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    Online Resource
    Online Resource
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Glucagon is synthesized and released by pancreatic α-cells and, along with insulin, maintains blood glucose levels within the physiological range. We seek to understand the impact of glucose on the biophysical properties of α-cells in T2D. We studied α-cells from human donors (34 nondiabetic, and 14 T2D) and from mice fed a high fat diet (HFD) by whole-cell patch-clamp electrophysiology, with and without combined single-cell RNA sequencing (patch-seq). We found that, opposite to what is observed in β-cells, depolarization-induced exocytosis and Ca2+-channel function is enhanced at low glucose (LG, 1 mM G) and suppressed at high glucose (HG, 5-20 mM G) in nondiabetic (ND) α-cells. This is reversed in α-cells from T2D donors, which display a β-cell-like phenotype where HG amplifies exocytosis and LG inhibits it. Using pharmacological antagonists of Ca2+ channels, we found that LG increases P/Q-type Ca2+ currents in human α-cells, which are specifically linked to glucagon exocytosis. Similar results were obtained from α-cells of HFD mice for 10-14 weeks, where α-cell exocytosis and glucagon secretion were both enhanced, while exocytosis shifted from a dependency on P/Q-type (α-cell-like) to L-type (β-cell-like) Ca2+ channels. Finally, given that the Ca2+ responsiveness of α-cells is variable (suggesting cell- to-cell heterogeneity) and the function of α-cells is dysregulated in diabetes, we applied combined computational approaches and single-cell RNA sequencing with patch-clamp analysis (patch-seq) to link single human α-cell function with transcriptomic profiles. We found distinct α-cell sub-populations in human islets that are either resistant to, or sensitive to, dysfunction in the form of a shift towards a more ’β-cell like’ functional phenotype in T2D. In all, we provide new information to understand normal function of α-cells and important determinants of glucagon secretion in health and diabetes. Disclosure X. Dai: None. J. Camunas Soler: None. L. Briant: None. A.F. Spigelman: None. Y. Hang: None. P. Rorsman: None. S. Kim: None. P. MacDonald: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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