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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

Abstract

Aim

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.

Methods

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.

Results

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.

Conclusion

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

Keywords

Pancreatic cancer KPC High-fat diet Diabetes Staging 

List of abbreviations

PDAC

pancreatic ductal adenocarcinoma

LSL

loxP-STOP-loxP

KPC

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

CRE

Pdx-1-Cre mice

SD

standard diet

HFD

high-fat diet

ADTM

abdominal adipose tissue measurement

DM

diabetes mellitus

VNN1

vanin 1

T2D

type 2 diabetes

PanIN

pancreatic intraepithelial neoplasia

MRI

magnetic resonance imaging

OGTT

oral glucose tolerance test

AUC

area under the curve

A.U.

arbitrary unit

HOMA-IR

homeostatic model assessment for insulin resistance

AFV

abdominal fat volume

SEM

standard error

MR

magnetic resonance

KC

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

SD-KPC

standard diet-fed KPC

HFD-KPC

high-fat diet-fed KPC

mPanc02

murine Panc02 cells

Notes

Acknowledgements

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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Supplementary material 1 (DOCX 31 kb)
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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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