Abstract
Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human β-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (Δ-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human β-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view.
| Original language | English |
|---|---|
| Pages (from-to) | 229-233 |
| Number of pages | 5 |
| Journal | Acta Diabetologica |
| Volume | 39 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Dec 2002 |
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Keywords
- Human islet
- Immunosuppressive agents
- Insulin gene
- Insulin secretion
ASJC Scopus subject areas
- Endocrinology
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Secretory defects induced by immunosuppressive agents on human pancreatic β-cells. / Polastri, L.; Galbiati, F.; Bertuzzi, F.; Fiorina, P.; Nano, R.; Gregori, S.; Aldrighetti, L.; Pozza, G.; Secchi, A.; Adorini, L.; Davalli, A. M.
In: Acta Diabetologica, Vol. 39, No. 4, 12.2002, p. 229-233.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Secretory defects induced by immunosuppressive agents on human pancreatic β-cells
AU - Polastri, L.
AU - Galbiati, F.
AU - Bertuzzi, F.
AU - Fiorina, P.
AU - Nano, R.
AU - Gregori, S.
AU - Aldrighetti, L.
AU - Pozza, G.
AU - Secchi, A.
AU - Adorini, L.
AU - Davalli, A. M.
PY - 2002/12
Y1 - 2002/12
N2 - Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human β-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (Δ-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human β-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view.
AB - Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human β-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (Δ-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human β-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view.
KW - Human islet
KW - Immunosuppressive agents
KW - Insulin gene
KW - Insulin secretion
UR - http://www.scopus.com/inward/record.url?scp=0036905423&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036905423&partnerID=8YFLogxK
U2 - 10.1007/s005920200039
DO - 10.1007/s005920200039
M3 - Article
VL - 39
SP - 229
EP - 233
JO - Acta Diabetologica
JF - Acta Diabetologica
SN - 0940-5429
IS - 4
ER -