Research progress of insulin resistance and hyperinsulinemia promoting pancreatic cancer
LI Shanshan, ZHAO Yulan
Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital to School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
Abstract:Pancreatic cancer is a common digestive tract carcinoma. It is strongly occult and lack of early diagnostic indicators, and the patients have quite low survival rates. The pathogenesis of pancreatic cancer remains unclear. It has been reported that smoking, family history, diabetes mellitus and obesity are associated with the incidence of pancreatic cancer; moreover, type 2 diabetes mellitus (T2DM) often occur as a comorbidity. Insulin resistance and compensatory hyperinsulinemia are the main metabolic characteristics of T2DM, which play an important role in the development and progression of pancreatic cancer. The molecular mechanisms of insulin resistance and hyperinsulinemia promoting pancreatic cancer are reviewed in this paper, in order to provide the evidence for the prevention and treatment of pancreatic cancer.
[1] POTHURAJU R,RACHAGANI S,JUNKER W M,et al.Pancreatic cancer associated with obesity and diabetes:an alternative approach for its targeting[J/OL].J Exp Clin Cancer Res,2018,37(2018-12-19)[2021-07-15].https://jeccr.biomedcentral.com/articles/10.1186/s13046-018-0963-4. [2] TEMPERO M A.NCCN guidelines updates:pancreatic cancer[J].J Natl Compr Canc Netw,2019,17(5.5):603-605. [3] VINCENT A,HERMAN J,SCHULICK R,et al.Pancreatic cancer[J].Lancet,2011,378(9791):607-620. [4] HUANG B Z,CHANG J I,LI E,et al.Influence of statins and cholesterol on mortality among patients with pancreatic cancer[J/OL].J Natl Cancer Inst,2016,109(5)(2016-12-31)[2021-07-15].https://academic.oup.com/jnci/article/109/5/djw275/2898139.DOI:10.1093/jnci/djw275. [5] ILIC M,ILIC I.Epidemiology of pancreatic cancer[J].World J Gastroenterol,2016,22(44):9694-9705. [6] KIM N H,CHANG Y,LEE S R,et al.Glycemic status,insulin resistance,and risk of pancreatic cancer mortality in individuals with and without diabetes[J].Am J Gastroenterol,2020,115(11):1840-1848. [7] ANDERSEN D K.Diabetes and cancer:placing the association in perspective[J].Curr Opin Endocrinol Diabetes Obes,2013,209(2):81-86. [8] MAKHOUL I,YACOUB A,SIEGEL E.Type 2 diabetes mellitus is associated with increased risk of pancreatic cancer:a veteran administration registry study[J/OL].SAGE Open Med,2016,4(2016-12-14)[2021-07-15].https://journals.sagepub.com/doi/10.1177/2050312116682257?url_ver=Z39.88-2003&rfr_id=o. [9] MUTGAN A C,BESIKCIOGLU H E,WANG S,et al.Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer[J/OL].Mol Cancer,2018,17(1)(2018-02-23)[2021-07-15].https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-018-0806-0. [10] LI D,YEUNG S J,HASSAN M M,et al.Antidiabetic therapies affect risk of pancreatic cancer[J].Gastroenterology,2009,137(2):482-488. [11] BAO Y,NIMPTSCH K,WOLPIN B M,et al.Dietary insulin load,dietary insulin index,and risk of pancreatic cancer[J].Am J Clin Nutr,2011,94(3):862-868. [12] ROBERT C T,MATTIAS J,VALERIE G,et al.The role of obesity,type 2 diabetes,and metabolic factors in pancreatic cancer:a Mendelian randomization study[J/OL].J Natl Cancer Inst,2017,109(9)(2018-04-28)[2021-07-15].https://academic.oup.com/jnci/article/109/9/djx012/3778207. [13] POLVANI S,TAROCCHI M,TEMPESTI S,et al.Peroxisome proliferator activated receptors at the crossroad of obesity,diabetes,and pancreatic cancer[J].World J Gastroenterol,2016,22(8):2441-2459. [14] ZHANG A,MAGRILL J,WINTER T,et al.Endogenous hyperinsulinemia contributes to pancreatic cancer development[J].Cell Metab,2019,30(3):403-404. [15] CUI Y F,ANDERSEN D K.Diabetes and pancreatic cancer[J].Endocr Relat Cancer,2012,19(5):F9-F26. [16] TRAJKOVIC-ARSIC M,KALIDERIS E,SIVEKE J T.The role of insulin and IGF system in pancreatic cancer[J].J Mol Endocrinol,2013,50(3):R67-R74. [17] VALSECCHI M E,MCDONALD M,BRODY J R,et