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Nguyen, Phuoc My
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Xie, B., Nguyen, P. M. & Idevall-Hagren, O. (2019). Feedback regulation of insulin secretion by extended synaptotagmin-1. The FASEB Journal, 33(4), 4716-4728
Öppna denna publikation i ny flik eller fönster >>Feedback regulation of insulin secretion by extended synaptotagmin-1
2019 (Engelska)Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, nr 4, s. 4716-4728Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Endoplasmic reticulum (ER)-plasma membrane (PM) contacts are dynamic structures with important roles in the regulation of calcium (Ca2+) and lipid homeostasis. The extended synaptotagmins (E-Syts) are ER-localized lipid transport proteins that interact with PM phosphatidylinositol 4,5-bisphosphate in a Ca2+-dependent manner. E-Syts bidirectionally transfer glycerolipids, including diacylglycerol (DAG), between the 2 juxtaposed membranes, but the biologic significance of this transport is still unclear. Using insulin-secreting cells and live-cell imaging, we now show that Ca2+-triggered exocytosis of insulin granules is followed, in sequence, by PM DAG formation and E-Syt1 recruitment. E-Syt1 counteracted the depolarization-induced DAG formation through a mechanism that required both voltage-dependent Ca2+ influx and Ca2+ release from the ER. E-Syt1 knockdown resulted in prolonged accumulation of DAG in the PM, resulting in increased glucose-stimulated insulin secretion. We conclude that Ca2+-triggered exocytosis is temporally coupled to Ca2+-triggered E-Syt1 PM recruitment and removal of DAG to negatively regulate the same process.

Nyckelord
Ca2+, beta-cell, membrane contact sites, TMEM24, PKC
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:uu:diva-382253 (URN)10.1096/fj.201801878R (DOI)000462888500007 ()30589572 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet
Tillgänglig från: 2019-05-03 Skapad: 2019-05-03 Senast uppdaterad: 2020-03-22Bibliografiskt granskad
Nguyen, P. M., Gandasi, N., Xie, B., Sugahara, S., Xu, Y. & Idevall Hagren, O. (2019). The PI(4)P phosphatase Sac2 controls insulin granule docking and release. Journal of Cell Biology, 218(11), 3714-3729
Öppna denna publikation i ny flik eller fönster >>The PI(4)P phosphatase Sac2 controls insulin granule docking and release
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2019 (Engelska)Ingår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 218, nr 11, s. 3714-3729Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Insulin granule biogenesis involves transport to, and stable docking at, the plasma membrane before priming and fusion. Defects in this pathway result in impaired insulin secretion and are a hallmark of type 2 diabetes. We now show that the phosphatidylinositol 4-phosphate phosphatase Sac2 localizes to insulin granules in a substrate-dependent manner and that loss of Sac2 results in impaired insulin secretion. Sac2 operates upstream of granule docking, since loss of Sac2 prevented granule tethering to the plasma membrane and resulted in both reduced granule density and number of exocytic events. Sac2 levels correlated positively with the number of docked granules and exocytic events in clonal beta cells and with insulin secretion in human pancreatic islets, and Sac2 expression was reduced in islets from type 2 diabetic subjects. Taken together, we identified a phosphoinositide switch on the surface on insulin granules that is required for stable granule docking at the plasma membrane and impaired in human type 2 diabetes.

Nationell ämneskategori
Endokrinologi och diabetes Cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-397680 (URN)10.1083/jcb.201903121 (DOI)000494843800017 ()31533953 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, MH-2015-03087
Tillgänglig från: 2019-11-28 Skapad: 2019-11-28 Senast uppdaterad: 2019-11-28Bibliografiskt granskad
Nguyen, P. M., Gandasi, N. R. & Idevall-Hagren, O. (2018). The lipid phosphatase INPP5F regulates insulin secretion. Paper presented at 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY. Diabetologia, 61, S197-S197
Öppna denna publikation i ny flik eller fönster >>The lipid phosphatase INPP5F regulates insulin secretion
2018 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S197-S197Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
Springer, 2018
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-367130 (URN)000443556002190 ()
Konferens
54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY
Forskningsfinansiär
Vetenskapsrådet
Tillgänglig från: 2018-11-29 Skapad: 2018-11-29 Senast uppdaterad: 2018-11-29Bibliografiskt granskad
Nguyen, P. M., Xie, B. & Idevall-Hagren, O. (2016). Plasma membrane PI(4,5)P-2 controls Ca2+-influx in clonal beta cells. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S189-S190
Öppna denna publikation i ny flik eller fönster >>Plasma membrane PI(4,5)P-2 controls Ca2+-influx in clonal beta cells
2016 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, s. S189-S190Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
SPRINGER, 2016
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-322050 (URN)000398373701191 ()
Konferens
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Tillgänglig från: 2017-05-16 Skapad: 2017-05-16 Senast uppdaterad: 2017-05-16Bibliografiskt granskad
Xie, B., Nguyen, P. M., Thonig, A. & Idevall-Hagren, O. (2016). Plasma membrane PI(4,5)P-2 is required for normal glucose-stimulated insulin secretion. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S219-S219
Öppna denna publikation i ny flik eller fönster >>Plasma membrane PI(4,5)P-2 is required for normal glucose-stimulated insulin secretion
2016 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, s. S219-S219Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
SPRINGER, 2016
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-322055 (URN)000398373701255 ()
Konferens
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Forskningsfinansiär
Vetenskapsrådet
Tillgänglig från: 2017-05-16 Skapad: 2017-05-16 Senast uppdaterad: 2017-05-16Bibliografiskt granskad
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