Impact of defined matrix interactions on insulin production by cultured human β-cells: Effect on insulin content, secretion, and gene transcription

The impact of extracellular matrix on insulin production needs to be understood both to optimize the derivation of functional β-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 β-cells. The integrin-dependent adhesion of fetal β-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 β-cells. Inhibition of extracellular signal-regulated kinase activation abrogates matrix-induced insulin secretion and effectively preserves the insulin content of adherent β-cells. Using real-time PCR, we demonstrate that adhesion of both fetal and adult β-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 β-cells. Such responses were not found to be associated with cell death but may precede β-cell dedifferentiation.