TY - JOUR

T1 - Direct effects of cyclosporin A on human pancreatic beta-cells

AU - Mandrup-Poulsen, T

AU - Nerup, J

AU - Nielsen, Jens Høiriis

PY - 1986/9

Y1 - 1986/9

N2 - Cyclosporin A (CyA) may induce clinical remission in newly diagnosed insulin-dependent diabetes mellitus patients. Recently, however, adverse effects of high doses of CyA on rodent islets have been reported in vivo and in vitro. The possible direct effects of CyA on the human endocrine pancreas were therefore evaluated. Islets isolated from eight necrokidney donors were cultured in the presence of a therapeutically relevant dose of CyA, i.e., 100 ng/ml. During a 5-day culture period the release of insulin was reduced by 36% (range 7-61%), whereas the islets' content of insulin was increased by 59% (range 3-268%). The glucagon content was not affected. Cyclosporin G inhibited the insulin release, whereas dihydrocyclosporin D had no consistent effects. Glucose-stimulated insulin release from perifused islets was markedly depressed in CyA-treated islets. This effect was not fully reversed 48 h after removal of the drug. We concluded that CyA has a direct inhibitory effect on insulin release from human pancreatic islets with a concomitant increase in the residual insulin content. If applicable to the in vivo condition, CyA may therefore, in addition to its immunosuppressive effect, have direct effects on the endocrine pancreas, which may be relevant for clinical application of the drug.

AB - Cyclosporin A (CyA) may induce clinical remission in newly diagnosed insulin-dependent diabetes mellitus patients. Recently, however, adverse effects of high doses of CyA on rodent islets have been reported in vivo and in vitro. The possible direct effects of CyA on the human endocrine pancreas were therefore evaluated. Islets isolated from eight necrokidney donors were cultured in the presence of a therapeutically relevant dose of CyA, i.e., 100 ng/ml. During a 5-day culture period the release of insulin was reduced by 36% (range 7-61%), whereas the islets' content of insulin was increased by 59% (range 3-268%). The glucagon content was not affected. Cyclosporin G inhibited the insulin release, whereas dihydrocyclosporin D had no consistent effects. Glucose-stimulated insulin release from perifused islets was markedly depressed in CyA-treated islets. This effect was not fully reversed 48 h after removal of the drug. We concluded that CyA has a direct inhibitory effect on insulin release from human pancreatic islets with a concomitant increase in the residual insulin content. If applicable to the in vivo condition, CyA may therefore, in addition to its immunosuppressive effect, have direct effects on the endocrine pancreas, which may be relevant for clinical application of the drug.

KW - Adolescent

KW - Adult

KW - Animals

KW - Cyclosporine

KW - Cyclosporins

KW - Female

KW - Glucagon

KW - Humans

KW - Insulin

KW - Islets of Langerhans

KW - Male

KW - Middle Aged

KW - Rats

KW - Rats, Inbred BB

M3 - Journal article

C2 - 3527825

VL - 35

SP - 1049

EP - 1052

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -