Glycemic Status, Insulin Resistance, and Risk of Pancreatic Cancer

Home , Hyperinsulinemia

a; Korea; ublic of 75th < www.amjgastro.com and 4 , 3 , 2 75th percentile was 1.49 < Department of Surgery, Kangbuk 5 75th percentile to the ‡ 9). Epidemiological and clinical studies ollow-up as time-varying covariates. – VOLUME 115 | NOVEMBER 2020 Hong Joo Kim, MD, PhD. E-mail: hongjoo3.kim@ , Seungho Ryu, MD, PhD 5 75th percentile to the Correspondence: ‡ Accumulating evidence indicates a positive association between diabetes and thediabetes risk is of etiologically pancreaticremains controversial involved cancer, (5 in but whether indicate pancreatic that carcinogenesis patientscreased with risk diabetes of incident have pancreaticcancer cancer an mortality (10,11) almost and (12), pancreatic and 2-fold theywith also in- shorter have a median higher survival mortalityabetes compared rate (13). with In those addition, without several di- studies have found that fasting 3). The – , Sung Ryol Lee, MD, PhD 4 , 3 , person-years. In the overall population, the risk of pancreatic cancer 2 5 1.95). These associations remained significant when introducing changes in – sulinemia, and other confounders during f ment of insulin resistance http://links.lww.com/AJG/B680 1848. https://doi.org/10.14309/ajg.0000000000000956 – 2.05), and the corresponding hazard ratio comparing the insulin , Yoosoo Chang, MD, PhD – 1 1 accompanies this paper at able risk factors is important to establish a GASTROENTEROLOGY ﬁ mortality increased with increasing levels ofand glucose this and association hemoglobin was A1c observed inwithout even a previously in dose-response diagnosed individuals manner, or without screen-detected diabetes.were diabetes, In positively insulin nondiabetic associated resistance individuals with and increased hyperinsulinemia adjusted pancreatic hazard cancer ratio mortality. (95% Specifically, confidence thehomeostatic intervals) multivariable- for model pancreatic assess cancer mortality comparing the Glycemic status, insulin resistance, andindependently hyperinsulinemia, associated even with in an individuals increased without risk diabetes, of were pancreatic cancer mortality. This is a cohort study ofscreening 572,021 examinations Korean which adults included without fasting cancer blood atfollowed glucose, baseline, for hemoglobin who a participated A1c, median in and repeat insulin, ofcancer and 8.4 were mortality years were (interquartile ascertained range, through 5.3 linkage -13.2 to years). national Vital deathDuring status 5,211,294 records. and person-years of pancreatic follow-up, 260 deaths frommortality pancreatic cancer rate were of identified, with 5.0 a per 10 The impact of glycemic status and insulinpopulation resistance remains on the uncertain. risk We of pancreatic aimedresistance cancer to in with examine the pancreatic nondiabetic the cancer association mortality of in glycemic individuals status with and and insulin without diabetes. insulin resistance, hyperin percentile was 1.43 (1.05 (1.08 © 2020 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.

cation of modi Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Kore 2 ﬁ

15% despite multidisciplinary therapies (1,4). Therefore, the –

Department of Occupational and Environmental Medicine, KangbukDepartment Samsung of Hospital, Sungkyunkwan Clinical University Research School Design of Medicine, and Seoul, Evaluation, Republic SAIHST, of Sungkyunkwan University, Seoul, Republic of Korea; Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Rep The American Journal of samsung.com. Seungho Ryu, MD, PhD.Received E-mail: April [email protected]. 28, 2020; accepted August 24, 2020; published online September 30, 2020 Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Korea; 3 4 1 Pancreatic cancer isleading a cause highly of lethal cancer-related disease deaths and worldwide the (1 seventh Am J Gastroenterol 2020;115:1840 INTRODUCTION SUPPLEMENTARY MATERIAL DISCUSSION: RESULTS: METHODS: INTRODUCTION: Without Diabetes Nam Hee Kim, MD, PhD Pancreatic Cancer Mortality in Individuals With and Glycemic Status, Insulin Resistance, and Risk of incidence of pancreatic cancerpast has increased decade, slightly and over3% the the 5-year survival rates remain as low as Hong Joo Kim, MD, PhD identi preventive strategy to reducecreatic cancer. morbidity and mortality from pan- ARTICLE Copyright PANCREAS 1840

