Advertisement

Diabetes with Pancreatic Ductal Adenocarcinoma

  • Gowru Srivani
  • Begum Dariya
  • Afroz Alam
  • Ganji Purnachandra NagarajuEmail author
Chapter

Abstract

Diabetes and pancreatic ductal adenocarcinoma (PDAC) are common diseases and affect the same organ, pancreas. PDAC has a poor prognosis and response to conservative therapy. Diabetes is recently been correlated with mortality and morbidity from PDAC. The association between diabetes and PDAC stems from the structural association between the endocrine and exocrine pancreas and aberrant expression of hormones from islets. It can also result from other etiological factors including stress, inflammation, smoking, alcohol consumption, change in the diet, as well as inherited syndromes that affect PDAC tissue. Epidemiological evidence suggests that diabetes increases the risk for PDAC development. Insulin resistance, hyperinsulimenia, hyperglycemia, chronic inflammation, and their elementary mechanisms can contribute to the development of diabetes-associated PDAC. Signal transduction pathways that regulate metabolic functions also play a crucial role in the development of PDAC, promoting tumor proliferation, cell growth, differentiation, angiogenesis, and metastasis. In another way, PDAC is also a causative factor for diabetes, although the mechanisms are not well understood. Effective biomarkers might thus help detect the increased risk of PDAC. Furthermore, greater understanding of the pathological mechanisms linking diabetes to PDAC could guide the development of new therapeutic agents to prevent diabetes associated with PDAC.

Keywords

PDAC Type 2 diabetes Exocrine Endocrine Hyperglycemia Hyperinsulinemia 

Abbreviations

4-HNE

4-hydroxyl-2-nonenal

Akt

Protein kinase B

AMP

Adenosine monophosphate

AMPK

AMP-activated protein kinase

ATP

Adenosine triphosphate

ASK-1

Apoptosis signaling kinase-1

CI

Confidence interval

COX2

Cyclooxygenase

DNA

Deoxyribonucleic acid

ERK

Extracellular signal-regulated kinases

ETC

electron transport chain

FGD-PET

F-18-Fluoro-deoxyglucose (FDG)-positron emission tomography (PET)

