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High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

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Abstract

While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y13-specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y13 receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y13 plays an important role in beta cell apoptosis and suggest that autocrine/paracrine mechanisms, related to ADP and P2Y13 receptors, contribute to glucolipotoxicity.

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Acknowledgments

This study was supported by the Swedish Heart and Lung Foundation, Swedish Scientific Research Council, Diabetes Wellness Network, Sweden, The Vascular Wall Program and Lund University.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Cardiology, Lund University, 22185, Lund, Sweden

    Chanyuan Tan, Siv Svensson, David Erlinge & Björn Olde

  2. Department of Experimental Medical Science, Lund University, 22185, Lund, Sweden

    Ulrikke Voss

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  1. Chanyuan Tan
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  2. Ulrikke Voss
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  3. Siv Svensson
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  4. David Erlinge
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Correspondence to Björn Olde.

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Tan, C., Voss, U., Svensson, S. et al. High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor. Purinergic Signalling 9, 67–79 (2013). https://doi.org/10.1007/s11302-012-9331-6

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  • DOI: https://doi.org/10.1007/s11302-012-9331-6

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