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blood glucose (FBG), postload plasma glucose, random plasma glucose, or hemoglobin A1c (HbA1c) has a dose-response relationship with the risk of pancreatic cancer, and this association was seen even in the nondiabetic range of blood markers for glucose metabolism (8,11,14,15). In contrast, a recent mendelian randomization study did not support a causal relationship between type 2 diabetes and pancreatic cancer, but suggested a causal role of body mass index (BMI) and fasting insulin in pancreatic cancer etiology (9). Insulin resistance and compensatory hyperinsulinemia are key pathogenic features of diabetes and can be an important mediator PANCREAS that links diabetes to pancreatic cancer (16,17). In several prospective studies, individuals with elevated levels of insulin, proinsulin, and nonfasting C peptide were found to have a significantly Figure 1. Flowchart of study participants. increased risk of pancreatic cancer, suggesting that insulin resistance confers an increased risk of pancreatic cancer (18–20). Measurements and definitions of variables Experimental evidence suggests that high levels of insulin promote Information on demographic characteristics, behavioral factors, proliferation and reduce apoptosis in pancreatic cancer cells medical history, and medication use was collected using a stan- (21,22). However, it remains unclear whether insulin resistance dardized, self-administered questionnaire as described previously and hyperinsulinemia would influence the risk of pancreatic cancer (25,26). Participants were categorized by smoking status as never, in individuals without diabetes. Indeed, insulin resistance and former, and current smokers. Current alcohol use was assessed as hyperinsulinemia precede prediabetes and type 2 diabetes (15,23) the frequency of alcohol drinking per week and the amount of and are more likely to be improved and corrected through lifestyle alcohol consumed per drinking day and categorized into none, modification in the prediabetes stage (15,24). Thus, it is of great ,20, and $20 g of ethanol/d. The weekly frequency of moderate clinical significance to determine whether insulin resistance and or vigorous physical activity was also assessed and categorized as hyperinsulinemia are associated with the risk of pancreatic cancer ,3 and $3 times/wk. A family history of cancer was defined as and its prognosis even in individuals without diabetes. having one or more first-degree relatives with any type of cancer Therefore, the aim of the current study was to investigate the disclosed in a self-reported questionnaire. associations of glycemic status, insulin resistance, and insulin Sitting blood pressure (BP), height, and weight were measured with pancreatic cancer mortality in a large sample of Korean by trained nurses. Overweight was defined as BMI $23 kg/m2, adults and to examine whether these associations exist among according to the proposed cutoff foradiagnosisofobesityinAsians people without diabetes. (27). Hypertension was defined as systolic BP $140 mm Hg, diastolic BP $90 mm Hg, or use of antihypertensive medication. METHODS Blood tests were measured after at least 10 hours of fasting and Study population included lipid profiles (total cholesterol, low-density lipoprotein This cohort study was a part of the Kangbuk Samsung Health cholesterol, high-density lipoprotein cholesterol, and triglycer- Study, a cohort study of Korean men and women who underwent a ides), alanine aminotransferase, gamma-glutamyltransferase, comprehensive annual or biennial health examination at one of the high-sensitivity C-reactive protein (hsCRP), and markers of Kangbuk Samsung Hospital Total Healthcare Center clinics in glucose metabolism including FBG, HbA1c, and insulin. Serum Seoul and Suwon, South Korea (25,26). In Korea, annual or bi- insulin levels were measured on the day of blood collection by ennial health-screening examinations of employees are required by immunoradiometric assays (Biosource, Nivelles, Belgium) be- the Industrial Safety and Health Law. Over 80% of participants tween 2002 and 2009 and thereafter by using an electro- were employees or spouses of employees of various companies chemiluminescence immunoassay with the Modular E170 system or local governmental organizations. The rest of the partici- (Roche Diagnostics, Tokyo, Japan). Insulin resistance was pants voluntarily purchased the health checkup program. assessed using the homeostatic model assessment of insulin re- This study population included individuals who participated sistance (HOMA-IR) equation as follows: fasting blood insulin in a comprehensive health-screening examination between 2002 (IU/L) 3 FBG (mg/dL)/405, and was defined as HOMA-IR values and 2016 (N 5 581,526). A total of 9,505 participants were ex- $ the 75th percentile among individuals without diabetes (the cluded due to the following exclusion criteria at baseline respective 75th percentile values: 2.41 for immunoradiometric (Figure 1): unknown vital status (n 5 5); missing data on glucose assay and 1.73 for electrochemiluminescence immunoassay) (28). or BMI (n 5 45); a history of malignancy including pancreatic Hyperinsulinemia was defined as an insulin level $ the 75th cancer (n 5 9,431); and occurrence of pancreatic cancer mortality percentile among individuals without diabetes (immunoradio- within the first 2 years (n 5 26). Some participants met more than metric assay: 10.36 uIU/mL; electrochemiluminescence immu- 1 exclusion criterion, and thus, a total of 572,021 participants noassay: 9.14 uIU/mL). were eligible for inclusion in the analysis. This study was ap- Previously diagnosed diabetes was defined as a history of proved by the Institutional Review Board of Kangbuk Samsung physician-diagnosed diabetes or the current use of antidiabetic Hospital (IRB No. KBSMC 2019-07-024) and was waived from medication based on self-reporting via a self-administered the requirement for informed consent because the study was structured questionnaire. Among those without previously di- designed to use anonymized retrospective data that were rou- agnosed diabetes, newly screen-detected diabetes at the health tinely collected during the health-screening process and linked to examination was defined as an FBG $126 mg/dL or mortality data from the Korea National Statistical Office (KNSO). HbA1c $6.5%.

