Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets.
Until recently, islet allotransplantation for type 1 diabetic patients has been largely unsuccessful. Previous pharmacologic studies of single drugs have suggested that one factor contributing to this poor success is toxicity of immunosuppressive drugs on transplanted islets. However, no comprehensive study of agents currently used for islet transplantation has been previously reported. Consequently, we exposed HIT-T15 cells and Wistar rat islets to various concentrations of five immunosuppressive agents for 48 and 24 hr, respectively, and measured glucose-stimulated insulin secretion during subsequent static incubations. Results are expressed as percent reduction of insulin secretion at the lower and upper limits, respectively, of plasma drug concentrations used in clinical transplantation compared with control (no drug exposure). Insulin secretion from HIT-T15 cells was significantly inhibited by 74% and 90% after exposure to methylprednisolone (P<0.05), 11% and 24% after exposure to cyclosporine (P<0.01), 60% and 83% after exposure to mycophenolate (P<0.05), 56% and 63% after exposure to sirolimus (P<0.001), and 10% and 20% after exposure to tacrolimus (P<0.001). Insulin secretion from Wistar rat islets was reduced by 0% and 48% after exposure to mycophenolate (P<0.001) and 20% and 31% after exposure to tacrolimus (P<0.05). No reduction in insulin secretion was observed from either HIT-T15 cells or rat islets after exposure to daclizumab. The results support the hypothesis that toxicity of certain immunosuppressive drugs on beta-cell function plays a role in the poor success of islet allotransplantation. This is especially true of intrahepatically transplanted islets, which are exposed to higher portal concentrations of immunosuppressive agents. These findings support the use of low-dose immunosuppressive drug protocols in clinical islet transplantation.
Paty
B W
BW
Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
Harmon
J S
JS
Marsh
C L
CL
Robertson
R P
RP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D000077561:Daclizumab; D005947:Glucose / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007328:Insulin; D016572:Cyclosporine; D000077561:Daclizumab; D009173:Mycophenolic Acid; D005947:Glucose; D016559:Tacrolimus; D008775:Methylprednisolone