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

Tables 1 and 2 present the baseline characteristics of the cohort population according to CA19-9 categories differentiated by sex (53.5% men). Mean values (SD) and median (interquartile range) of CA19-9 levels in men were 7.8 (6.6) U/mL and 6.3 (4.2–10.0) U/mL, respectively, and those in women were 11.2 (11.1) and 8.7 (5.7–14.3) U/mL, respectively. In men, the proportions for CA19-9 levels of < 10.0, 10.0–19.9, 20.0–29.9, and ≥ 30.0 U/mL were 74.9%, 22.0%, 2.6%, and 0.5%, respectively, whereas in women, the proportions were 58.0%, 30.0%, 8.9%, and 3.2%, respectively. In men, higher CA19-9 levels were positively associated with older age, history of hypertension, medication for dyslipidemia, and higher HOMA-IR levels. In contrast, higher CA19-9 levels in women were associated with younger age, lower smoking and alcohol consumption rates, lower prevalence of fatty liver and obesity, and reduced HOMA-IR levels. Table 1 Baseline characteristics of study participants by CA19-9 levels among men. Characteristic Overall CA19-9 category (U/mL) p for trend  < 10.0 10.0–19.9 20.0–29.9  ≥ 30.0 Number 166,199 124,507 36,520 4,395 777 Age (years) a 37.8 (8.1) 37.6 (7.9) 38.3 (8.5) 39.6 (9.6) 41.4 (10.4)  < 0.001 Current smoker (%) 33.8 34 33.3 32.8 33.2 0.008 Alcohol intake (%) c 33.9 33.7 34.1 36.1 34.3 0.008 HEPA (%) 18.3 18.3 18.3 17.7 22.1 0.842 Higher education (%) d 88.2 88.4 87.9 86.6 83.5  < 0.001 History of hypertension (%) 9.6 9.2 10.5 13.1 14  < 0.001 Family history of diabetes (%) 13.2 13.3 12.8 14.2 15.8 0.959 Medication for dyslipidemia (%) 2.0 1.9 2.2 2.6 3.3  < 0.001 Fatty liver (%) 39.8 39.7 40.3 38.9 38.1 0.568 Obesity (%) e 40 40.3 39.4 37.4 40.3  < 0.001 Abdominal obesity (%) f 29.3 29.5 29.1 26.0 28.7 0.002 BMI (kg/m 2 ) 24.6 (3) 24.6 (3) 24.5 (3.1) 24.3 (3.1) 24.4 (3.1)  < 0.001 Systolic BP (mmHg) a 114.7 (11.3) 114.6 (11.2) 115 (11.5) 115.3 (11.5) 115.5 (11.8)  < 0.001 Diastolic BP (mmHg) a 73.2 (9.2) 73.1 (9.2) 73.6 (9.3) 74.2 (9.4) 74.3 (10.0)  < 0.001 Total cholesterol (mg/dL) a 197.7 (34.0) 196.9 (33.8) 199.5 (34.2) 205.0 (36) 200.2 (36.5)  < 0.001 LDL-C (mg/dL) a 128.9 (31.5) 128.4 (31.3) 130.1 (31.8) 133.7 (33.5) 127.9 (34.1)  < 0.001 HDL-C (mg/dL) a 53.7 (13.1) 53.6 (13.0) 54 (13.3) 54.2 (13.8) 55.1 (14.7)  < 0.001 Triglycerides (mg/dL) b 109 (78–158) 109 (77–157) 112 (79–163) 118 (82–176) 112 (80–161)  < 0.001 ALT (U/l) b 24 (17–35) 24 (17–35) 24 (17–35) 24 (17–36) 28 (19–48)  < 0.001 hsCRP (mg/L) b 0.5 (0.3–1.0) 0.5 (0.3–1.0) 0.5 (0.3–1.0) 0.5 (0.3–1.0) 0.6 (0.3–1.1) 0.433 HOMA-IR 1.30 (0.86–1.94) 1.30 (0.86–1.93) 1.32 (0.87–1.98) 1.33 (0.89–2.01) 1.48 (0.97–2.16)  < 0.001 HEPA, health-enhancing physical activity; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol. Data are presented as a means (standard deviation), b medians (interquartile range), or percentage. c  ≥ 20 g of ethanol per day; d  ≥ college graduate; e  ≥ 25 kg/m 2 ; f waist circumference ≥ 90 cm. Table 2 Baseline characteristics of study participants by CA19-9 levels among women. Characteristic Overall CA19-9 category (U/mL) p for trend  < 10.0 10.0–19.9 20.0–29.9  ≥ 30.0 Number 144,186 83,590 43,189 12,809 4,598 Age (years) a 36.9 (8.4) 37.2 (8.5) 36.6 (8) 36.6 (8.5) 35.8 (8.0)  < 0.001 Current smoker (%) 2.4 2.6 2.1 1.9 1.6  < 0.001 Alcohol intake (%) c 7.2 7.5 7 6.8 6.0  < 0.001 HEPA (%) 13.8 14.2 13.6 12.5 12.4  < 0.001 Higher education (%) d 77.8 76.7 79 79.1 82.5  < 0.001 History of hypertension (%) 3.1 3.2 