Mortality follow-up metabolism and other covariates as a time-varying covariate in Mortality follow-up until the end of 2018 was based on nation- the models. To test for linear trends, the median value of each wide death certificate data from the KNSO. Death certificate data category was included in each model as a continuous variable. for Koreans are virtually complete because all Korean deaths are Statistical analyses were performed using STATA version 16.0 required to be reported to the KNSO. The cause of death is listed (StataCorp LP, College Station, TX). All reported P values were 2 on each death certificate, classified according to the 10th revision tailed. Differences with a P value ,0.05 were considered statis- of the International Statistical Classification of Diseases and Re- tically significant. lated Health Problems (ICD-10). Concordance between the cause of death on the death certificate and patient diagnosis in the RESULTS medical utilization data was 72.2% for all-cause deaths and 94.9% At baseline, the mean (6SD) age of study participants was 39.6

PANCREAS for cancer deaths (29). Pancreatic cancer mortality was defined as (610.5) years, and 53.1% of participants were male (Table 1). Par- death due to malignant neoplasms of the pancreas (ICD-10, ticipants who died of pancreatic cancer were more likely to be older C25) (2). and male. After adjustments for age and sex, pancreatic cancer mortality had positive associations with previously diagnosed di- Statistical analysis abetes and markers of glucose metabolism including FBG, HbA1c, The characteristics of the participants were presented by pan- insulin, and HOMA-IR. Pancreatic cancer mortality was also posi- creatic cancer mortality. Because there was a difference in age and tively associated with systolic BP and inversely associated with sex between those with pancreatic cancer mortality and those medication for hyperlipidemia, low-density lipoprotein cholesterol, without, all baseline characteristics are presented as age- and sex- and education level. Information on family history of pancreatic adjusted means or proportions with 95% confidence intervals cancer was available in only a proportion of participants (68.4%, n 5 (CIs). In the overall population, FBG was categorized into 5 391,181) because the data were collected since May 2006. None of groups as follows: FBG , 90, 90–99, 100–125, $ 126 mg/dL, and the participants who died of pancreatic cancer had a family history of previously diagnosed diabetes, whereas HbA1c was also catego- pancreatic cancer in the pancreatic cancer mortality group. The rized into 5 groups as follows: HbA1c , 5.7, 5.7–5.9, 6.0–6.4, $ baseline characteristics of the study participants are shown in as- 6.5%, and previously diagnosed diabetes. Insulin and HOMA-IR sociation with serum glucose and HbA1c (see Tables 1 and 2, were categorized into ,75th percentile and $75th percentile Supplementary Digital Content 1, http://links.lww.com/AJG/B680). based on their own distribution of individuals without diabetes Table 2 shows the associations of FBG and HbA1c with the because these markers may not be reliable predictors of insulin risk of pancreatic cancer mortality in the overall population and resistance in individuals with diabetes and can be affected by the the associations with insulin resistance and hyperinsulinemia in use of antidiabetic medication (28,30,31). individuals without previously diagnosed diabetes. The median Pancreatic cancer mortality was the primary outcome. Par- duration of follow-up was 8.4 years (interquartile range, 5.3–13.2 ticipants who died of other causes were censored at the date of years and maximum 17 years). During 5,211,294 person-years of death. Analyses were performed after implementing a 2-year follow-up, 260 deaths from pancreatic cancer were identified, washout period by excluding pancreatic cancer mortality. cases with a mortality rate of 5.0 (95% CI, 4.4–5.6) per 105 person-years. that occurred within the first 2 years from the analysis to deal with Previously diagnosed diabetes and markers of glucose metabo- the possible reverse causality in which cancer of the pancreas was lism were significantly associated with an increased risk of pan- present but undiagnosed. creatic cancer mortality. After adjustment for possible Cox proportional hazards regression analyses were used to confounders, multivariable-adjusted HRs (95% CI) for pancreatic estimate hazard ratios (HRs) and 95% CIs for pancreatic cancer cancer mortality comparing FBG 90–99, 100–125, and $ 126 mortality. Age was used as the timescale, which was documented mg/dL and previously diagnosed diabetes with FBG ,90 mg/dL by the age at which subjects underwent their first health checkup were 1.09 (0.78–1.54), 1.17 (0.81–1.68), 1.91 (1.05–3.49), and 1.70 examination (left truncation) and the age at which subjects exited (1.07–2.69), respectively (model 1). Corresponding HRs (95% CI) the analysis at the date of death or on December 31, 2018. This comparing HbA1c 5.7–5.9, 6.0–6.4, and $6.5% and previously approach was effectively controlled for age. The proportional diagnosed diabetes with HbA1c ,5.7% were 1.09 (0.68–1.74), hazards assumption was assessed by examining graphs of esti- 1.73 (1.04–2.88), 2.25 (1.12–4.53), and 1.90 (1.13–3.20), re- mated log (2log SURVIVAL); no violation of the assumption was spectively. Further adjustment for hsCRP did not qualitatively found. change the results. Among individuals without previously di- Models were initially adjusted for age (as the timescale) and agnosed diabetes, multivariable-adjusted HR (95% CI) for pan- sex and then further adjusted for potential confounders including creatic cancer mortality comparing HOMA-IR $75th percentile study center (Seoul and Suwon), year of screening, smoking status with HOMA-IR ,75th percentile was 1.48 (1.09–2.00), and the (never, former, current, or unknown), alcohol intake (0, , 20, $ corresponding HR (95% CI) comparing insulin $75th percentile 20 g/d, or unknown), regular exercise (,3, $ 3 times a week, or with insulin ,75th percentile was 1.35 (1.001–1.81) (model 1). unknown), BMI, education level (,12 years, $ 12 years, or un- After further adjustment for hsCRP, these associations did not known), history of hypertension, history of cardiovascular dis- change substantially (model 2). When the association was eval- ease, medication for dyslipidemia, and family history of cancer uated after introducing changes in glucose metabolism markers (model 1). Given the potential impact of inflammation on the (FBG, HbA1c, HOMA-IR, and insulin, separately) and con- relationship between glycemic status and pancreatic cancer founders during follow-up as time-varying covariates, the asso- mortality (32), the model was additionally adjusted for hsCRP ciations of insulin resistance and hyperinsulinemia with (model 2). To evaluate the impact of the updated status of FBG, pancreatic cancer mortality were attenuated, whereas the asso- HbA1c, HOMA-IR, insulin, and covariates over follow-up, we ciation of FBG and HbA1c with pancreatic cancer mortality be- conducted additional analyses introducing markers of glucose came stronger than in the previous model.

