1840 ARTICLE Glycemic Status, Insulin Resistance, and Risk of Pancreatic Cancer Mortality in Individuals With and Without Diabetes PANCREAS Nam Hee Kim, MD, PhD1, Yoosoo Chang, MD, PhD2,3,4, Sung Ryol Lee, MD, PhD5, Seungho Ryu, MD, PhD2,3,4 and Hong Joo Kim, MD, PhD1 INTRODUCTION: The impact of glycemic status and insulin resistance on the risk of pancreatic cancer in the nondiabetic 11/05/2020 on BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60Etgtdnn9T1vLQWJq/+R2O4Kjt58 by http://journals.lww.com/ajg from Downloaded population remains uncertain. We aimed to examine the association of glycemic status and insulin Downloaded resistance with pancreatic cancer mortality in individuals with and without diabetes. from METHODS: This is a cohort study of 572,021 Korean adults without cancer at baseline, who participated in repeat http://journals.lww.com/ajg screening examinations which included fasting blood glucose, hemoglobin A1c, and insulin, and were followed for a median of 8.4 years (interquartile range, 5.3 -13.2 years). Vital status and pancreatic cancer mortality were ascertained through linkage to national death records. by RESULTS: BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60Etgtdnn9T1vLQWJq/+R2O4Kjt58 During 5,211,294 person-years of follow-up, 260 deaths from pancreatic cancer were identified, with a mortality rate of 5.0 per 105 person-years. In the overall population, the risk of pancreatic cancer mortality increased with increasing levels of glucose and hemoglobin A1c in a dose-response manner, and this association was observed even in individuals without diabetes. In nondiabetic individuals without previously diagnosed or screen-detected diabetes, insulin resistance and hyperinsulinemia were positively associated with increased pancreatic cancer mortality. Specifically, the multivariable- adjusted hazard ratio (95% confidence intervals) for pancreatic cancer mortality comparing the homeostatic model assessment of insulin resistance ‡75th percentile to the <75th percentile was 1.49 (1.08–2.05), and the corresponding hazard ratio comparing the insulin ‡75th percentile to the <75th percentile was 1.43 (1.05–1.95). These associations remained significant when introducing changes in insulin resistance, hyperinsulinemia, and other confounders during follow-up as time-varying covariates. DISCUSSION: Glycemic status, insulin resistance, and hyperinsulinemia, even in individuals without diabetes, were on 11/05/2020 independently associated with an increased risk of pancreatic cancer mortality. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B680 Am J Gastroenterol 2020;115:1840–1848. https://doi.org/10.14309/ajg.0000000000000956 INTRODUCTION Accumulating evidence indicates a positive association be- Pancreatic cancer is a highly lethal disease and the seventh tween diabetes and the risk of pancreatic cancer, but whether leading cause of cancer-related deaths worldwide (1–3). The diabetes is etiologically involved in pancreatic carcinogenesis incidence of pancreatic cancer has increased slightly over the remains controversial (5–9). Epidemiological and clinical studies past decade, and the 5-year survival rates remain as low as indicate that patients with diabetes have an almost 2-fold in- 3%–15% despite multidisciplinary therapies (1,4). Therefore, the creased risk of incident pancreatic cancer (10,11) and pancreatic identification of modifiable risk factors is important to establish a cancer mortality (12), and they also have a higher mortality rate preventive strategy to reduce morbidity and mortality from pan- with shorter median survival compared with those without di- creatic cancer. abetes (13). In addition, several studies have found that fasting 1Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 4Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea; 5Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Correspondence: Hong Joo Kim, MD, PhD. E-mail: hongjoo3.kim@ samsung.com. Seungho Ryu, MD, PhD. E-mail: [email protected]. Received April 28, 2020; accepted August 24, 2020; published online September 30, 2020 The American Journal of GASTROENTEROLOGY VOLUME 115 | NOVEMBER 2020 www.amjgastro.com Copyright © 2020 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited. Glucose Metabolism and Pancreatic Cancer Mortality 1841 blood glucose (FBG), postload plasma glucose, random plasma glucose, or hemoglobin A1c (HbA1c) has a dose-response re- lationship 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 be- tween 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 pro- spective studies, individuals with elevated levels of insulin, pro- insulin, and nonfasting C peptide were found to have a significantly Figure 1. Flowchart of study participants. increased risk of pancreatic cancer, suggesting that insulin re- sistance 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, di- astolic 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,