FTZ-F1

Fushi-tarazu factor-1

GI

Glycemic index

GLUT

Glucose transporter

GWAS

Genome-wide association studies

HNF-3β

Hepatocyte nucleoside factor-3β

IER

Intermittent energy restriction

IGFBP-1

Insulin growth factor-binding protein-1

IGF

Insulin growth factor

IGFR

Insulin growth factor receptors

IKK

Inhibitor of kB kinase

IL-6

Interleukin-6

IL-8

Interleukin-8

IR

Insulin receptor

IRS

Insulin receptor substrate 1

JNK

c-Jun N-terminal kinases

LKB1

Liver kinase B1

LOOH

Lipid hydroperoxides

LRH1

Liver receptor homolog-1

MDA

Malondialdehyde

MEK

Mitogen-activated protein kinase

MMP-7

Matrix metalloproteinase-7

mTOR

Mammalian target of rapamycin

NADPH

Nicotinamide adenine dinucleotide

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

NR5A2

Nuclear receptor superfamily member

PDAC

Pancreatic ductal adenocarcinoma

PDX-1

Pancreatic duodenal homeobox

PI3K

Phosphatidylinositol 3 kinase

RIP-1

Receptor interacting protein

RO

Alkoxyl radical

ROS

Reactive oxygen species

RR

Relative risk

SO4

Sulfate radical

SODD

Silencer of death domain

STAT

Signal transducer and activator of transcription 3

TNF-α

Tumor necrosis factor-α

TRADD

TNF receptor-associated death domain

VAT

Vascular adipose tissue

VEGF

Vascular endothelial growth factor

References

  1. 1.
    Becker AE, Hernandez YG, Frucht H, Lucas AL (2014) Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J Gastroenterol 20(32):11182–11198PubMedPubMedCentralGoogle Scholar
  2. 2.
    Saad AM, Turk T, Al-Husseini MJ, Abdel-Rahman O (2018) Trends in pancreatic adenocarcinoma incidence and mortality in the United States in the last four decades; a SEER-based study. BMC Cancer 18(1):688–688PubMedPubMedCentralGoogle Scholar
  3. 3.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29PubMedGoogle Scholar
  4. 4.
    Howlader N, Noone A, Krapcho M, Garshell J, Neyman N, Altekruse S (2013) SEER cancer statistics review, 1975–2010. National Cancer Institute, BethesdaGoogle Scholar
  5. 5.
    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res 74:2913PubMedGoogle Scholar
  6. 6.
    Sah RP, Nagpal SJS, Mukhopadhyay D, Chari ST (2013) New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 10(7):423–433PubMedPubMedCentralGoogle Scholar
  7. 7.
    Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123PubMedGoogle Scholar
  8. 8.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. Diabetes Care 33(7):1674–1685PubMedPubMedCentralGoogle Scholar
  9. 9.
    Aggarwal G, Kamada P, Chari ST (2013) Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas 42(2):198–201PubMedPubMedCentralGoogle Scholar
  10. 10.
    Everhart J, Wright D (1995) Diabetes mellitus as a risk factor for pancreatic cancer: a meta-analysis. JAMA 273(20):1605–1609PubMedGoogle Scholar
  11. 11.
    Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, Zhang H, Li Z (2011) Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies. Eur J Cancer 47(13):1928–1937PubMedGoogle Scholar
  12. 12.
    Silverman DT (2001) Risk factors for pancreatic cancer: A case-control study based on direct interviews. Teratog Carcinog Mutagen 21(1):7–25PubMedGoogle Scholar
  13. 13.
    Li D, Tang H, Hassan MM, Holly EA, Bracci PM, Silverman DT (2011) Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control 22(2):189–197PubMedGoogle Scholar
  14. 14.
    Himsworth H, Kerr R (1939) Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci 4:119–152Google Scholar
  15. 15.
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY) 324(5930):1029–1033Google Scholar
  16. 16.
    Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JKV, Markowitz S, Zhou S et al (2009) Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science (New York, NY) 325(5947):1555–1559Google Scholar
  17. 17.
    Hine RJ, Srivastava S, Milner JA, Ross SA (2003) Nutritional links to plausible mechanisms underlying pancreatic cancer: a conference report. Pancreas 27(4):356–366PubMedGoogle Scholar
  18. 18.
    Mulholland HG, Murray LJ, Cardwell CR, Cantwell MM (2008) Glycemic index, glycemic load, and risk of digestive tract neoplasms: a systematic review and meta-analysis. Am J Clin Nutr 89(2):568–576PubMedGoogle Scholar
  19. 19.
    Reaven GM (1993) Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 44(1):121–131PubMedGoogle Scholar
  20. 20.
    Lakka H-M, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288(21):2709–2716PubMedGoogle Scholar
  21. 21.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60(4):207–221PubMedGoogle Scholar
  22. 22.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8(12):915PubMedGoogle Scholar
  23. 23.
    Singh P, Alex JM, Bast F (2014) Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol 31(1):805PubMedGoogle Scholar
  24. 24.