al.Epidermal growth factor receptor and insulin like growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma[J].Cancer,2012,118(14):3484-3493. [18] SIDDLE K.Signalling by insulin and IGF receptors:supporting acts and new players[J].J Mol Endocrinol,2011,47(1):R1-R10. [19] APPLEMAN V A,AHRONIAN L G,CAI J,et al.KRASG12D-and BRAFV600E-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling[J].Mol Cancer Res,2012,10(9):1228-1239. [20] EIBL G,CRUZ-MONSERRATE Z,KORC M,et al.Diabetes mellitus and obesity as risk factors for pancreatic cancer[J].J Acad Nutr Diet,2018,118(4):555-567. [21] OMARY M B,LUGEA A,LOWE A W,et al.The pancreatic stellate cell:a star on the rise in pancreatic diseases[J].J Clin Invest,2007,117(1):50-59. [22] DAWSON D W,HERTZER K,MORO A,et al.High-fat,high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model[J].Cancer Prev Res(Phila),2013,6(10):1064-1073. [23] MOHAPATRA S,MAJUMDER S,SMYRK T C,et al.Diabetes mellitus is associated with an exocrine pancreatopathy:conclusions from a review of literature[J].Pancreas,2016,45(8):1104-1110. [24] BIOCHEM A R.Fat and beyond:the diverse biology of PPARγ[J].Annu Rev Biochem,2008,77(1):289-312. [25] GUPTA D,JETTON T L,MORTENSEN R M,et al.In vivo and in vivo studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter[J].J Biol Chem,2008,283(47):32462-32470. [26] GUPTA D,KONO T,EVANS-MOLINA C.The role of peroxisome proliferator activated receptor γ in pancreatic β cell function and survival:therapeutic implications for the treatment of type 2 diabetes mellitus[J].Diabetes Obes Metab,2010,12(12):1036-1047. [27] POLVANI S,TAROCCHI M,TEMPESTI S,et al.Nuclear receptors and pathogenesis of pancreatic cancer[J].World J Gastroenterol,2014,20(34):12062-12081. [28] KOGA H,SELVENDIRAN K,SIVAKUMAR R,et al.PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells[J].Int J Oncol,2012,40(3):679-685. [29] RIUS-PÉREZ S,TORRES-CUEVAS I,MILLÁN I,et al.PGC-1α,inflammation,and oxidative stress:an integrative view in metabolism[J/OL].Oxid Med Cell Longev,2020(2020-03-09)[2021-07-15].https://www.hindawi.com/journals/omcl/2020/1452696.DOI:10.1155/2020/1452696. [30] HOTAMISLIGIL G S,BUDAVARI A,MURRAY D L,et al.Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes.Central role of tumor necrosis factor-alpha[J].J Clin Invest,1994,94(4):1543-1549. [31] ALJADA A,GHANIM H,ASSIAN E,et al.Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells[J].Metabolism,2002,51(4):487-491. [32] GUILHERME A,VIRBASIUS J V,PURI V,et al.Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes[J].Nat Rev Mol Cell Biol,2008,9(5):367-377. [33] HOTAMISLIGIL G S.Inflammation,metaflammation and immunometabolic disorders[J].Nature,2017,542(7640):177-185. [34] SOLINAS G,BECATTINI B.JNK at the crossroad of obesity,insulin resistance,and cell stress response[J].Mol Metab,2016,6(2):174-184. [35] ZHONG Y,NAITO Y,COPE L,et al.Functional p38 MAPK identified by biomarker profiling of pancreatic cancer restrains growth through JNK inhibition and correlates with improved survival[J].Clin Cancer Res,2014,20(23):6200-6211. [36] LIU M Y,ZHANG Y Q,YANG J X,et al.ZIP4 increases expression of transcription factor ZEB1 to promote integrin α3β1 signaling and inhibit expression of the gemcitabine transporter ENT1 in pancreatic cancer cells[J].Gastroenterology,2020,158(3):679-692. [37] HAMARSHEH S,GROβ O,BRUMMER T,et al.Immune modulatory effects of oncogenic KRAS in cancer[J/OL].Nat Commun,2020,11(1)(2020-11-28)[2021-07-15].https://www.nature.com/articles/s41467-020-19288-6.DOI:10.1038/s41467-020-19288-6. [38] PADOAN A,PLEBANI M,BASSO D.Inflammation and pancreatic cancer:focus on metabolism,cytokines,and immunity[J/OL].Int J Mol Sci,2019,20(3):676(2019-09-05)[2021-07-15].https://www.mdpi.com/1422-0067/20/3/676.DOI:10.3390/ijms20030676. [39] SENN J J,KLOVER P J,NOWAK I A,et al.Interleukin-6 induces cellular insulin resistance in hepatocytes[J].Diabetes,2002,51(12):3391-3399.