Abstract A61: Smoking modifies the association of insulin sensitivity biomarkers and pancreatic cancer risk
Authors: Nogueira Leticia , Newton Christina , Silverman Debra , Albanes Demetrius , Manniston Satu , Jacobs Eric , Stolzemberg-Solomon Rachel 
Published: May 2019

Abstract
Cigarette smoking is the most important known risk factor for pancreatic cancer. Smoking leads to imbalances in metabolic hormones that are conducive to insulin resistance. Cigarette smoke also damages the exocrine pancreas, which can lead to pancreatogenic diabetes, also known as Type 3c diabetes mellitus (T3cDM). In contrast to type 2 diabetes mellitus (T2DM), which is associated with obesity and characterized by high levels of C-peptide, a marker of insulin secretion, T3cDM is characterized by low C-peptide concentrations, reflecting low pancreatic function. High Molecular Weight (HMW) adiponectin, on the other hand, is the most biologically active isoform of the insulin-sensitizing hormone adiponectin, and is inversely associated with obesity and T2DM incidence.
We evaluated the association of serum biomarkers [C-peptide, adiponectin, and HMW adiopnectin] and pancreatic cancer by smoking status in a nested case control study of 759 cases and 1069 controls from the Alpha-Tacopherol, Beta Carotene Cancer Prevention Study (ATBC n=888), the Cancer Prevention Study II Nutrition Cohort (CPS II n=180), and the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO n=760). Controls were matched to cases on age, date of blood draw (+ 3 months), sex, and race and were free from pancreatic cancer on the date the matched case was diagnosed. Spline regression models were used to examine the possible non-linear relation between the biomarkers and pancreatic cancer risk and logistic regression stratified on smoking status was used to calculate odds ratios and 95% confidence intervals.
Smoking status modified the association of pancreatic cancer risk and prediagnostic C-peptide (p interaction=0.009) and HMW adiponectin (p interaction=0.02). Prediagnostic C-peptide concentration was inversely associated with pancreatic cancer in smokers [Odds Ratio = 0.76 (95% Confidence Interval = 0.63-, 0.91) per standard deviation], while no association was found in non-smokers [1.09 (0.96, 1.24)]. Similarly, prediagnostic HMW adiponectin concentration was associated with increased risk in smokers [1.23 (1.02, 1.47)]. As expected, HMW adiponectin tended to be inversely associated with pancreatic cancer risk in non-smokers [0.81 (0.63, 1.05)]. Spline analysis showed that both the association of C-peptide (p=0.01) and HMW (p=0.004) with pancreatic cancer risk were linear. Total adiponectin was not associated with pancreatic cancer risk either in smokers or non-smokers.
Our findings with c-peptide and HMW adiponectin may be consistent with Type 3c diabetes which has recently been recognized to play a role in pancreatic carcinogenesis. In smokers, low C-peptide concentration may reflect low pancreatic function from smoke-induced damage to the pancreas, which is concordant with increased pancreatic cancer risk. Given the functional interaction between hormone-secreting pancreatic cells and adipocytes, HMW adiponectin concentration is a marker for peripheral insulin sensitivity and may be elevated to compensate for diminished pancreatic function. Hence, the positive association for both low C-peptide and high HMW adiponectin with pancreatic cancer in smokers supports the notion that cigarette smoking both decreases pancreatic function leading to pancreatogenic diabetes and increases pancreatic cancer risk. These results suggest that the associations of C-Peptide and HMW Adiponectin with pancreatic cancer may be more complex than previously appreciated and differ according to smoking status. A better understanding of the metabolic profile of smokers may be helpful in identifying high-risk individuals who could be targeted for pancreatic cancer prevention interventions.
Citation Format: Leticia Nogueira, Christina Newton, Debra Silverman, Demetrius Albanes, Satu Manniston, Eric Jacobs, Rachel Stolzemberg-Solomon. Smoking modifies the association of insulin sensitivity biomarkers and pancreatic cancer risk. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A61.