    Zong CS, Zeng L, Jiang Y, Sadowski HB, Wang L-H (1998) Stat3 plays an important role in oncogenic Ros-and insulin-like growth factor I receptor-induced anchorage-independent growth. J Biol Chem 273(43):28065–28072PubMedGoogle Scholar
  25. 25.
    Resnicoff M, Baserga R (1998) The Role of the Insulin-like Growth Factor I Receptor in Transformation and Apoptosis. Ann N Y Acad Sci 842(1):76–81PubMedGoogle Scholar
  26. 26.
    Zeng H, Datta K, Neid M, Li J, Parangi S, Mukhopadhyay D (2003) Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line. Biochem Biophys Res Commun 302(1):46–55PubMedGoogle Scholar
  27. 27.
    Ding X-Z, Fehsenfeld DM, Murphy LO, Permert J, Adrian TE (2000) Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. Pancreas 21(3):310–320PubMedGoogle Scholar
  28. 28.
    Levitt RJ, Pollak M (2002) Insulin-like growth factor-I antagonizes the antiproliferative effects of cyclooxygenase-2 inhibitors on BxPC-3 pancreatic cancer cells. Cancer Res 62(24):7372–7376PubMedGoogle Scholar
  29. 29.
    Hu H, Han T, Zhuo M, Wu LL, Yuan C, Wu L, Lei W, Jiao F, Wang L-W (2017) Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent signalling in pancreatic cancer. Sci Rep 7(1):470PubMedPubMedCentralGoogle Scholar
  30. 30.
    Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN (2007) Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. Cancer Res 67(16):7923–7928PubMedGoogle Scholar
  31. 31.
    Suzuki H, Li Y, Dong X, Hassan MM, Abbruzzese JL, Li D (2008) Effect of insulin-like growth factor gene polymorphisms alone or in interaction with diabetes on the risk of pancreatic cancer. Cancer Epidemiol Biomark Prev 17(12):3467–3473Google Scholar
  32. 32.
    Van Kruijsdijk RC, Van Der Wall E, Visseren FL (2009) Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev 18(10):2569–2578Google Scholar
  33. 33.
    Ramos EJ, Xu Y, Romanova I, Middleton F, Chen C, Quinn R, Inui A, Das U, Meguid MM (2003) Is obesity an inflammatory disease? Surgery 134(2):329–335PubMedGoogle Scholar
  34. 34.
    Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296(5573):1634–1635Google Scholar
  35. 35.
    Parameswaran N, Patial S (2010) Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 20(2):87–103PubMedPubMedCentralGoogle Scholar
  36. 36.
    Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009, 1171(1):59–76PubMedPubMedCentralGoogle Scholar
  37. 37.
    Heinrich PC, Behrmann I, Serge H, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374(1):1–20PubMedPubMedCentralGoogle Scholar
  38. 38.
    Hertzer KM, Xu M, Moro A, Dawson DW, Du L, Li G, Chang H-H, Stark AP, Jung X, Hines OJ (2016) Robust Early Inflammation of the Peri-pancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer. Pancreas 45(3):458PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kalaany NY, Sabatini DM (2009) Tumours with PI3K activation are resistant to dietary restriction. Nature 458(7239):725PubMedPubMedCentralGoogle Scholar
  40. 40.
    Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, Mosley M, Notterpek L, Ravussin E, Scheer FA (2014) Meal frequency and timing in health and disease. Proc Natl Acad Sci 111(47):16647–16653PubMedGoogle Scholar
  41. 41.
    Pollak M (2009) Do cancer cells care if their host is hungry? Cell Metab 9(5):401–403PubMedGoogle Scholar
  42. 42.
    Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, Ono H, Fujishiro M, Kushiyama A, Fukushima Y (2004) Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia 47(5):794–805PubMedGoogle Scholar
  43. 43.
    Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462PubMedPubMedCentralGoogle Scholar
  44. 44.
    Martinez-Useros J, Li W, Cabeza-Morales M, Garcia-Foncillas J (2017) Oxidative stress: a new target for pancreatic cancer prognosis and treatment. J Clin Med 6(3):29PubMedCentralGoogle Scholar
  45. 45.
    Pani G, Galeotti T, Chiarugi P (2010) Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev 29(2):351–378PubMedGoogle Scholar
  46. 46.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313PubMedGoogle Scholar
  47. 47.
    Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94(3):909–950PubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee JK, Edderkaoui M, Truong P, Ohno I, Jang KT, Berti A, Pandol SJ, Gukovskaya AS (2007) NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology 133(5):1637–1648PubMedGoogle Scholar
  49. 49.
    Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS (2004) Reactive oxygen species produced by NAD (P) H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem 279(33):34643–34654PubMedGoogle Scholar
  50. 50.
    Narendhirakannan R, Hannah MAC (2013) Oxidative stress and skin cancer: an overview. Indian J Clin Biochem 28(2):110–115PubMedGoogle Scholar
  51. 51.
    Bastard J-P, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17(1):4–12PubMedGoogle Scholar
  52. 52.
