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Intra-islet α-cell Gs signaling promotes glucagon release

Author

Listed:
  • Liu Liu

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Kimberley El

    (Duke University)

  • Diptadip Dattaroy

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Luiz F. Barella

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Yinghong Cui

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Sarah M. Gray

    (Duke University)

  • Carla Guedikian

    (Duke University)

  • Min Chen

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Lee S. Weinstein

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Emily Knuth

    (University of Wisconsin-Madison)

  • Erli Jin

    (University of Wisconsin-Madison)

  • Matthew J. Merrins

    (University of Wisconsin-Madison)

  • Jeffrey Roman

    (University of Pennsylvania)

  • Klaus H. Kaestner

    (University of Pennsylvania)

  • Nicolai Doliba

    (University of Pennsylvania)

  • Jonathan E. Campbell

    (Duke University)

  • Jürgen Wess

    (National Institute of Diabetes and Digestive and Kidney Diseases)

Abstract

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell Gs signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell Gs signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α−cell Gs-coupled A2A adenosine receptors. Studies with α-cell-specific Gαs knockout mice showed that α-cell Gs also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched Gs-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

Suggested Citation

  • Liu Liu & Kimberley El & Diptadip Dattaroy & Luiz F. Barella & Yinghong Cui & Sarah M. Gray & Carla Guedikian & Min Chen & Lee S. Weinstein & Emily Knuth & Erli Jin & Matthew J. Merrins & Jeffrey Roma, 2024. "Intra-islet α-cell Gs signaling promotes glucagon release," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49537-x
    DOI: 10.1038/s41467-024-49537-x
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    References listed on IDEAS

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    1. Shicheng Zhang & Ryan H. Gumpper & Xi-Ping Huang & Yongfeng Liu & Brian E. Krumm & Can Cao & Jonathan F. Fay & Bryan L. Roth, 2022. "Molecular basis for selective activation of DREADD-based chemogenetics," Nature, Nature, vol. 612(7939), pages 354-362, December.
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