Glucose metabolism during tumorigenesis in the genetic mouse model of pancreatic cancer

  • Valentina Pasquale
  • Erica Dugnani
  • Daniela Liberati
  • Paolo Marra
  • Antonio Citro
  • Tamara Canu
  • Martina Policardi
  • Libera Valla
  • Antonio Esposito
  • Lorenzo PiemontiEmail author
Original Article



More than 40% of pancreatic ductal adenocarcinoma (PDAC) patients have glucose intolerance or diabetes. The association has led to two hypotheses: PDAC causes diabetes or diabetes shares risk factors for the development of PDAC. In order to elucidate the relationship between diabetes and PDAC, we investigated the glucose metabolism during tumorigenesis in the LSL-KrasG12D/+; LSL-Trp53R172H/+; and Pdx-1-Cre (KPC) mouse, a genetically engineered model of PDAC.


Male and female KPCs have been fed with standard diet (SD) or high-fat diet (HFD). The imaging-based 4-class tumor staging was used to follow pancreatic cancer development. Not fasting glycemia, 4-h fasting glycemia, insulin, C-peptide, glucose tolerance after OGTT and abdominal fat volume were measured during tumorigenesis.


PDAC development did not lead to an overt diabetic phenotype or to any alterations in glucose tolerance in KPC fed with SD. Consumption of HFD induced higher body weight/abdominal fat volume and worsened glucose homeostasis both in control CRE mice and only in early tumorigenesis stages of the KPC mice, excluding that the cancer development itself acts as a trigger for the onset of dysmetabolic features.


Our data demonstrate that carcinogenesis in KPC mice is not associated with paraneoplastic diabetes.


Pancreatic cancer KPC High-fat diet Diabetes Staging 

List of abbreviations


pancreatic ductal adenocarcinoma




LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx-1-Cre mice


Pdx-1-Cre mice


standard diet


high-fat diet


abdominal adipose tissue measurement


diabetes mellitus


vanin 1


type 2 diabetes


pancreatic intraepithelial neoplasia


magnetic resonance imaging


oral glucose tolerance test


area under the curve


arbitrary unit


homeostatic model assessment for insulin resistance


abdominal fat volume


standard error


magnetic resonance


LSL-KrasG12D/+ and Pdx-1-Cre mice


standard diet-fed KPC


high-fat diet-fed KPC


murine Panc02 cells



This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, bando 5 X 1,000 N_12182).

Authors’ contributions

VP, ED and LP contributed to study concept and design; VP, ED, DL, PM, AC, TC, MP and LV helped in acquisition of data; VP, ED, PM, AE and LP contributed to analysis and interpretation of data; VP, ED and LP contributed to statistical analysis of data; VP, ED, DL and LP helped in drafting of the manuscript; and AE, LP contributed to critical revision of the manuscript. All authors have approved the submitted manuscript.

Compliance with ethical statement

Conflict of interest

The authors have nothing to disclose.

Ethics statement

This study was approved by the Animal Care and Use Committee of San Raffaele Scientific Institute (IACUC number 559) and performed in accordance with their guidelines.

Informed consent

For this type of study informed consent is not required.