    Zhang C, Cao S, Toole BP, Xu Y (2015) Cancer may be a pathway to cell survival under persistent hypoxia and elevated ROS: a model for solid-cancer initiation and early development. Int J Cancer 136(9):2001–2011PubMedGoogle Scholar
  53. 53.
    Ramanathan B, Jan K-Y, Chen C-H, Hour T-C, Yu H-J, Pu Y-S (2005) Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res 65(18):8455–8460PubMedGoogle Scholar
  54. 54.
    Fiorini C, Cordani M, Gotte G, Picone D, Donadelli M (2015) Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner. Biochim Biophys Acta 1853(3):549–560PubMedGoogle Scholar
  55. 55.
    Midaoui AE, Elimadi A, Wu L, Haddad PS, De Champlain J (2003) Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens 16(3):173–179PubMedGoogle Scholar
  56. 56.
    Tirosh A, Potashnik R, Bashan N, Rudich A (1999) Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-Kinase in 3T3-L1 adipocytes A Putative Cellular Mechanism For Impaired Protein Kinase B activation and glut4 translocation. J Biol Chem 274(15):10595–10602PubMedGoogle Scholar
  57. 57.
    Andersen DK, Andren-Sandberg Å, Duell EJ, Goggins M, Korc M, Petersen GM, Smith JP, Whitcomb DC (2013) Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 42(8):1227–1237PubMedGoogle Scholar
  58. 58.
    Duffy DL (2007) Genetic determinants of diabetes are similarly associated with other immune-mediated diseases. Curr Opin Allergy Clin Immunol 7(6):468–474PubMedGoogle Scholar
  59. 59.
    Imamura M, Maeda S (2011) Genetics of type 2 diabetes: the GWAS era and future perspectives [Review]. Endocr J 58(9):723–739PubMedGoogle Scholar
  60. 60.
    Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M et al (2010) A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 42(3):224–228PubMedPubMedCentralGoogle Scholar
  61. 61.
    de Mendonça RL, Bouton D, Bertin B, Escriva H, Noël C, Vanacker J-M, Cornette J, Laudet V, Pierce RJ (2002) A functionally conserved member of the FTZ-F1 nuclear receptor family from Schistosoma mansoni. Eur J Biochem 269(22):5700–5711PubMedGoogle Scholar
  62. 62.
    Paré J-F, Malenfant D, Courtemanche C, Jacob-Wagner M, Roy S, Allard D, Bélanger L (2004) The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and cholesterol homeostasis and is regulated by a DR4 element. J Biol Chem 279(20):21206–21216PubMedGoogle Scholar
  63. 63.
    Repa JJ, Mangelsdorf DJ (1999) Nuclear receptor regulation of cholesterol and bile acid metabolism. Curr Opin Biotechnol 10(6):557–563PubMedGoogle Scholar
  64. 64.
    W-w L, Wang HW, Sum C, Liu D, Hew CL, Chung B (2000) Zebrafish ftz-f1 gene has two promoters, is alternatively spliced, and is expressed in digestive organs. Biochem J 348(2):439–446Google Scholar
  65. 65.
    Benod C, Vinogradova MV, Jouravel N, Kim GE, Fletterick RJ, Sablin EP (2011) Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation. Proc Natl Acad Sci 108:16927PubMedGoogle Scholar
  66. 66.
    Lin Q, Aihara A, Chung W, Li Y, Chen X, Huang Z, Weng S, Carlson RI, Nadolny C, Wands JR (2014) LRH1 promotes pancreatic cancer metastasis. Cancer Lett 350(1–2):15–24PubMedGoogle Scholar
  67. 67.
    Brissova M, Shiota M, Nicholson WE, Gannon M, Knobel SM, Piston DW, Wright CV, Powers AC (2002) Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem 277(13):11225–11232PubMedGoogle Scholar
  68. 68.
    Ashizawa S, Brunicardi FC, Wang X-P (2004) PDX-1 and the pancreas. Pancreas 28(2):109–120PubMedGoogle Scholar
  69. 69.
    Annicotte J-S, Fayard E, Swift GH, Selander L, Edlund H, Tanaka T, Kodama T, Schoonjans K, Auwerx J (2003) Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development. Mol Cell Biol 23(19):6713–6724PubMedPubMedCentralGoogle Scholar
  70. 70.
    Bell M, Crawford H (2006) The role of PDX-1 in the regulation of the MMP-7 gene expression in pancreatic cancer. In: AACR; 2006Google Scholar
  71. 71.
    Roy N, Takeuchi KK, Ruggeri JM, Bailey P, Chang D, Li J, Leonhardt L, Puri S, Hoffman MT, Gao S et al (2016) PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. Genes Dev 30(24):2669–2683PubMedPubMedCentralGoogle Scholar
  72. 72.
    Defronzo RA (2009) Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4):773–795PubMedPubMedCentralGoogle Scholar
  73. 73.
    Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST (2013) Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol 108(4):510PubMedGoogle Scholar
  74. 74.
    Landman GWD, Kleefstra N, van Hateren KJJ, Groenier KH, Gans ROB, Bilo HJG (2010) Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33(2):322–326PubMedGoogle Scholar
  75. 75.
    DeCensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461.  https://doi.org/10.1158/1940-6207.CAPR-10-0157CrossRefGoogle Scholar
  76. 76.
    Currie C, Poole C, Gale E (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52(9):1766–1777PubMedGoogle Scholar
  77. 77.
    Li D, Yeung S-CJ, Hassan MM, Konopleva M, Abbruzzese JL (2009) Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137(2):482–488PubMedPubMedCentralGoogle Scholar