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Table 1. Estimateda mean values (95% CI) and adjusteda proportion (95% CI) of baseline characteristics of study participants according to pancreatic cancer mortality (n 5 572,021)

Characteristics Pancreatic cancer mortality (2) Pancreatic cancer mortality (1) P value Number 571,761 260 Age (yr) 39.6 (39.6–39.6) 55.6 (54.3–56.9) ,0.001 Male (%) 53.1 (53.0–53.3) 63.4 (57.5–69.2) 0.001 BMI (kg/m2) 23.4 (23.3–23.4) 23.4 (23.1–23.8) 0.674 b Overweight (%) 51.8 (51.6–51.9) 57.4 (51.0–63.8) 0.091 PANCREAS Current smoker (%) 23.8 (23.7–23.9) 26.9 (22.3–31.6) 0.183 Alcohol intake (%)c 18.6 (18.5–18.7) 19.4 (15.1–23.7) 0.706 Regular exercise (%)d 14.9 (14.8–15.0) 17.3 (13.2–21.4) 0.223 High education level (%)e 72.9 (72.8–73.1) 66.0 (59.8–72.2) 0.021 Hypertension (%) 14.8 (14.7–14.9) 14.7 (11.8–17.7) 0.948 Diabetes (%) 4.3 (4.3–4.4) 5.9 (4.3–7.5) 0.032 Antidiabetic medication (%) 1.85 (1.81–1.88) 1.73 (0.97–2.49) 0.766 Medication for dyslipidemia (%) 1.99 (1.95–2.03) 0.94 (0.25–1.62) 0.041 Family history of cancer (%) 23.0 (22.8–23.1) 21.5 (17.0–25.9) 0.524 Family history of pancreatic cancer (%)f 0.99 (0.96–1.02) 0 — Systolic BP (mm Hg) 112.2 (112.2–112.2) 114.4 (112.9–116.0) 0.004 Diastolic BP (mm Hg) 72.1 (72.0–72.1) 72.0 (70.8–73.0) 0.779 Glucose (mg/dL) 94.7 (94.7–94.8) 98.5 (96.6–100.4) ,0.001 HbA1c (%)g 5.6 (5.6–5.6) 5.7 (5.7–5.8) ,0.001 Total cholesterol (mg/dL) 193.9 (193.8–194.0) 192.1 (188.0–196.2) 0.398 LDL-C (mg/dL) 116.0 (115.9–116.1) 109.4 (105.7–113.1) ,0.001 HDL-C (mg/dL) 57.4 (57.3–57.4) 57.4 (55.8–59.0) 0.934 Triglycerides (mg/dL) 117.7 (117.5–117.9) 125.8 (116.4–135.3) 0.119 ALT (U/L) 25.1 (25.0–25.1) 24.2 (21.2–27.2) 0.291 GGT (U/L) 30.4 (30.3–30.5) 35.6 (30.8–40.4) 0.490 hsCRP (mg/L) 0.1 (0.1–0.1) 0.1 (0.1–0.2) 0.264 HOMA-IRh 1.66 (1.66–1.67) 1.92 (1.78–2.06) ,0.001 Insulin (uIU/mL)h 7.18 (7.17–7.19) 8.25 (7.67–8.83) ,0.001

ALT, alanine aminotransferase; BMI, body mass index; BP, blood pressure; GGT, gamma-glutamyltransferase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol. aAdjusted for age and sex. bBMI $23 kg/m2. c$20 g/d. d$3 times/wk. e$College graduate. fIn 391,181 subjects with available family history of pancreatic cancer. gIn 447,101 subjects with available HbA1c data. hIn 506,386 subjects with available insulin data and without diabetes.