2.9 3.1 2.8 0.005 Family history of diabetes (%) 15.7 15.9 15.5 15.1 14.7 0.001 Medication for dyslipidemia (%) 1.3 1.3 1.2 1.3 1.3 0.402 Fatty liver (%) 10.4 11.1 10.0 8.6 7.1  < 0.001 Obesity (%) e 12.2 13.5 11.2 9.2 7.3  < 0.001 Abdominal obesity (%) f 11.3 12.3 10.5 9.1 6.6  < 0.001 BMI (kg/m 2 ) 21.6 (3.1) 21.8 (3.1) 21.5 (3) 21.2 (2.9) 20.9 (2.7)  < 0.001 Systolic BP (mmHg) a 102.6 (11.2) 102.8 (11.2) 102.4 (11) 102.3 (11.1) 102 (10.7)  < 0.001 Diastolic BP (mmHg) a 65.4 (8.2) 65.4 (8.3) 65.4 (8.2) 65.4 (8.2) 65.3 (8.1) 0.142 Total cholesterol (mg/dL) a 185.4 (31.6) 184.7 (31.6) 185.7 (31.4) 187.9 (32.0) 190.2 (33.0)  < 0.001 LDL-C (mg/dL) a 110.6 (29.4) 110.4 (29.4) 110.4 (29.1) 111.8 (29.8) 113.3 (30.4)  < 0.001 HDL-C (mg/dL) a 66.7 (15.3) 66.1 (15.1) 67.2 (15.4) 67.8 (15.5) 68.3 (15.9)  < 0.001 Triglycerides (mg/dL) b 70 (54–94) 70 (54–94) 70 (54–94) 70 (54–94) 70 (54–95) 0.123 ALT (U/l) b 13 (10–17) 13 (10–17) 13 (10–17) 13 (10–17) 13 (10–17)  < 0.001 hsCRP (mg/L) b 0.3 (0.2–0.7) 0.3 (0.2–0.7) 0.3 (0.2–0.6) 0.3 (0.2–0.6) 0.3 (0.2–0.7)  < 0.001 HOMA-IR 1.12 (0.75–1.64) 1.13 (0.75–1.65) 1.12 (0.75–1.63) 1.11 (0.74–1.61) 1.07 (0.71–1.56)  < 0.001 HEPA, health-enhancing physical activity; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol. Data are presented as a means (standard deviation), b medians (interquartile range), or percentage. c  ≥ 20 g of ethanol per day; d  ≥ college graduate; e  ≥ 25 kg/m 2 ; f waist circumference ≥ 85 cm. Baseline characteristics of study participants by CA19-9 levels among men. HEPA, health-enhancing physical activity; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol. Data are presented as a means (standard deviation), b medians (interquartile range), or percentage. c  ≥ 20 g of ethanol per day; d  ≥ college graduate; e  ≥ 25 kg/m 2 ; f waist circumference ≥ 90 cm. Baseline characteristics of study participants by CA19-9 levels among women. HEPA, health-enhancing physical activity; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol. Data are presented as a means (standard deviation), b medians (interquartile range), or percentage. c  ≥ 20 g of ethanol per day; d  ≥ college graduate; e  ≥ 25 kg/m 2 ; f waist circumference ≥ 85 cm. During a median follow-up of 6.1 years (interquartile range, 3.3–9.3 years) involving 166,199 men and 144,186 women without T2D at baseline, there were 10,571 new T2D cases in men and 3,107 in women. The incidence rate was 9.9/1,000 person-years in men and 3.6/1,000 person-years in women. The association between CA19-9 levels and incident T2D significantly differed by sex ( p for interaction = 0.006). In men, an increase of 10 U/mL in CA19-9 levels was associated with an increased risk of developing T2D, but this association was not observed in women. Age-adjusted HRs (95% CI) for every 10-U/mL increase in CA19-9 levels were 1.04 (1.03–1.05) in men and 0.93 (0.89–0.97) in women (Table 3 ). This association in men remained significant even after accounting for additional covariates, including HOMA-IR, hsCRP levels, and waist circumference (Supplementary Table 5 ). In the time-dependent analysis, adjusted HRs (95% CI) comparing CA19-9 levels of 10.0–19.9, 20.0–29.9, and ≥ 30 U/mL in men relative 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. However, in women, corresponding HRs (95% CI) were 1.01 (0.93–1.09), 1.06 (0.93–1.20), and 1.18 (0.94–1.48), respectively. Given the potential impact of endometriosis on elevated CA19-9 levels in women, a sensitivity analysis was