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Impact of Defined Matrix Interactions on Insulin Production by Cultured Human ß-Cells

Effect on Insulin Content, Secretion, and Gene Transcription

¹ Islet Research Laboratory at the Whittier Institute for Diabetes, Department of Pediatrics, University of California at San Diego, La Jolla, California
² Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Anthony M. Montgomery, Islet Research Laboratory at the Whittier Institute for Diabetes, Department of Pediatrics, University of California at San Diego, 9894 Genesee Ave., La Jolla, CA 92037. E-mail: ammontgo{at}ucsd.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–regulated kinase; GFP, green fluorescent protein; JNK, c-Jun NH₂-terminal kinase; mAb, monoclonal antibody; pAb, polyclonal antibody

The impact of extracellular matrix on insulin production needs to be understood both to optimize the derivation of functional ß-cells for transplantation and to understand mechanisms controlling islet neogenesis and glucose homeostasis. In this study, we present evidence that adhesion to some common matrix constituents has a profound impact on the transcription, secretion, and storage of insulin by human ß-cells. The integrin-dependent adhesion of fetal ß-cells to both collagen IV and vitronectin induces significant glucose-independent insulin secretion and a substantial reciprocal decline in insulin content. Collagen IV, but not vitronectin, induces comparable responses in adult ß-cells. Inhibition of extracellular signal–regulated kinase activation abrogates matrix-induced insulin secretion and effectively preserves the insulin content of adherent ß-cells. Using real-time PCR, we demonstrate that adhesion of both fetal and adult ß-cells to collagen IV and vitronectin also results in the marked suppression of insulin gene transcription. Based on these findings, we contend that integrin-dependent adhesion and signaling in response to certain matrices can have a significant negative impact on insulin production by primary human ß-cells. Such responses were not found to be associated with cell death but may precede ß-cell dedifferentiation.

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