Supplementary material

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  1. 1.
    Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362(17):1605–1617CrossRefGoogle Scholar
  2. 2.
    Zhou B et al (2017) Early detection of pancreatic cancer: where are we now and where are we going? Int J Cancer 141(2):231–241. CrossRefGoogle Scholar
  3. 3.
    Lucas AL et al (2016) Global trends in pancreatic cancer mortality from 1980 through 2013 and predictions for 2017. Clin Gastroenterol Hepatol 14(10):1452–1462 e4CrossRefGoogle Scholar
  4. 4.
    Wei M et al (2017) The need for differentiating diabetes-specific mortality from total mortality when comparing metformin with insulin regarding cancer survival. Acta Diabetol 54(2):219–220CrossRefGoogle Scholar
  5. 5.
    Yang WS et al (2017) Association between type 2 diabetes and cancer incidence in Taiwan: data from a prospective community-based cohort study. Acta Diabetol 54(5):455–461CrossRefGoogle Scholar
  6. 6.
    Balzano G et al (2014) Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients. Acta Diabetol 51(5):801–811CrossRefGoogle Scholar
  7. 7.
    Dugnani E et al (2016) Diabetes associated with pancreatic ductal adenocarcinoma is just diabetes: results of a prospective observational study in surgical patients. Pancreatology 16(5):844–852CrossRefGoogle Scholar
  8. 8.
    Pannala R et al (2008) Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 134(4):981–987CrossRefGoogle Scholar
  9. 9.
    Sah RP et al (2013) New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 10(7):423–433CrossRefGoogle Scholar
  10. 10.
    Chari ST et al (2005) Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 129(2):504–511CrossRefGoogle Scholar
  11. 11.
    Aggarwal G et al (2012) Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in beta cells and mice. Gastroenterology. 143(6):1510–1517 e1CrossRefGoogle Scholar
  12. 12.
    Basso D et al (2006) Pancreatic cancer-derived S-100A8 N-terminal peptide: a diabetes cause? Clin Chim Acta 372(1–2):120–128CrossRefGoogle Scholar
  13. 13.
    Basso D et al (2011) Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: relevance of the S100A8 N-terminal peptide (NT-S100A8). J Cell Physiol 226(2):456–468CrossRefGoogle Scholar
  14. 14.
    Kang M et al (2016) VNN1, a potential biomarker for pancreatic cancer-associated new-onset diabetes, aggravates paraneoplastic islet dysfunction by increasing oxidative stress. Cancer Lett 373(2):241–250CrossRefGoogle Scholar
  15. 15.
    Hingorani SR et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7(5):469–483CrossRefGoogle Scholar
  16. 16.
    Dugnani E et al (2018) Four-class tumor staging for early diagnosis and monitoring of murine pancreatic cancer using magnetic resonance and ultrasound. Carcinogenesis 39(9):1197–1206CrossRefGoogle Scholar
  17. 17.
    Garg SK et al (2014) Diabetes and cancer: two diseases with obesity as a common risk factor. Diabetes Obes Metab 16(2):97–110CrossRefGoogle Scholar
  18. 18.
    McAuliffe MJ et al (2001) Medical image processing, analysis and visualization in clinical research. In: Proceedings 14th IEEE symposium on computer-based medical systems. CBMS 2001Google Scholar
  19. 19.
    van Dijk TH et al (2013) A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice. Lab Anim 47(2):79–88CrossRefGoogle Scholar
  20. 20.
    Ben Q et al (2011) The relationship between new-onset diabetes mellitus and pancreatic cancer risk: a case-control study. Eur J Cancer 47(2):248–254CrossRefGoogle Scholar
  21. 21.
    Li D et al (2011) Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control 22(2):189–197CrossRefGoogle Scholar
  22. 22.
    Chari ST et al (2008) Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134(1):95–101CrossRefGoogle Scholar
  23. 23.
    Danai LV et al (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558(7711):600–604CrossRefGoogle Scholar
  24. 24.
    Lee JW et al (2016) Genetically engineered mouse models of pancreatic cancer: the KPC model (LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre), its variants, and their application in immuno-oncology drug discovery. Curr Protoc Pharmacol 73:14 39 1–14 39 20CrossRefGoogle Scholar
  25. 25.
    Parks BW et al (2015) Genetic architecture of insulin resistance in the mouse. Cell Metab 21(2):334–346CrossRefGoogle Scholar
  26. 26.
    Zechner D et al (2015) Characterization of novel carcinoma cell lines for the analysis of therapeutical strategies fighting pancreatic cancer. Cell Biosci 5:51CrossRefGoogle Scholar
  27. 27.
    Khasawneh J et al (2009) Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc Natl Acad Sci U S A 106(9):3354–3359CrossRefGoogle Scholar
  28. 28.
    Cheon EC et al (2011) Alteration of strain background and a high omega-6 fat diet induces earlier onset of pancreatic neoplasia in EL-Kras transgenic mice. Int J Cancer 128(12):2783–2792CrossRefGoogle Scholar
  29. 29.
    Dawson DW et al (2013) High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev Res (Phila) 6(10):1064–1073CrossRefGoogle Scholar
  30. 30.
    Philip B et al (2013) A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology 145(6):1449–1458CrossRefGoogle Scholar
  31. 31.
    McDevitt TM, Tisdale MJ (1992) Tumour-associated hypoglycaemia in a murine cachexia model. Br J Cancer 66(5):815–820CrossRefGoogle Scholar
  32. 32.
    Liang C et al (2016) Energy sources identify metabolic phenotypes in pancreatic cancer. Acta Biochim Biophys Sin (Shanghai) 48(11):969–979CrossRefGoogle Scholar
  33. 33.
    Basturk O et al (2011) GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis, diagnosis, and prognosis. Pancreas 40(2):187–192CrossRefGoogle Scholar
  34. 34.
    Yu M et al (2015) Metabolic phenotypes in pancreatic cancer. PLoS ONE 10(2):e0115153CrossRefGoogle Scholar
  35. 35.
    Geng Y et al (2015) Prognostic nutritional index predicts survival and correlates with systemic inflammatory response in advanced pancreatic cancer. Eur J Surg Oncol 41(11):1508–1514CrossRefGoogle Scholar
  36. 36.
    Balzano G et al (2017) A preoperative score to predict early death after pancreatic cancer resection. Digest Liver Dis 49(9):1050–1056CrossRefGoogle Scholar
  37. 37.
    Kimura Y, Kikuyama M, Kodama Y (2015) Acute pancreatitis as a possible indicator of pancreatic cancer: the importance of mass detection. Intern Med 54(17):2109–2114CrossRefGoogle Scholar
  38. 38.
    Bracci PM et al (2009) Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control 20(9):1723–1731CrossRefGoogle Scholar
  39. 39.
    Chan YC, Leung PS (2007) Acute pancreatitis: animal models and recent advances in basic research. Pancreas 34(1):1–14CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  • Valentina Pasquale
    • 1
  • Erica Dugnani
    • 1
  • Daniela Liberati
    • 2
  • Paolo Marra
    • 3
  • Antonio Citro
    • 1
  • Tamara Canu
    • 3
  • Martina Policardi
    • 1
  • Libera Valla
    • 1
  • Antonio Esposito
    • 3
    • 4
  • Lorenzo Piemonti
    • 1
    • 4
    Email author
  1. 1.Diabetes Research InstituteIRCCS San Raffaele Scientific InstituteMilanItaly
  2. 2.Division of Genetics and Cell biology, Genomic Unit for the diagnosis of human pathologiesIRCCS San Raffaele Scientific InstituteMilanItaly
  3. 3.Department of Radiology, Experimental Imaging CenterIRCCS San Raffaele Scientific InstituteMilanItaly
  4. 4.Vita-Salute San Raffaele UniversityMilanItaly

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