  78. 78.
    Li D (2012) Diabetes and pancreatic cancer. Mol Carcinog 51(1):64–74PubMedPubMedCentralGoogle Scholar
  79. 79.
    Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schonbeck U, Libby P (2006) Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26(3):611–617PubMedGoogle Scholar
  80. 80.
    Gallagher EJ, LeRoith D (2011) Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann N Y Acad Sci 1243(1):54–68PubMedGoogle Scholar
  81. 81.
    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122(6):253–270Google Scholar
  82. 82.
    Hadad SM, Fleming S, Thompson AM (2008) Targeting AMPK: a new therapeutic opportunity in breast cancer. Crit Rev Oncol Hematol 67(1):1–7PubMedGoogle Scholar
  83. 83.
    Shaw RJ, Lamia KA, Vasquez D, Koo S-H, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science (New York, NY) 310(5754):1642–1646Google Scholar
  84. 84.
    Batandier C, Guigas B, Detaille D, El-Mir M, Fontaine E, Rigoulet M, Leverve XM (2006) The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 38(1):33–42PubMedGoogle Scholar
  85. 85.
    He L, Wondisford FE (2015) Metformin action: concentrations matter. Cell Metab 21(2):159–162PubMedGoogle Scholar
  86. 86.
    Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226PubMedPubMedCentralGoogle Scholar
  87. 87.
    Williams T, Brenman JE (2008) LKB1 and AMPK in cell polarity and division. Trends Cell Biol 18(4):193–198PubMedGoogle Scholar
  88. 88.
    He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S, Wondisford FE (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137(4):635–646PubMedPubMedCentralGoogle Scholar
  89. 89.
    Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang L-S, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107PubMedPubMedCentralGoogle Scholar
  90. 90.
    Liang J, Shao SH, Xu Z-X, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL (2007) The energy sensing LKB1–AMPK pathway regulates p27 kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9(2):218PubMedGoogle Scholar
  91. 91.
    Li X, Li T, Liu Z, Gou S, Wang C (2017) The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis. Sci Rep 7(1):5825–5825PubMedPubMedCentralGoogle Scholar
  92. 92.
    Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E (2009) Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 69(16):6539–6545PubMedPubMedCentralGoogle Scholar
  93. 93.
    Sadeghi N, Abbruzzese JL, Yeung S-CJ, Hassan M, Li D (2012) Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 18(10):2905–2912PubMedPubMedCentralGoogle Scholar
  94. 94.
    Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM (2001) Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120(5):1263–1270PubMedGoogle Scholar
  95. 95.
    Krisztina K, Aune M, James S-S, Guido E, Enrique R (2013) Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas 42(5):781PubMedCentralGoogle Scholar
  96. 96.
    Tan X-L, Bhattacharyya KK, Dutta SK, Bamlet WR, Rabe KG, Wang E, Smyrk TC, Oberg AL, Petersen GM, Mukhopadhyay D (2015) Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. Pancreas 44(4):636–647PubMedPubMedCentralGoogle Scholar
  97. 97.
    Qian W, Li J, Chen K, Jiang Z, Cheng L, Zhou C, Yan B, Cao J, Ma Q, Duan W (2018) Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer. Life Sci 208:253–261PubMedGoogle Scholar
  98. 98.
    Sola D, Rossi L, Schianca GPC, Maffioli P, Bigliocca M, Mella R, Corlianò F, Fra GP, Bartoli E, Derosa G (2015) Sulfonylureas and their use in clinical practice. Arch Med Sci 11(4):840PubMedPubMedCentralGoogle Scholar
  99. 99.
    Ashcroft FM (1996) Mechanisms of the glycaemic effects of sulfonylureas. Horm Metab Res 28(09):456–463PubMedGoogle Scholar
  100. 100.
    Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29(2):254–258PubMedGoogle Scholar
  101. 101.
    Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case–control study. Acta Diabetol 46(4):279PubMedGoogle Scholar
  102. 102.
    Smith U, Gale EAM (2009) Does diabetes therapy influence the risk of cancer? Diabetologia 52(9):1699–1708PubMedGoogle Scholar
  103. 103.
    Gerstein HC (2010) Does insulin therapy promote, reduce, or have a neutral effect on cancers? JAMA 303(5):446–447PubMedGoogle Scholar
  104. 104.
    Wang F, Gupta S, Holly EA (2006) Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomark Prev 15(8):1458–1463Google Scholar
  105. 105.
    Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66(5):1103–1110PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Gowru Srivani
    • 1
  • Begum Dariya
    • 1
  • Afroz Alam
    • 1
  • Ganji Purnachandra Nagaraju
    • 2
    Email author
  1. 1.Department of Bioscience and BiotechnologyBanasthali UniversityVanasthaliIndia
  2. 2.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA

Personalised recommendations