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Submitted on March 13, 2003
Accepted on August 19, 2003
1 Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, California; University of California Los Angeles, California, National Institutes of Health, Bethesda, Maryland; Division of Neonatology, Cedars-Sinai Medical Center, Los Angeles, California; Department of Clinical Sciences, University "La Sapienza", Rome, Italy
* To whom correspondence should be addressed. E-mail: perfettir{at}cshs.org.
The peptide hormone GLP-1 has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass and inhibit 
-cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured for five days in the presence, or absence, of GLP-1 (10 nM, added every 12 h) and studied for viability, expression of pro-apoptotic (caspase-3) and anti-apoptotic factors (bcl-2), as well as for glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1 treated islets compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1 treated islets was particularly evident at day 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at day 5 (8.9% vs. 18.9%; P < 0.01). The anti-apoptotic effect of GLP-1 was associated with the down-regulation of active caspase-3 (P < 0.001) and the up-regulation of bcl-2 (P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and at the protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control (P < 0.001, at day 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion (P < 0.01, at day 3; P < 0.05 at day 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function, and inhibits cell apoptosis.
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