performed excluding participants with confirmed endometriosis based on pelvic ultrasound findings; however, no significant association was identified (Supplementary Table 4 ). In sensitivity analyses, we further adjusted for the menstrual cycle, considering the potential association between the menstrual cycle and CA19-9 levels in women with undiagnosed endometriosis, given reports of elevated CA19-9 levels peaking during the menstrual period 22 . However, the results remained qualitatively unchanged (Supplementary Tables 6 and 7 ). In the spline regression models, the incidence of T2D increased across the range of CA19-9 levels in men; however, no clear association was observed in women (Fig.  2 ). We also stratified by menopausal status, but found no significant link between CA19-9 levels and T2D in either premenopausal or postmenopausal women (Fig.  2 ). Table 3 Development of diabetes according to CA19-9 levels by sex. CA19-9 category (U/mL) Person-years Incident cases Incidence rate (per 1,000 person-years) Age-adjusted HR (95% CI) Multivariable-adjusted HR a (95% CI) HR (95% CI) b in model using time-dependent variables Model 1 Model 2 Women ( n  = 144,186)  < 10 494,382.3 1912 3.9 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)  10–19 257,284.8 872 3.4 0.91 (0.84–0.99) 1.01 (0.94–1.10) 1.00 (0.92–1.08) 1.01 (0.93–1.09)  20–29 76,963.4 239 3.1 0.83 (0.72–0.95) 0.99 (0.86–1.13) 0.95 (0.83–1.09) 1.06 (0.93–1.20)  ≥ 30 28,127.5 84 3.0 0.83 (0.67–1.04) 1.14 (0.92–1.42) 1.08 (0.87–1.35) 1.18 (0.94–1.48) p for trend 0.001 0.499 0.910 0.298 Per 10-U/mL increase 0.93 (0.89–0.97) 1.01 (0.98–1.05) 1.00 (0.96–1.04) 0.97 (0.91–1.04) Men (n = 166,199)  < 10 800,599.7 7751 9.7 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)  10–19 231,187.3 2414 10.4 1.04 (1.00–1.09) 1.06 (1.01–1.11) 1.02 (0.98–1.07) 1.08 (1.04–1.13)  20–29 27,715.0 321 11.6 1.07 (0.96–1.20) 1.13 (1.01–1.27) 1.06 (0.95–1.18) 1.18 (1.07–1.30)  ≥ 30 4,817.9 85 17.6 1.56 (1.26–1.94) 1.59 (1.29–1.97) 1.48 (1.20–1.84) 1.64 (1.35–1.99) p for trend 0.001  < 0.001 0.013 0.002 Per 10-U/mL increase 1.04 (1.03–1.05) 1.05 (1.03–1.06) 1.04 (1.03–1.06) 1.05 (1.03–1.07) CI, confidence interval; HR, hazard ratio. p  = 0.006 for the overall interaction between sex and CA19-9 category for incident diabetes (adjusted model 2). a Estimated from the Cox proportional hazards model. Multivariable model 1 was adjusted for age, center, year of screening examination, educational level, smoking status, alcohol intake, physical activity, body mass index, family history of diabetes, history of hypertension, and medication for dyslipidemia. Model 2: model 1 plus adjustment for systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein. b Estimated from the Cox proportional hazards model with CA19-9 category, alcohol intake, smoking status, physical activity, history of hypertension, medication for dyslipidemia, body mass index, systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein as time-dependent categorical variables and baseline age, sex, center, year of screening examination, family history of diabetes, and education level as time-fixed variables. Fig. 2 Multivariable-adjusted hazard ratios for ( A ) men, ( B ) women, ( C ) premenopausal women, and ( D ) postmenopausal women. Estimated from Cox proportional hazards model with CA19-9 category, alcohol intake, smoking status, physical activity, history of hypertension, medication for dyslipidemia, body mass index, systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein