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Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Author

Listed:
  • Muhmmad Omar-Hmeadi

    (Uppsala University)

  • Per-Eric Lund

    (Uppsala University)

  • Nikhil R. Gandasi

    (Uppsala University)

  • Anders Tengholm

    (Uppsala University)

  • Sebastian Barg

    (Uppsala University)

Abstract

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.

Suggested Citation

  • Muhmmad Omar-Hmeadi & Per-Eric Lund & Nikhil R. Gandasi & Anders Tengholm & Sebastian Barg, 2020. "Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15717-8
    DOI: 10.1038/s41467-020-15717-8
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    Cited by:

    1. Lihua Chen & Nannan Wang & Tongran Zhang & Feng Zhang & Wei Zhang & Hao Meng & Jingyi Chen & Zhiying Liao & Xiaopeng Xu & Zhuo Ma & Tao Xu & Huisheng Liu, 2024. "Directed differentiation of pancreatic δ cells from human pluripotent stem cells," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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