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bioRxiv · 10.64898/2026.08.04.742875

Laminin-511 protects pancreatic β-cells from cytokine-induced death through integrin-mediated pro-survival signaling and modulation of protein kinase C δ

El-Dirani, C.·Shivananda Murthy, M. H.·Holcomb, K.·Gutierrez, G.·Starzel, R.·Pena, B.·Park, D.·Benninger, R. K.·Farnsworth, N. L.
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Abstract

During the progression of type 1 diabetes (T1D), the extracellular matrix (ECM) surrounding pancreatic islets is degraded concurrent with infiltration of autoreactive immune cells and {beta}-cell death. Among the lost ECM proteins, laminin-511 is known to be essential for islet survival under healthy and T1D associated conditions, including high levels of pro-inflammatory cytokines. However, the key {beta}-cell signaling pathways regulated by laminin and the contributions to T1D pathogenesis when these cues are lost are poorly understood. This study utilizes a biomimetic reverse thermal gel (RTG) with laminin-511 to determine if laminin protects {beta}-cells against cytokine-induced death and elucidate the signaling pathways involved. MIN6 cells, C57Bl/6 mouse islets and human islets were encapsulated in RTG scaffolds with laminin-511 and treated with a cytokine cocktail for 24 hours. Islet viability and the activities of several pro- and anti-apoptotic proteins were studied. Laminin-511 was shown to protect islets against cytokine-induced death by interacting with {beta}1 integrins and activating pro-survival Akt signaling. Pro-survival signaling was mediated by reduced activity of protein kinase C{delta} (PKC{delta}), a key mediator of cytokine-induced {beta}-cell death, at the cell membrane in the presence of laminin via reduced levels of diacylglycerol (DAG), a canonical activator of PKC{delta}. Taken together, these results demonstrate that laminin-511 is an essential factor in protecting {beta}-cells against cytokine-induced death by downregulation of membrane DAG, inhibiting activation of pro-apoptotic PKC{delta}. Our results suggest that loss of ECM in T1D may make {beta}-cells more susceptible to cytokine-induced death by increasing activation of PKC{delta}. HighlightsO_LILaminin-511 improves islet survival under cytokine treatment C_LIO_LIPro-survival Akt is upregulated by laminin-511 C_LIO_LIPro-apoptotic PKC{delta} activity is downregulated at the cell membrane by laminin-511 C_LIO_LILaminin-511 decreases membrane DAG levels leading to reduced PKC{delta} activation C_LIO_LILaminin-511 is an essential ECM component for islet survival during type 1 diabetes C_LI

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El-Dirani, C., Shivananda Murthy, M. H., Holcomb, K., Gutierrez, G., Starzel, R., Pena, B., Park, D., Benninger, R. K., Farnsworth, N. L.. 2026-08-05. Laminin-511 protects pancreatic β-cells from cytokine-induced death through integrin-mediated pro-survival signaling and modulation of protein kinase C δ. https://doi.org/10.64898/2026.08.04.742875

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