as time-dependent categorical variables and baseline age, sex, center, year of screening exam, family history of diabetes, and education level as time-fixed variables. These splines had knots placed at the 5th, 35th, 65th, and 95th percentiles of the distribution within our sample. The solid line represents relative hazard, and the dashed lines represent the confidence intervals for the spline model. The horizontal red line corresponds to the normal reference hazard ratio of 1.0. Development of diabetes according to CA19-9 levels by sex. CI, confidence interval; HR, hazard ratio. p  = 0.006 for the overall interaction between sex and CA19-9 category for incident diabetes (adjusted model 2). a Estimated from the Cox proportional hazards model. Multivariable model 1 was adjusted for age, center, year of screening examination, educational level, smoking status, alcohol intake, physical activity, body mass index, family history of diabetes, history of hypertension, and medication for dyslipidemia. Model 2: model 1 plus adjustment for systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein. b Estimated from the Cox proportional hazards model with CA19-9 category, alcohol intake, smoking status, physical activity, history of hypertension, medication for dyslipidemia, body mass index, systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein as time-dependent categorical variables and baseline age, sex, center, year of screening examination, family history of diabetes, and education level as time-fixed variables. Multivariable-adjusted hazard ratios for ( A ) men, ( B ) women, ( C ) premenopausal women, and ( D ) postmenopausal women. Estimated from Cox proportional hazards model with CA19-9 category, alcohol intake, smoking status, physical activity, history of hypertension, medication for dyslipidemia, body mass index, systolic blood pressure, total cholesterol, triglyceride, high-density lipoprotein cholesterol, homeostatic model assessment of insulin resistance, and high-sensitivity C-reactive protein as time-dependent categorical variables and baseline age, sex, center, year of screening exam, family history of diabetes, and education level as time-fixed variables. These splines had knots placed at the 5th, 35th, 65th, and 95th percentiles of the distribution within our sample. The solid line represents relative hazard, and the dashed lines represent the confidence intervals for the spline model. The horizontal red line corresponds to the normal reference hazard ratio of 1.0. In the subgroup analyses, the association between CA19-9 levels and incident T2D did not differ according to the presence of fatty liver, obesity, or abdominal obesity in either men or women. In men, the CA19-9 highest category of ≥ 30U/mL showed significantly increased risk of incident T2D regardless of the presence of fatty liver and obesity (BMI ≥ 25 kg/m 2 ). This association was similarly observed in both non-obese and obese men with abdominal obesity, but it was statistically significant only in those with abdominal obesity; the highest incidence of T2D in men occurred in those with abdominal obesity and elevated CA19-9 levels of ≥ 30 U/mL (48.2/1,000 person-years, HR of 2.11 [95% CI, 1.48–3.01], compared to the reference group). In contrast, the relationship between CA19-9 levels and incident T2D displayed no clear pattern in women across the predetermined subgroups, with no significant interactions noted (Supplementary Tables 1 , 2 , and 3 ).

