We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Effects of Therapeutical Concentration of Immunosuppressant Drugs on Isolated Human Pancreatic Islets: Functional and Molecular Studies.
- Authors
Bugliani, Marco; Masini, Matilde; Torri, Scilla; Lupi, Roberto; Del Guerra, Silvia; Mancarella, Rita; Vistoli, Fabio; Del Chiaro, Marco; Del Prato, Stefano; Boggi, Ugo; Mosca, Franco; Marchetti, Piero
- Abstract
A proper use of immunosuppressive drugs is crucial for successful pancreas or islet transplantation. However, immunosuppressant agents can have deleterious side effects on the beta-cell. Such results have been obtained more frequently with no longer used molecules or with pharmacological, more than therapeutical, drug concentrations. We investigated the effects of prolonged exposure of isolated human islets to 10 ng/ml Tacrolimus (Tac) or 150 ng/ml Cyclosporin A (CsA). Islets were isolated from the pancreas of 12 multiorgan donors (age: 64±15 years; gender: 8M/4F; BMI: 26.6±3.0 kg/m²) by enzymatic digestion and density gradient centrifugation. Morphological, functional and survival studies were then performed after 96 hr incubation with Tac or CsA. Glucose-induced insulin secretion was significantly decreased in Tac (p<0.05), but not in CsA exposed islets, (stimulation index, i.e. the ratio of insulin release at 16.7 vs 3.3 mmol/1 glucose: Control islets, Ctrl, 2.3±0.5; Tac 1.6±0.2; CsA, 2.0±0.4). This was associated with unchanged mRNA expression of insulin and glut2, and increased expression of glucokinase in Tac exposed cells. Furthermore, electron microscopy (EM) showed a significant (p<0.05) decrease of insulin granules in Tac exposed beta-cells (volume density, ml%: 0.63±0.39), but not in the CsA group (1.55±0.01 ), as compared to Ctrl (1.54±0.09). Finally, by EM it was shown that the percentage of apoptotic beta-cells was higher in Tac (11.7±4.7) than Ctrl (2.7±1.2) (the respective value in CsA was 6.3±1.2). Therefore, Tac has more deleterious effects on the function and survival of human beta-cells compared to CsA, when both agents were used at therapeutical concentration.
- Subjects
IMMUNOSUPPRESSIVE agents; ISLANDS of Langerhans; PANCREATIC beta cells; TACROLIMUS; CYCLOSPORINE; INSULIN
- Publication
Diabetes, 2007, Vol 56, pA718
- ISSN
0012-1797
- Publication type
Article