entrenched in both development gradients and biological susceptibilities. While population aging imposes unavoidable burdens, most of ASMR increases stem from preventable factors\u0026mdash;a clarion call for precision prevention tailored to SDI contexts and sex-age vulnerabilities.\u003c/p\u003e\u003cp\u003eHowever, there are several limitations in using GBD data to analyze global pancreatic cancer attributable to HFPG. Firstly, GBD 2021 estimates rely on aggregated global data rather than primary sources, introducing potential biases in extrapolation across diverse populations. Secondly, the study focuses on global and regional trends without examining within-country disparities. Additionally, the analysis assumes HFPG acts as an independent risk factor, whereas in reality, HFPG often coexists and interacts synergistically with other metabolic and lifestyle factors worldwide\u0026mdash;this may compromise the accuracy of attribution. Finally, variations in data quality and reporting standard.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis study reveals the substantial global burden of PC and its association with HFPG from 1990 to 2021. Globally, PC mortality and DALYs increased markedly, with pronounced regional disparities: high SDI regions bear the heaviest burden, while low SDI regions show steeper growth. The burden is disproportionately concentrated in older populations (60\u0026ndash;89 years), with high SDI regions exhibiting a bimodal age distribution, including secondary peaks in younger groups. HFPG-related PC burden, negligible before 60, rises with age thereafter, with males experiencing greater losses across all SDI strata. Decomposition analysis identifies population growth and epidemiological changes as key drivers of increased deaths and DALYs. Additionally, cross-country inequalities persist and widen, with higher burdens in high SDI regions. These findings highlight the need for targeted interventions addressing aging, lifestyle factors, and healthcare disparities to mitigate PC burden, particularly in high-risk groups and regions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e1.Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis manuscript is for public database research and does not involve any ethical issues,Not applicable\u003c/p\u003e\n\u003cp\u003e2.Consent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e3.Availability of data and materials\u003c/p\u003e\n\u003cp\u003eThe manuscript data are all from GBD2021, a public database, and the website is http://ghdx.healthdata.org/.\u003c/p\u003e\n\u003cp\u003e4.Competing interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e5.Funding\u003c/p\u003e\n\u003cp\u003eThis article is supported by the National Natural Science Foundation of China (Project Code: 82460507) .\u003c/p\u003e\n\u003cp\u003e6.Authors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eSiyuan Li is mainly responsible for data visualization and article writing, Xizhuang Pan is mainly responsible for topic selection and data visualization, \u0026nbsp;Song Chen is mainly responsible for organizing data, and Wang Xing and Pan Yaozhen are responsible for reviewing and modifying manuscripts.\u003c/p\u003e\n\u003cp\u003e7.Acknowledgements\u003c/p\u003e\n\u003cp\u003eThanks to the Institute for Health Metrics and Evaluation (IHME), and the Global Burden of Disease study collaborations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMizrahi JD, Surana R, Valle JW, Shroff RT. 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J Natl Compr Canc Netw, 2023, 21:1149-1155 e3.\u003c/li\u003e\n\u003cli\u003eCheruiyot A, Hollister-Lock J, Sullivan B, Pan H, Dreyfuss JM, Bonner-Weir S, et al. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion. J Clin Invest, 2023, 134:.\u003c/li\u003e\n\u003cli\u003eWang W, Hapach LA, Griggs L, Smart K, Wu Y, Taufalele PV, et al. Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening. Sci Adv, 2022, 8:eabo1673.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7063506/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7063506/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Pancreatic cancer (PC), a highly aggressive malignancy with poor prognosis, is frequently diagnosed at advanced stages. High fasting plasma glucose (HFPG), a key metabolic risk factor, significantly contributes to pancreatic cancer mortality and disability-adjusted life years (DALYs). This study aimed to quantify the global burden of pancreatic cancer attributable to HFPG from 1990 to 2021 and inform targeted prevention strategies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eWe extracted data on the burden of pancreatic cancer attributable to high fasting blood glucose from 1990 to 2021 from the Global Burden of Disease (GBD) 2021 database. We characterized this burden across different ages, sexes, age groups, Socio-demographic Index (SDI) regions, and countries. To illustrate temporal trends in the pancreatic cancer burden, we computed the estimated annual percentage change (EAPC) for the period 1990–2021. Decomposition analysis was used to identify drivers of changes in burden, while inequality analysis assessed disparities across SDI levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eGlobally, the ASMR and ASDR of PC related to HFPG showed an upward trend between 1990 and 2021, and the absolute number of deaths and DALYs cases increased more than threefold. High SDI regions exhibit a higher burden due to a higher number of HFPG patients, population growth, and aging, while low SDI regions face higher EAPCs due to limited resources. Moreover, this inequality has become even more pronounced. Men are more susceptible in all age groups. There are significant differences in burden management among countries, with some low SDI countries showing better performance than high SDI countries.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIt was found that PC attributable to HFPG was generally on the rise from 1990 to 2021 around the world. The age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) for PC linked to HFPG increased with higher SDI. Older and middle-aged populations bore the heaviest burden, with males carrying a greater PC burden than females. Population growth and epidemiological shifts drove this increase, while SDI-related inequalities are worsening. Targeted interventions addressing metabolic risks and healthcare access are warranted.\u003c/p\u003e","manuscriptTitle":"An analysis of the global burden of pancreatic cancer attributable to High fasting plasma glucose: 1990– 2021","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 11:38:05","doi":"10.21203/rs.3.rs-7063506/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e7e5148-f72c-483d-a263-bd0064d23792","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T13:29:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-25 11:38:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7063506","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7063506","identity":"rs-7063506","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}