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 Korea 12 . 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 ). Fig. 1 Flowchart of study participants. Note that some individuals met more than one criterion for exclusion. CA19-9, carbohydrate antigen 19–9. Flowchart of study participants. Note that some individuals met more than one criterion for exclusion. CA19-9, carbohydrate antigen 19–9. 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 Form 13 . 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/week 14 . 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 medication 15 . 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 performed by experienced radiologists 16 . Obesity was defined as BMI ≥ 25 kg/m 2 17 , and abdominal obesity was defined as waist circumference ≥ 90 cm for men or ≥ 85 cm for women 18 . Endometriosis was defined as the presence of endometriomas, deep infiltrating endometriosis, or endometriotic cysts on pelvic ultrasound performed by experienced gynecologists 19 , 20 . Blood tests were conducted after a minimum 10-h fasting period. These tests assessed lipid profiles (total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, and triglyceride levels) and alanine aminotransferase and high-sensitivity C-reactive protein (hsCRP) levels. Additionally, markers related to glucose metabolism, including fasting blood glucose, HbA1c, and serum insulin levels, were measured; we utilized these values to calculate the homeostasis model assessment of insulin resistance (HOMA-IR) as follows: fasting blood insulin (μU/mL) × fasting blood glucose (mmol/L)/22.5. CA19-9 levels were measured using an electrochemiluminescence immunoassay (Modular E170; Roche Diagnostics, Tokyo, Japan from January 2012 to April 2015 and the Cobas 8000 e602 (Roche Diagnostics, Indianapolis, IN, USA until February 2018). Thereafter, measurements were performed using the Cobas 8000 e802 (Roche Diagnostics). Kangbuk Samsung Hospital’s Laboratory Medicine Department is accredited by the Korean Society of Laboratory Medicine and the Korean Association of Quality Assurance for Clinical Laboratories 21 . In addition, the laboratory participated in the College of American Pathologists Survey Proficiency Testing Program. Participants were categorized into four groups based on increases of 10 U/mL in their CA19-9 levels as follows: < 10.0, 10.0– 19.9, 20.0–29.9 and ≥ 30.0 U/mL. T2D was defined as a fasting serum glucose level ≥ 126 mg/dL, HbA1c ≥ 6.5% (48 mmol/mol), a history of physician-diagnosed T2D, or the use of insulin or glucose-lowering medication. Descriptive statistics were used to summarize the characteristics of the participants according to the CA19-9 categories. The study endpoint was the development of incident T2D during follow-up among participants without T2D at baseline. The participants were followed up from baseline until the development of T2D or until the end of 2022, whichever occurred first. Using Cox proportional hazards regression analysis, we calculated hazard ratios (HRs) and the associated 95% confidence intervals (CIs) to assess the incidence of T2D development. The models were adjusted as follows: Model 1 was adjusted for age, center (Seoul or Suwon), year of screening examination, educational level, smoking status, alcohol intake, physical activity, BMI, family history of T2D, history of hypertension, and medication for dyslipidemia; and Model 2 was further adjusted for SBP, total cholesterol, triglyceride, HDL-C, HOMA-IR, and hsCRP levels. Time-dependent analyses were performed to account for changes in CA19-9 levels and other covariates during follow-up. CA19-9 levels were measured an average of 4 times per participant during the study period, excluding the initial measurement, for a total of average 5 measurements throughout the study period. In these analyses, CA19-9 and other covariates were measured multiple times during the follow-up period and treated as time-varying covariates. Specifically, we used time-dependent Cox proportional hazard models that updated the status of the CA19-9 category, alcohol intake, smoking status, physical activity, history of hypertension, medication for dyslipidemia, BMI, SBP, total cholesterol, triglycerides, HDL-C, HOMA-IR, and hsCRP as time-varying covariates, whereas baseline age, examination center, year of the initial screening exam, family history of diabetes, and education level were treated as time-fixed variables. To evaluate the link between continuous CA19-9 levels and the risk of T2D, we used restricted cubic splines to model CA19-9 levels. These splines have knots placed at the 5th, 35th, 65th, and 95th percentiles of the distribution within our sample. This approach allowed us to flexibly estimate the relationship between varying levels of CA19-9 and T2D onset. Given the pivotal role of excessive adiposity in T2D development and possible effects of obesity phenotypes on the relationship between CA19-9 levels and T2D onset, we conducted subgroup analyses based on the presence or absence of fatty liver, obesity, and abdominal obesity (yes vs. no). We assessed the interactions between CA19-9 stratifications and participant characteristics using likelihood ratio tests, comparing models with and without interaction terms. All statistical analyses were conducted using Stata (version 17.0; StataCorp LP, College Station, TX, USA). Statistical significance was defined as a two-sided P- value of < 0.05. The study protocol was approved by the Institutional Review Board of Kangbuk Samsung Hospital (No: KBSMC 2023-08-027). All procedures involving human participants were conducted in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards. The IRB of Kangbuk Samsung Hospital waived the requirement for informed consent because we used de-identified data routinely collected as part of health screening examinations for the analyses.

