Abstract | OBJECTIVE: Peripheral benzodiazepine receptors (PBRs) are part of the mitochondrial permeability transition pore, and their activation may induce cell death. PBRs are expressed in human pancreatic islets, and cytokine-induced damage is accompanied by changes in their properties. We hypothesized that PBRs can have a role in human islet physiopathology, and evaluated the effects of prolonged exposure to two specific PBR ligands, PK11195 and Ro5-4864 on the function and survival of isolated human islets. DESIGN: Isolated human islets were prepared from the pancreas of 25 multiorgan cadaveric donors and incubated for 12 h in the presence of PK11195 or Ro5-4864. Insulin secretion studies and apoptosis experiments were then performed, together with assessment of intracellular pathways involved in islet cell function and survival. METHODS: Islets were prepared by enzymatic digestion and density gradient purification. Insulin secretion was assessed by the batch incubation method, and glucose oxidation was evaluated by the use of D-[U-(14)C] glucose. Apoptosis was studied using the TUNEL technique, ELISA methods, and electron microscopy evaluation. PCR experiments were performed by the use of specific primers. RESULTS: CONCLUSIONS: Prolonged binding to PBRs may cause human beta-cells functional damage and apoptosis, a phenomenon which is prevented by stabilizing the mitochondrial membrane; occurs without changes of iNOS, Bax and Bcl-2 mRNA expression; and involves caspase activation. These results suggest an involvement of PBRs in human pancreatic beta-cell function and survival.
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Authors | Lorella Marselli, Letizia Trincavelli, Carmela Santangelo, Roberto Lupi, Silvia Del Guerra, Ugo Boggi, Alessandra Falleni, Vittorio Gremigni, Franco Mosca, Claudia Martini, Francesco Dotta, Umberto Di Mario, Stefano Del Prato, Piero Marchetti |
Journal | European journal of endocrinology
(Eur J Endocrinol)
Vol. 151
Issue 2
Pg. 207-14
(Aug 2004)
ISSN: 0804-4643 [Print] England |
PMID | 15296476
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- BAX protein, human
- Benzodiazepinones
- Caspase Inhibitors
- Excitatory Amino Acid Transporter 2
- Hypolipidemic Agents
- Insulin
- Isoquinolines
- Ligands
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- Receptors, GABA-A
- bcl-2-Associated X Protein
- 4'-chlorodiazepam
- NOS2 protein, human
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type II
- CASP3 protein, human
- CASP9 protein, human
- Caspase 3
- Caspase 9
- Caspases
- PK 11195
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Topics |
- Antineoplastic Agents
(metabolism, pharmacology)
- Apoptosis
(drug effects)
- Benzodiazepinones
(metabolism, pharmacology)
- Caspase 3
- Caspase 9
- Caspase Inhibitors
- Caspases
(metabolism)
- Cell Survival
(drug effects, physiology)
- Cells, Cultured
- Excitatory Amino Acid Transporter 2
(genetics)
- Gene Expression
(drug effects)
- Humans
- Hypolipidemic Agents
(metabolism, pharmacology)
- Insulin
(genetics)
- Islets of Langerhans
(cytology, drug effects, metabolism)
- Isoquinolines
(metabolism, pharmacology)
- Ligands
- Mitochondria
(metabolism)
- Nitric Oxide Synthase
(genetics)
- Nitric Oxide Synthase Type II
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins c-bcl-2
(genetics)
- Receptors, GABA-A
(metabolism)
- bcl-2-Associated X Protein
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