• Texas Cancer Registry, Department of State Health Services, Austin, Texas.
• Epidemiology Research Program, American Cancer Society, Atlanta Georgia.
• Department of Oncology, Lady Davis Research Institute of the Jewish General Hospital and McGill University, Montreal, Quebec, Canada.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Rockville, Maryland.
• Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
• Epidemiology Research Program, American Cancer Society, Atlanta Georgia. rs221z@nih.gov Eric.jacobs@cancer.org.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Rockville, Maryland. rs221z@nih.gov Eric.jacobs@cancer.org.

Background: Studies examining associations between circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity and pancreatic ductal adenocarcinoma (PDA) risk have shown inconsistent results and included limited numbers of smokers.Methods: We examined associations of these biomarkers and high molecular weight (HMW) adiponectin with PDA, overall, and by smoking status. We conducted a pooled nested case-control analysis in 3 cohorts (Prostate, Lung, Colorectal, and Ovarian Cancer Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study-II), with 758 cases (435 current smokers) and 1,052 controls (531 smokers) matched by cohort, age, sex, race, blood draw date and follow-up time. We used conditional logistic regression adjusted for age, smoking, diabetes, and body mass index to calculate ORs and 95% confidence intervals (CI).Results: Circulating C-peptide concentration was not associated with PDA in never or former smokers, but was inversely associated with PDA in current smokers (per SD OR = 0.67; 95% CI, 0.54-0.84; P_interaction = 0.005). HMW adiponectin was inversely associated with PDA in never smokers (OR = 0.43; 95% CI, 0.23-0.81), not associated in former smokers, and positively associated in smokers (OR = 1.23; 95% CI, 1.04-1.45; P_interaction = 0.009). Total adiponectin was not associated with PDA in nonsmokers or current smokers.Conclusions: Associations of biomarkers of insulin secretion and sensitivity with PDA differ by smoking status. Smoking-induced pancreatic damage may explain the associations in smokers while mechanisms related to insulin resistance associations in nonsmokers.Impact: Future studies of these biomarkers and PDA should examine results by smoking status. Cancer Epidemiol Biomarkers Prev; 26(6); 914-22. ©2017 AACR.