In this large cohort of healthy adults, an elevated CA19-9 level of ≥ 30 U/mL was significantly associated with increased T2D risk even after adjusting for baseline factors such as BMI, HOMA-IR, alcohol consumption, and other covariates in men. This association remained significant, even when the updated status of these variables during follow-up was considered a time-dependent covariate. This significance was exclusively apparent among men, with no such significance observed among pre- or post-menopausal women. These findings suggest that elevated CA19-9 levels have the potential to identify men at risk of developing T2D. CA19-9 levels are used in the diagnosis of pancreatic cancer and as indicators of diabetes-induced pancreatic tissue damage. Studies link CA19-9 with various diabetes-related factors, such as glycemic control, duration of T2D, insulin resistance, and chronic complications in patients with T2D 2 , 5 , 6 , 23 . However, the role of CA19-9 in the development of T2D remains unclear. In a prospective cohort of 2,391 Chinese participants aged ≥ 40 years (mean age, 59.4 ± 9.6 years) with 3.8 years of follow-up, higher CA19-9 levels were associated with higher risk of incident diabetes (odds ratio 1.58; 95% CI, 1.02–2.44) 24 . Stratified analysis revealed that this association tended to be stronger in older participants, women, individuals with BMI ≥ 24 kg/m 2 , current nondrinkers, and those with impaired glucose regulation 24 . In contrast to our findings, an association between CA19-9 levels and incident diabetes was evident in women, although no significant sex-based interactions were observed. However, this previous study was limited by a small sample size and the inclusion of only middle- and old-aged participants, and the analysis was constrained by relying solely on CA19-9 levels measured at the initial visit. In contrast, the present study encompassed 310,385 adults aged ≥ 19 years, with a median follow-up of 6.2 years, and it accounted for changes in CA19-9 levels and other covariates over time. In addition, these associations became evident even at lower CA19-9 levels, showing a dose–response relationship in a time-dependent manner. Although the precise mechanism underlying the association between CA19-9 and incident T2D remains unclear, various plausible explanations have been proposed. Studies suggest that higher serum CA19-9 levels may be linked to abnormal glucose and lipid metabolism and are associated with an increased risk of metabolic syndrome, insulin resistance, dyslipidemia, and subclinical atherosclerosis, as indicated by coronary artery calcification 25 – 27 . Given these associations, the interrelationship among insulin resistance, cardiometabolic factors, and CA19-9 levels suggests that these elements are significant risk factors for T2D. However, in our study, the association between CA19-9 levels and the incidence of T2D remained significant, even after adjusting for metabolic factors, including HOMA-IR and hsCRP levels, suggesting that CA19-9 may independently predict risk of developing T2D. CA19-9 is predominantly secreted by pancreatic exocrine tissue and is closely associated with the islets, both functionally and anatomically. Expression of CA19-9 in mice leads to the rapid and severe onset of pancreatitis 3 . Furthermore, CA19-9-triggered pancreatitis was reversible and could be suppressed using CA19-9 antibodies 3 . In a systematic review, the pooled prevalence of newly diagnosed prediabetes or diabetes in individuals after acute pancreatitis was 43% (95% CI, 30%–56%), and the pooled prevalence of pancreatic exocrine insufficiency in individuals after acute pancreatitis was 29% (95% CI, 19%–39%) 4 . However, a recent Mendelian randomization study that utilized five single-nucleotide polymorphisms identified in a previous genome-wide association study on serum CA19-9 levels (rs17271883, rs3760776, and rs3760775 in FUT6; rs11880333 in CA11; rs265548 in B3GNT3; and rs1047781 in FUT2) did not support a causal association between serum CA19-9 levels and T2D risk 28 . Consequently, elevated levels of CA19-9 may serve as a predictable indirect marker of acute or chronic pancreatitis and contribute to an increased risk of developing T2D. The chronic inflammatory state of the pancreas due to intra-organ fat accumulation is considered crucial in the pathogenesis of an increased incidence risk of T2D 24 , 29 , 30 . Various previous studies have reported a correlation between intra-organ fat deposition and the risk of developing T2D 30 – 33 . According to the research findings, substantial weight loss can reverse the processes underlying T2D, with normalized liver fat content and decreased pancreas fat content observed in all individuals; however, the restoration to non-diabetic glucose control depends upon ability of the beta cells to recover. In the present study, the association between CA19-9 levels and incident T2D did not differ according to the presence of fatty liver, obesity, or abdominal obesity. However, we were unable to analyze pancreatic fat, which plays a significant role in predicting diabetes 34 and fatty infiltration into the pancreas may lead to pancreatitis 35 , a potential cause of elevated CA19-9 levels. Therefore, further studies are needed to determine the role of CA19-9 in T2D development, considering the influence of fatty pancreas. We found a risk of incident T2D in men with higher CA19-9 levels than in women, implying that sex modifies this association. Increasing evidence implies that CA19-9 and T2D manifest distinctive features that vary between sexes 8 – 10 . Sex influence the pathogenesis of diabetes, with a higher prevalence of T2D in middle-aged men. Women show specific energy utilization patterns favoring storage in subcutaneous fat and protection against visceral and ectopic fat accumulation 36 . Women also have greater insulin sensitivity, insulin secretion capacity, and incretin responses than men. Endogenous estrogens, particularly through estrogen receptor α activation, exhibit protective effects in various tissues such as the brain, liver, skeletal muscle, adipose tissue, and pancreatic beta cells 10 . Moreover, CA19-9 is associated with the functionality of the endometrium and ovaries in women. The mean serum CA19-9 levels in patients at all stages of endometriosis were significantly higher than those in patients without endometriosis, and serum CA19-9 levels were significantly correlated with the Revised American Fertility Society classification scores 9 . In addition, a study involving diabetic patients showed that CA19-9 levels tended to be significantly higher in women than in men (22.89 [standard error (SE), 15.03] vs. 15.97 [SE, 18.89], p < 0.01) 8 . Similarly, in the current study, CA19-9 levels were higher in women (11.2 ± 11.1 U/mL) than in men (7.8 ± 6.6 U/mL), and the prevalence of participants with CA19-9 levels ≥ 30 U/mL was more than six times higher in women (3.2%) than in men (0.5%). The mean age of the women at baseline was 36.9 (SD, 8.4) years, the majority of whom were premenopausal women. Although the exact mechanism underlying the sex-specific differences in CA19-9 levels and T2D remains unclear, the higher prevalence of elevated CA19-9 levels in premenopausal women might be attributed to factors different from those in men, including the menstrual cycle or endometriosis, a common condition affecting an estimated 5%–10% of women 22 , 37 . In patients with endometriosis, CA19-9 levels have been shown to peak during the menstrual period 22 . In our study, we performed an additional adjustment in a subset of female participants with available endometriosis and menstrual cycle data, but this adjustment did not alter main findings. Consequently, the present results showed no clear association between CA19-9 levels and T2D risk in women, unlike the association observed in men. Further studies are needed to explore the risk of T2D in women with varying CA19-9 levels, considering the menstrual cycle, different reproductive hormone levels, and conditions specific to women, such as endometriosis and ovarian disorders, beyond the subset analyses conducted in this study. The current study had some limitations. First, the potential factors that could elevate CA19-9 levels are diverse; we may have missed potential malignancies, pancreatitis, or other conditions that could have contributed to increased CA 19–9 levels. To exclude potential factors that could elevate CA19-9 levels, we excluded individuals with a history of malignancy and adjusted for alcohol consumption, which is the most common risk