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Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining ß-Cell Function

Molecular Pharmacology Research Center (K.M., E.C.T., C.C., M.B.), Molecular Cardiology Research Institute, Tufts-New England Medical Center, and Department of Neuroscience (B.L.), Tufts University, Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Martin Beinborn, Tufts-New England Medical Center, Mailbox 7703, 750 Washington Street, Boston, Massachusetts 02111. E-mail: MBeinborn{at}Tufts-NEMC.org.

Glucagon-like peptide 1 (GLP-1) is a physiological stimulus of pancreatic ß-cell function. This enteroendocrine hormone is produced by intestinal L cells, and is delivered via the bloodstream to GLP-1 receptors (GLP-1Rs) on pancreatic ß-cells. In addition, there is evidence that ß-cell GLP-1Rs maintain sustained basal activity even in the absence of intestinal peptide, an observation that has raised the question whether these receptors have some degree of ligand-independent function. Here, we provide an alternative explanation for basal receptor activity based on our finding that biologically relevant amounts of fully processed GLP-1 are locally generated by insulinoma cell lines, as well as by -cells of isolated rat islets in primary culture. Presence of GLP-1 was established by immunocytochemistry, as well as by selective ELISAs and bioassays of cell supernatants. A GLP-1R antagonist significantly reduced insulin secretion/production in ß-TC-6 insulinoma cells and isolated rat islets, suggesting a functionally important loop between locally produced GLP-1 and its cognate receptor. Treatment with this antagonist also inhibited the growth of ß-TC-6 cells. These observations provide novel insight into the function of insulin-producing cell lines and native ß-cells during in vitro culture, and they support the idea that locally produced GLP-1 may play a role in intraislet regulation.

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