Table 3 shows the associations of HOMA-IR and insulin with corresponding HR (95% CI) comparing insulin $75th percentile the risk of pancreatic cancer mortality among participants with insulin ,75th percentile was 1.43 (1.05–1.95). These rela- without diabetes without either previously diagnosed or screen- tionships remained significant after further adjustment for detected diabetes (n 5 534,919). Insulin resistance defined as hsCRP (model 2) or in time-dependent models while introducing HOMA-IR $75th percentile and hyperinsulinemia defined as changes in HOMA-IR, insulin, and other confounders during insulin $75th percentile were significantly associated with an follow-up as time-varying covariates. increased risk of pancreatic cancer mortality even in individuals When we performed further analysis after implementing without diabetes. Multivariable-adjusted HR (95% CI) for pan- longer washout periods by excluding pancreatic cancer mortality creatic cancer mortality comparing HOMA-IR $75th percentile cases that occurred within the first 3, 4, or 5 years of follow-up, with HOMA-IR ,75th percentile was 1.49 (1.08–2.05), and the similar trends were observed in the association of

Table 2. HRs (95% CIs) for pancreatic cancer mortality by glucose category in the overall population (n 5 572,021)

Mortality Multivariable-adjusted HRa HR (95% CI)b in rate (105 (95% CI) model using Person- No. of person- Sex-adjusted HR (95% time-dependent years events years) CI) Model 1 Model 2 variables FBG category (mg/dL) ,90 1,888,032.5 56 3.0 1.00 (reference) 1.00 1.00 1.00 (reference) (reference) (reference)

PANCREAS 90–99 2,146,566.0 87 4.1 1.09 (0.78–1.52) 1.09 1.09 1.18 (0.81–1.72) (0.78–1.54) (0.78–1.53) 100–125 976,611.0 71 7.3 1.19 (0.83–1.69) 1.17 1.17 1.57 (1.07–2.30) (0.81–1.68) (0.81–1.68) $126 (screen-detected 71,205.9 14 19.7 2.02 (1.12–3.66) 1.91 1.93 3.49 (2.00–6.09) diabetes) (1.05–3.49) (1.06–3.53) P for trend 0.015 0.023 0.022 , 0.001 Previously diagnosed 128,878.5 32 24.8 1.62 (1.04–2.54) 1.70 1.70 1.91 (1.20–3.04) diabetes (1.07–2.69) (1.07–2.69) HbA1c category (%)c ,5.7 2,343,029.8 55 2.3 1.00 (reference) 1.00 1.00 1.00 (reference) (reference) (reference) 5.7–5.9 641,811.8 28 4.4 1.01 (0.63–1.60) 1.09 1.10 1.29 (0.88–1.88) (0.68–1.74) (0.69–1.76) 6.0–6.4 187,099.4 23 12.3 1.60 (0.97–2.64) 1.73 1.74 1.82 (1.18–2.83) (1.04–2.88) (1.04–2.91) $6.5 (screen-detected 47,007.1 10 21.3 2.26 (1.14–4.48) 2.25 2.26 2.55 (1.36–4.79) diabetes) (1.12–4.53) (1.12–4.56) P for trend 0.003 0.002 0.002 0.001 Previously diagnosed 128,878.5 32 24.8 1.75 (1.10–2.76) 1.90 1.91 1.78 (1.15–2.74) diabetes (1.13–3.20) (1.13–3.21) Insulin resistanced HOMA-IR ,75th percentile 3,724,569.1 141 3.8 1.00 (reference) 1.00 1.00 1.00 (reference) (reference) (reference) HOMA-IR $75th percentile 1,215,832.5 77 6.3 1.52 (1.15–2.00) 1.48 1.49 1.45 (1.08–1.94) (1.09–2.00) (1.10–2.02) Hyperinsulinemiad Insulin ,75th percentile 3,496,069.0 134 3.8 1.00 (reference) 1.00 1.00 1.00 (reference) (reference) (reference) Insulin $75th percentile 1,444,332.5 84 5.8 1.43 (1.09–1.88) 1.35 1.36 1.13 (0.83–1.53) (1.001–1.81) (1.01–1.83)

HOMA-IR 75th percentile level: RIA: 2.41, EIA: 1.73; insulin 75th percentile level: RIA: 10.36 uIU/mL, EIA: 9.14 uIU/mL. BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; DM, diabetes mellitus; EIA, electrochemiluminescence immunoassay; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; HR, hazard ratio; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; RIA, immunoradiometric assay. aCox proportional hazard models with age as a timescale were used to estimate HRs and 95% CIs; Multivariable model 1 was adjusted for age (timescale), sex, center, year of screening, smoking status, alcohol intake, regular exercise, BMI, education level, history of hypertension, history of CVD, medication for dyslipidemia, and family history of cancer; model 2: model 1 plus adjustment for hsCRP. bEstimated from Cox proportional hazard models with glucose/HbA1c/HOMA-IR category, alcohol intake, smoking status, exercise, BMI, and medication for dyslipidemia as time-dependent categorical variables and baseline age, sex, center, year of screening examination and education level, history of hypertension, history of CVD, and family history of cancer as time-fixed variables. cIn 447,101 subjects with available HbA1c data. dIn 544,482 subjects with available insulin data and without previously diagnosed diabetes.

hyperinsulinemia/insulin resistance with pancreatic cancer DISCUSSION mortality (see Table 3, Supplementary Digital Content 1, http:// In this large cohort study of young and middle-aged participants links.lww.com/AJG/B680). who attended a routine health-screening program with a median

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Table 3. HRs (95% CIs) for pancreatic cancer mortality by insulin resistance and hyperinsulinemia among participants without diabetes (N 5 534,919)

