Sex-specific association between carbohydrate antigen 19–9 and incident type 2 diabetes

www.nature.com/scientificreports OPEN Sex-specific association between carbohydrate antigen 19–9 and incident type 2 diabetes Sujeong Shin1, Yoosoo Chang2,3,4 & Seungho Ryu2,3,4 Carbohydrate antigen 19–9 (CA19-9) levels are associated with glycemic control, insulin resistance, and chronic complications in patients with type 2 diabetes (T2D). Women generally show higher CA19-9 levels despite a greater T2D prevalence in men. We evaluated the sex-specific longitudinal associations between CA19-9 levels and T2D incidence. Korean adults (n = 329,380) without previous cancer or T2D were categorized into four groups based on their CA19-9 levels. The study end point was the development of incident T2D during follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) according to CA19-9 levels. During a median follow-up of 6.1 years (3.3–9.3 years), the incidence rates of T2D were 9.9 per 1,000 person-years in men and 3.6 per 1,000 person-years in women. In the time-dependent analysis, adjusted HRs (95% confidence intervals) for incident T2D comparing CA19-9 levels of 10.0–19.9, 20.0–29.9, and ≥ 30 U/mL to the reference (< 10 U/ mL) were 1.08 (1.04–1.13), 1.18 (1.07–1.30), and 1.64 (1.35–1.99), respectively, among men. However, this association was not observed in women. The association between CA19-9 category and incident T2D significantly differed by sex (Pinteraction = 0.006). Among young and middle-aged Korean adults, elevated CA19-9 levels were significantly associated with increased risk of type 2 diabetes in men but not in women. Elevated CA19-9 levels in men could be a useful marker for identifying individuals at high risk of developing T2D. Evaluation approaches for individuals with elevated CA19-9 levels should be sex-specific. Keywords Carbohydrate antigen 19–9, Diabetes mellitus, Type 2, Sex differences Carbohydrate antigen 19–9 (CA19-9), a tumor-associated antigen, was initially characterized using a hybridomagenerated monoclonal antibody derived from murine spleen cells immunized with a human colorectal cancer cell line1. In humans, CA19-9 is expressed in the exocrine pancreas in vivo and serves as a valuable marker for detecting neoplastic invasion-induced damage to pancreatic exocrine function2. In an animal study, mice expressing CA19-9 demonstrated rapid induction of severe pancreatitis3. Pancreatitis induces apoptosis in pancreatic exocrine cells and has been associated with concurrent dysfunction of pancreatic endocrine cells and newly diagnosed type 2 diabetes (T2D) in 40% of patients4. Because T2D is associated with impaired pancreatic cell function and damage, studies have explored the correlation between CA19-9 and T2D5–7. CA19-9 levels are associated with glycemic control status, insulin resistance, and chronic complications in patients with T2D2,5,6. Notably, CA19-9 levels are higher in women than in men8, despite a higher risk of T2D in men. In women, elevated CA19-9 levels can be attributed not only to pancreatic pathology, but also to conditions affecting non-pancreatic organs, such as malignant and benign ovarian tumors and endometriosis9. Sex-based variations in T2D risk10 and the varied sources of increased CA19-9 levels underscore the importance of considering sex differences in the association between CA19-9 and T2D incidence. Given the inflammatory nature of T2D and the link between elevated CA19-9 serum levels and T2D, which is connected to pancreatic beta cell function and insulin resistance11, we hypothesized that increased CA19-9 levels may indicate risk for T2D development, influenced by sex. Hence, we aimed to evaluate the sex-specific 1Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea. 2Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Samsung Main Building B2, 250, Taepyung-ro 2ga, Seoul, Jung-gu 04514, South Korea. 4Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea. email: ; Scientific Reports | (2024) 14:22506 | https://doi.org/10.1038/s41598-024-73404-w 1 www.nature.com/scientificreports/ longitudinal association between CA19-9 levels and the incidence of T2D in a large cohort of healthy Korean adults. Materials and methods Study population The Kangbuk Samsung Health Study was a cohort study of Korean men and women aged > 18 years, who underwent regular health examinations at the Kangbuk Samsung Hospital Total Healthcare Screening Centers in Seoul and Suwon, South Korea12. To ascertain T2D incidence, we tracked the study population (n = 329,380), which underwent comprehensive health examinations, including CA19-9 levels, from 2011 to 2020 and had at least one follow-up examination until 2022. Exclusion criteria were as follows: history of malignancy (n = 7,075); prevalent T2D at baseline (n = 11,580); or missing data on T2D, body mass index (BMI), blood pressure, and laboratory data including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, and hemoglobin A1c (HbA1c) (n = 884). Because some individuals met more than one exclusion criterion, the total number of eligible participants was 310,385 (Fig. 1). Measurements Information regarding sociodemographic characteristics, medical history, medication use, family history, physical activity, alcohol intake, and smoking habits was collected using a self-administered questionnaire. Smoking status was categorized as never, past, or current. Daily alcohol consumption was calculated based on the weekly frequency and number of drinks consumed per drinking day and categorized as < 20 g/day or ≥ 20 g/ day. Physical activity was assessed using the Korean version of the International Physical Activity Questionnaire Short Form13. Health-enhancing physical activity (HEPA) was defined as physical activity that meets either of two criteria: (1) vigorous intensity activity on three or more days per week accumulating ≥ 1,500 metabolic equivalent (MET) min/week or (2) 7 days with any combination of walking, moderate intensity, or vigorous intensity activities achieving ≥ 3,000 MET min/week14. Trained nurses measured anthropometric variables and blood pressure. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of BP-lowering medication15. Dyslipidemia was defined as use of cholesterol-lowering medication. Abdominal ultrasonography, conducted by experienced radiologists blinded to the study objectives, was performed on all participants. Fatty liver was defined as increased liver echoes compared to the kidney or spleen parenchyma, along with deep beam attenuation and bright vessel walls on abdominal ultrasonography (...truncated)