Circulating Leptin and Branched Chain Amino Acids—Correlation with Intraductal Papillary Mucinous Neoplasm Dysplastic Grade
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The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN.
Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology.
Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p = 0.0086). Leptin levels were positively correlated with BMI (r = 0.65, p < 0.0001) and were higher in females (p < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p = 0.011). No significant differences in RBP-4 levels were observed.
Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.
KeywordsLeptin BCAA IPMN Biomarker Pancreatic cyst
Intraductal papillary mucinous neoplasm
Branched chain amino acids
Enzyme-linked immunosorbent assay
Pancreatic ductal adenocarcinoma
This study was supported by the National Institutes of Health Grant #1R21CA209366-01, Indiana Clinical and Translational Sciences Institute funded in part by Grant #UL1TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, and National Center for Research Resources Construction Grant #RR020128.
Yip-Schneider, Zhang, and Schmidt significantly contributed to the conception/design/data interpretation, drafting/revision of the work, as well as approve of the final version and agree to be accountable for all aspects of the work.
Liu and Korc significantly contributed to data interpretation and revision of the work as well as approve of the final version and agree to be accountable for all aspects of the work.
Simpson, Carr, Wu, and Hao significantly contributed to data acquisition/analysis, revision of the work, as well as approval of the final version and agree to be accountable for all aspects of the work.
Compliance with Ethical Standards
All patients and healthy controls provided informed consent in accordance with the Indiana University Institutional Review Board.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. Accessed March 20, 2018.Google Scholar
- 5.Tanaka M, Fernandez-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, Kimura W, Levy P, Pitman MB, Schmidt CM, Shimizu M, Wolfgang CL, Yamaguchi K, Yamao K. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–197.CrossRefGoogle Scholar
- 8.Arcidiacono B, Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, Foti D, Chiefari E, Brunetti A. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res 2012;2012:789174.Google Scholar
- 13.Nowak C, Sundstrom J, Gustafsson S, Giedraitis V, Lind L, Ingelsson E, Fall T. Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts. Diabetes 2016;65:276–284.Google Scholar
- 16.Zhao X, Han Q, Liu Y, Sun C, Gang X, Wang G. The Relationship between Branched-Chain Amino Acid Related Metabolomic Signature and Insulin Resistance: A Systematic Review. Journal Diabetes Res 2016;2016:2794591.Google Scholar
- 23.Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS, Davidson SM, Papagiannakopoulos T, Yang A, Dayton TL, Ogino S, Stampfer MJ, Giovannucci EL, Qian ZR, Rubinson DA, Ma J, Sesso HD, Gaziano JM, Cochrane BB, Liu S, Wactawski-Wende J, Manson JE, Pollak MN, Kimmelman AC, Souza A, Pierce K, Wang TJ, Gerszten RE, Fuchs CS, Heiden MGV, Wolpin BM. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 2014;20:1193–1198.CrossRefGoogle Scholar
- 26.Moris D, Damaskos C, Spartalis E, Papalampros A, Vernadakis S, Dimitroulis D, Griniatsos J, Felekouras E, Nikiteas N. Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas. Anticancer Res 2017;37:2185–2194.CrossRefGoogle Scholar
- 29.Wang W, Zhang L, Chen L, Wei J, Sun Q, Xie Q, Zhou X, Zhou D, Huang P, Yang Q, Xie H, Zhou L, Zheng S. Serum carcinoembryonic antigen and carbohydrate antigen 19-9 for prediction of malignancy and invasiveness in intraductal papillary mucinous neoplasms of the pancreas: A meta-analysis. Biomed Rep 2015;3:43–50.CrossRefGoogle Scholar