Multivariable-adjusted HRa HR (95% CI)b in Mortality rate (95% CI) model using Person- No. of (105 person- Sex-adjusted time-dependent years events years) HR (95% CI) Model 1 Model 2 variables Insulin resistance HOMA-IR ,75th 3,706,340.4 135 3.6 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)

percentile PANCREAS HOMA-IR $75th 1,147,490.6 65 5.7 1.52 (1.13–2.04) 1.49 (1.08–2.05) 1.51 (1.10–2.09) 1.44 (1.05–1.96) percentile Hyperinsulinemia Insulin ,75th percentile 3,454,686.4 123 3.6 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Insulin $75th percentile 1,399,144.7 77 5.5 1.49 (1.12–1.98) 1.43 (1.05–1.95) 1.45 (1.06–1.97) 1.17 (1.85–1.61)

HOMA-IR 75th percentile level: RIA: 2.41, EIA: 1.73. Insulin 75th percentile level: RIA: 10.36 uIU/mL, EIA: 9.14 uIU/mL. BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; DM, diabetes mellitus; EIA, electrochemiluminescence immunoassay; FBG, fasting blood glucose; HR, hazard ratio; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; RIA, immunoradiometric assay. aCox proportional hazard models with age as a timescale were used to estimate HRs and 95% CIs; multivariable model 1 was adjusted for age (timescale), sex, center, year of screening, smoking status, alcohol intake, regular exercise, BMI, education level, history of hypertension, history of CVD, medication for dyslipidemia, and family history of cancer; model 2: model 1 plus adjustment for hsCRP. bEstimated from Cox proportional hazard models with glucose/hbA1c/HOMA-IR category, alcohol intake, smoking status, exercise, BMI, and medication for dyslipidemia as time-dependent categorical variables and baseline age, sex, center, year of screening examination and education level, history of hypertension, history of CVD, and family history of cancer as time-fixed variables.

follow-up of 8.4 years (maximum 17 years), individuals with di- even among the individuals with HbA1c levels within the non- abetes (either previously diagnosed or screen detected) had a diabetic range (14). Most prior studies did not consider changes 2-fold increased risk of pancreatic cancer mortality. Among in glycemic status over time, although glycemic status and other participants without a prior diagnosis of diabetes, hyperglycemia, confounders can change over time during follow-up. In the based on FBG and HbA1c, was independently associated with an present study, the associations of glucose and HbA1c with pan- increased risk of pancreatic cancer mortality in a dose-response creatic cancer mortality in both prediabetic and diabetic ranges manner, and these associations were observed in the nondiabetic were consistently observed and even slightly stronger in the time- range. Insulin resistance and hyperinsulinemia were also signif- dependent analyses of our study, when changes in glycemic status icantly associated with an increased risk of pancreatic cancer and covariates during follow-up were incorporated as time- mortality, and this positive association was consistently observed varying covariates. Our study ﬁndings are in line with those of even in individuals without previously diagnosed or screen- previous studies proposing that hyperglycemia, even in the detected diabetes. Our results indicate that hyperglycemia, nondiabetic range, can predict the risk of pancreatic cancer and insulin resistance, and hyperinsulinemia were independent pre- pancreatic cancer mortality (8,11,14). However, it is still unclear dictors for pancreatic cancer mortality even among individuals whether hyperglycemia itself or hyperglycemia as a marker of without diabetes. preexisting insulin resistance and hyperinsulinemia can con- A large body of epidemiological studies suggests a positive tribute to the development of pancreatic cancer mortality. relationship between diabetes and the risk of pancreatic cancer, Insulin resistance is a hallmark of type 2 diabetes, in which indicating that diabetes is closely related to the risk of pancreatic insulin fails to maintain normal plasma glucose levels through the cancer and poor prognosis (5–8,10–13,33). However, only a few suppression of hepatic glucose production and stimulation of studies have reported the association of hyperglycemia with glucose utilization in peripheral tissues (32,34). Hyper- pancreatic cancer risk in individuals without diabetes (11). In a insulinemia is often both a result and a driver of insulin resistance, prospective study of 0.5 million Chinese adults, it was docu- and insulin resistance and hyperinsulinemia are tightly linked to mented that each 1 mmol/L increase in random plasma glucose each other (35). Thus, the association between diabetes and was associated with a 12% increased incidence of pancreatic pancreatic cancer might be attributed to insulin resistance and cancer in individuals without a prior diagnosis of diabetes (cor- hyperinsulinemia. Recent studies have reported positive associ- responding adjusted HR, 1.12; 95% CI, 1.04–1.21) (11). Another ations between insulin resistance/hyperinsulinemia and the risk prospective study of 20,475 men and 15,183 women in the United of pancreatic cancer. In a case-cohort prospective study of male States also showed a positive dose-response relationship between Finnish smokers comprising 169 patients with pancreatic cancer postload plasma glucose concentration and pancreatic cancer and 400 controls, a comparison of fasting serum insulin between mortality among individuals without self-reported diabetes (8). the highest and lowest quartile showed a signiﬁcant 2-fold in- In addition, a nested prospective case-control study reported an creased incidence of pancreatic cancer (adjusted HR, 2.01; 95% increased risk of pancreatic cancer with increasing HbA1c levels CI, 1.03–3.93), and the risk of pancreatic cancer increased with

