Acta Diabetologica

, Volume 49, Supplement 1, pp 123–131

In vitro effects of mycophenolic acid on survival, function, and gene expression of pancreatic beta-cells

  • R. Gallo
  • M. Natale
  • F. Vendrame
  • U. Boggi
  • F. Filipponi
  • P. Marchetti
  • F. Laghi Pasini
  • F. Dotta
Original Article

DOI: 10.1007/s00592-011-0368-8

Cite this article as:
Gallo, R., Natale, M., Vendrame, F. et al. Acta Diabetol (2012) 49(Suppl 1): 123. doi:10.1007/s00592-011-0368-8

Abstract

Post-transplant diabetes mellitus represents an important complication of prolonged immunosuppressive treatment after solid organ transplantation. The immunosuppressive toxicity, responsible for a persistent impairment of glucose metabolism in pancreatic islet-transplanted patients, is mainly attributed to calcineurin inhibitors and steroids, while other immunosuppressive molecules (azathioprine and mycophenolic acid, MPA) are considered not to have a toxic effect. In the present study, in vitro effects of MPA have been investigated in mouse beta-cell lines (βTC-1 and βTC-6) and in purified human pancreatic islets. βTC-1, βTC-6, and human pancreatic islets were exposed to various concentrations of MPA for different times. Consequently, we evaluated the viability, the induction of apoptosis, the glucose-stimulated insulin secretion, and the expression of β-cell function genes (Isl1, Pax6, Glut-2, glucokinase) and apoptosis-related genes (Bax and Bcl2). βTC-1, βTC-6, and human islets treated, respectively, for 48 and 72 h with 15–30 nM MPA showed altered islet architecture, as compared with control cells. We observed for βTC-1 and βTC-6 almost 70% reduction in cell viability; three to sixfold induction of TUNEL/apoptotic-positive cells quantified by FACS analysis. A twofold increase in apoptotic cells was observed in human islets after MPA exposure associated with strong inhibition of glucose-stimulated insulin secretion. Furthermore, we showed significant down-regulation of gene expression of molecules involved in β-cell function and increase rate between Bax/Bcl2. Our data demonstrate that MPA has an in vitro diabetogenic effect interfering at multiple levels with survival and function of murine and human pancreatic β-cells.

Keywords

Mycophenolic acidImmunosuppressive drugsBeta-cellsHuman isletsNODAT

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • R. Gallo
    • 1
    • 2
  • M. Natale
    • 3
  • F. Vendrame
    • 1
    • 2
  • U. Boggi
    • 4
  • F. Filipponi
    • 4
  • P. Marchetti
    • 5
  • F. Laghi Pasini
    • 3
  • F. Dotta
    • 1
    • 2
  1. 1.Department of Internal Medicine, Diabetes Unit, Endocrine and Metabolic Sciences and BiochemistryUniversity of SienaSienaItaly
  2. 2.Fondazione Umberto Di Mario ONLUSToscana Life Sciences ParkSienaItaly
  3. 3.Department of Clinical Medicine and Immunological SciencesUniversity of SienaSienaItaly
  4. 4.Department of SurgeryUniversity of PisaPisaItaly
  5. 5.Department of Endocrinology and Metabolism, Metabolic UnitUniversity of PisaPisaItaly