Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes [Elektronisk resurs]
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Omar-Hmeadi, Muhmmad (författare)
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Lund, Per-Eric (författare)
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Gandasi, Nikhil (författare)
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Tengholm, Anders, 1971- (författare)
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Barg, Sebastian, 1969- (författare)
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Barg (medarbetare)
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Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet (utgivare)
- Publicerad: 2020
- Engelska.
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Ingår i: Nature Communications. - 2041-1723. ; 11:1
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Sammanfattning
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- 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.
Ämnesord
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Cell and Molecular Biology (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska och farmaceutiska grundvetenskaper (hsv)
- Cell- och molekylärbiologi (hsv)
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- government publication (marcgt)
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Nature Communications