increasing levels of serum insulin and insulin resistance (HOMA- insulin can bind to and activate the insulin-like growth factor 1 IR) in a dose-dependent manner (18). A meta-analysis of 2 receptor (IGF-1R) and also indirectly increase the bioavailable prospective studies also found a signiﬁcantly excessive risk of fraction of IGF-1 through downregulation of the IGF-binding pancreatic cancer associated with higher levels of circulating in- protein 1 (41,42). Especially, IGF-1 has potent mitogenic and sulin or C peptide with an overall relative risk when comparing antiapoptotic activities and can act as a growth stimulus in cells the highest vs lowest category of 1.70 (95% CI, 1.10–2.63) expressing insulin and IGF-1R (43,44). Importantly, IGF-1 and (18,19,36). Notably, a recent mendelian randomization study, IGF-1R are highly expressed in pancreatic cancer cells, and IGF- which uses genetic instrumental variables, demonstrated that 1–mediated signaling transduction increases proliferation, in- increased fasting insulin levels are causally associated with an vasion, and expression of angiogenesis mediators and decreases increased risk of pancreatic cancer (odds ratio, 1.66; 95% CI, apoptosis in pancreatic cancer cells (44–46). Interestingly, a study

PANCREAS 1.05–2.63; per SD, 44.4 pmol/L), providing evidence of a robust by Zhang et al. (22) in mice with reduced insulin gene dosage causal relationship between hyperinsulinemia and pancreatic demonstrated that a modest reduction in endogenous insulin cancer risk (9). In that study, no evidence of a causal relationship production decreased pancreatic intraepithelial neoplasia pre- between type 2 diabetes and pancreatic cancer was observed (9). cancerous lesions independent of changes in fasting glucose. In- Furthermore, a pooled, nested case-control study of 449 cases and sulin resistance is also associated with a decrease in the level of 982 controls with no diabetes history from 5 large prospective US adiponectin, an endogenous insulin sensitizer secreted by adi- cohorts demonstrated that circulating markers of insulin re- pocyte. Although it is not clear whether hypoadiponectinemia is sistance (proinsulin), rather than hyperglycemia, were in- the cause or consequence of insulin resistance, it has been dependently associated with increased pancreatic cancer risk, reported to be involved in the proliferation and metastasis of with a nearly 2.5-fold higher risk of pancreatic cancer in the pancreatic cancer (47). Our results would also support the hy- highest compared with the lowest quintile of serum proinsulin pothesis that insulin resistance may be a potential detrimental levels (adjusted OR, 2.55; 95% CI, 1.54–4.21; P for trend ,0.001) factor for pancreatic cancer mortality, regardless of diabetes (20). Interestingly, the risk of pancreatic cancer in patients with status. diabetes has been reported to be different according to the type of The current study has several limitations. First, the definition antidiabetic medication (37); metformin use, which reduces in- of insulin resistance in our study was based on either insulin or sulin resistance, was associated with a lowered risk of pancreatic HOMA-IR levels, but not on invasive and time-consuming cancer compared with metformin nonuse (adjusted OR, 0.38; euglycemic insulin clamp analyses, the gold standard for assess- 95% CI, 0.22–0.69), whereas insulin or insulin secretagogue use vs ing insulin sensitivity. HOMA-IR is reasonably well correlated nonuse of these drugs was associated with an increased risk of with euglycemic insulin clamp data and widely used in epide- pancreatic cancer (adjusted OR, 4.99; 95% CI, 2.59–9.61 and miological studies (48). Second, diabetes was determined from a adjusted OR, 2.52; 95% CI, 1.32–4.84, respectively) (37). More- single fasting glucose and HbA1c measurement, whereas di- over, insulin resistance based on HOMA-IR was positively as- agnostic criteria recommend confirmation by repeated testing; sociated with advanced cancer stages at diagnosis, residual disease however, HbA1c is a reliable measure of chronic hyperglycemia of after surgery, and poor overall survival, indicating a close re- the preceding 2–3 months with good preanalytical stability (49). lationship between insulin resistance and the aggressiveness of In our study, when self-reporting of physician-diagnosed diabetes pancreatic cancer (38). In the present study, even individuals and diabetic range of glucose and HbA1c were all separately without diabetes with insulin resistance and hyperinsulinemia, analyzed in relation to pancreatic cancer mortality, the associa- free of both previously diagnosed and screen-detected diabetes, tion between diabetes and pancreatic cancer mortality was con- were found to have significant and independent increased risks of sistently observed. In addition, these associations remained pancreatic cancer mortality. Our study findings extend to significant in time-dependent analyses when introducing re- whether insulin resistance and hyperinsulinemia would affect peated measurements of glucose and HbA1c during follow-up as pancreatic cancer mortality even in individuals without diabetes, time-varying covariates. A glucose tolerance test, one of the cri- suggesting that insulin resistance and hyperinsulinemia might teria to diagnose diabetes, was not performed in this study, but contribute to the development of pancreatic cancer mortality this test is usually not feasible for large-scale population-based regardless of diabetes. Given that insulin resistance and hyper- studies. Only 2.6% of adults aged 20 years or older with fasting insulinemia precede diabetes and already exist in impaired glu- nondiabetic glucose were reported to have undiagnosed diabetes cose tolerance and prediabetes stages (15,23), early detection and by an additional 2-hour glucose test, and this small degree of control of insulin resistance in individuals without diabetes may misclassification might not have affected overall results. In ad- provide important opportunities for the prevention of pancreatic dition, type 2 diabetes was not distinguished from type 1 diabetes; cancer and reduce mortality. however, multiple studies have suggested that type 1 diabetes is The exact mechanisms that link insulin resistance to pancre- not associated with an increased risk of pancreatic cancer (5). atic cancer mortality are not fully understood but can be Therefore, if the diabetic group had a higher proportion of type 1 explained in several ways. Insulin resistance leads to an increase diabetes, although type 2 diabetes is considered to constitute the in insulin, which is a growth-promoting hormone with mitogenic majority (about 80%–90%) of diabetes, the association between effect (39). Indeed, 1 experimental study showed that insulin has a diabetes and pancreatic cancer mortality in our study might have direct dose-dependent growth-promoting effect on pancreatic been attenuated. Third, the primary outcome of this study was not cancer cell lines in vitro (40). An in vivo study also tested the role occurrence of pancreatic cancer, but death from pancreatic can- of insulin in the initiation of pancreatic cancer in the absence of cer using mortality data from the KNSO, which included only fasting glucose changes and revealed a direct causal role of en- date and cause of death according to ICD-10. In addition, other dogenous hyperinsulinemia in the development of pancreatic information on incidence, pathologic diagnosis, subtypes of cancer regardless of hyperglycemia (22). High concentrations of pancreatic cancer, and stages at diagnosis was not available.