factor of pancreatitis. We conducted sensitivity analyses considering the menstrual cycle of women and a separate analysis on a subset of participants who underwent pelvic ultrasound to exclude those with confirmed endometriosis. However, pelvic ultrasound results were not available for the entire female cohort. Additionally, hormone levels (such as estrogen, progesterone and androgen) were not available, which could have provided insights into their influence on the association between CA19-9 and T2D. Furthermore, there is a possibility that women with a prior diagnosis of endometriosis may not have undergone pelvic ultrasound during the screening. The sensitivity of transvaginal ultrasound in diagnosing endometriosis also varies by the location and size of lesions, potentially leading to under-diagnosis of deep or small lesions. Second, the definition of T2D in our study relied on fasting glucose and HbA1c measurements, without including data from a 2-h oral glucose tolerance test. HbA1c is globally recognized as a diagnostic and monitoring tool for T2D in clinical practice. Its application is valuable in large cohort studies owing to its resilience to acute perturbations induced by factors such as exercise or dietary changes, and the measurement of HbA1c is known for its robustness, reproducibility, and lower biological variability 38 . Third, all study participants underwent abdominal ultrasonography. However, measuring ectopic pancreatic fat deposition was not feasible using this method because of the retroperitoneal location of the pancreas. Various imaging techniques such as magnetic resonance imaging, computed tomography, and endoscopic ultrasonography are required to diagnose fatty pancreas. However, these tests were not performed in the present cohort. Although we conducted additional analyses based on the association between fatty pancreas and fatty liver, obesity, and abdominal obesity 39 , further research employing more accurate measures of fat infiltration into the pancreas may provide deeper insights into the relationship between CA19-9, fatty pancreas, and T2D. Finally, because we included relatively healthy young Korean adults, our results may not be generalizable to other populations, including those with comorbidities, older age groups, and diverse ethnic backgrounds. In conclusion, this study of relatively young and middle-aged Korean adults found that men with elevated CA19-9 levels were at a higher risk of developing T2D than those with normal CA19-9 levels, whereas no similar association was observed in women. Elevated CA19-9 levels in men could serve as a potential marker for identifying patients at high risk of diabetes. However, the approach to evaluating relatively young men and women with elevated CA19-9 levels should differ between sexes. Further studies are necessary to explore the correlation between CA19-9 levels from different origins, including fatty pancreatic and non-pancreatic sources, and their impact on the incidence of T2D.

Carbohydrate antigen 19–9 (CA19-9), a tumor-associated antigen, was initially characterized using a hybridoma-generated monoclonal antibody derived from murine spleen cells immunized with a human colorectal cancer cell line 1 . 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 function 2 . In an animal study, mice expressing CA19-9 demonstrated rapid induction of severe pancreatitis 3 . 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 patients 4 . Because T2D is associated with impaired pancreatic cell function and damage, studies have explored the correlation between CA19-9 and T2D 5 – 7 . CA19-9 levels are associated with glycemic control status, insulin resistance, and chronic complications in patients with T2D 2 , 5 , 6 . Notably, CA19-9 levels are higher in women than in men 8 , 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 endometriosis 9 . Sex-based variations in T2D risk 10 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 resistance 11 , we hypothesized that increased CA19-9 levels may indicate risk for T2D development, influenced by sex. Hence, we aimed to evaluate the sex-specific longitudinal association between CA19-9 levels and the incidence of T2D in a large cohort of healthy Korean adults.

Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 1