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Recently, a few studies have reported the differences in survival CONFLICTS OF INTEREST by histological types of pancreatic cancer (50,51). However, Guarantor of the article: Hong Joo Kim, MD, PhD. most pancreatic cancers are adenocarcinomas, and it has been Specific author contributions: Nam Hee Kim, MD, PhD, and reported that the incidence and mortality rates from pancreatic Yoosoo Chang, MD, PhD, contributed equally as co–first authors. cancers are nearly similar due to the lethal nature of the disease N.H.K., Y.C., S.R.L., and H.J.K.: study concept and design. Y.C. and (52). Pancreatic cancer mortality, our study end point, more S.R.L.: acquisition of data. N.H.K, Y.C., and S.R.L.: analysis and likely reflects pancreatic cancers with rather than without poor interpretation of data. N.H.K., Y.C., and S.R.L.: drafting of the prognosis. Further studies are needed to evaluate the relation- manuscript. S.R.L.: critical revision of the manuscript for important ship of glycemic status/insulin resistance with pancreatic cancer intellectual content. S.R.L.: statistical analysis. H.J.K, Y.C., and S.R.L.: incidence using pancreatic cancer incidence data with its stage study supervision. Final approval of the article: all authors. and histological subtypes. Fourth, we cannot exclude the pos- Financial support: None to report. PANCREAS sibility of pancreatic cancer-associated diabetes, which means Potential competing interests: None to report. reverse causality between diabetes and pancreatic cancer. Pa- tients with pancreatic cancer are found to have diabetes in about 40%–50% of patients at the time of pancreatic cancer diagnosis Study Highlights (53,54). Previous studies suggest that higher risk of pancreatic cancer among individuals with a short duration of diabetes (#2 WHAT IS KNOWN ff years) might be a ected by reverse causality (54,55); thus, we 3 Epidemiological studies have reported a positive association performed analyses after implementing a 2-year washout period between diabetes and risk of pancreatic cancer, whereas a by excluding pancreatic cancer mortality cases that occurred mendelian randomization study did not support a causal within the first 2 years of follow-up to deal with possibility of relationship between type 2 diabetes and pancreatic cancer. reverse causality in which pancreatic cancer was present but 3 It remains still unclear whether glycemic status and insulin undiagnosed. Furthermore, in the sensitivity analyses with resistance influence the risk of pancreatic cancer mortality in longer washout periods (excluding pancreatic cancer mortality individuals without diabetes. cases that occurred during the first3,4,or5yearsoffollow-up), similar trends were observed. Because pancreatic cancer is a WHAT IS NEW HERE rapidly fatal disease, it is unlikely that an individual with di- 3 Glycemic status, in the nondiabetic range, was associated abetes related to pancreatic cancer would live for many years with an increased risk of pancreatic cancer mortality, and without being diagnosed with cancer (56). In addition, our these associations persisted when changes in glycemic status findings derived from asymptomatic, young and middle-aged and confounders during follow-up were updated as time- adults (average age, 39.1 years) who participated in a routine varying covariates. screening program may be less likely to be affected by biases 3 Insulin resistance and hyperinsulinemia were consistently related to comorbidities than findings from previous studies of associated with increased pancreas mortality even among older individuals or specific patient samples. Fifth, information individuals without either previously diagnosed or screen- on the specific types of antidiabetic drugs that could change detected diabetes. blood glucose and insulin levels was not available, limiting our 3 Insulin resistance and its related metabolism appear to ability to evaluate the differential effect of antidiabetic medica- contribute the development of pancreatic cancer mortality. tion on pancreatic cancer mortality. However, newly screen- 3 Further studies are required to confirm the causal role of detected diabetes and prior diagnosed diabetes were separately insulin metabolism on pancreatic cancer and to determine evaluated, and the analyses were also performed in individuals whether interventions to improve insulin resistance might without diabetes, suggesting that antidiabetic medication had benefit pancreatic cancer mortality. little effect on overall findings. 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