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Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Lund University Diabetes Centre, Malmö, Sweden.
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2018 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 27, no 2, p. 470-478Article in journal (Refereed) Published
Abstract [en]

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D.

Place, publisher, year, edition, pages
2018. Vol. 27, no 2, p. 470-478
Keywords [en]
GLP-1, biphasic secretion, dense core vesicle, docking, exocytosis, genome-wide association, insulin secretion, priming, somatostatin, type 2 diabetes
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-341518DOI: 10.1016/j.cmet.2017.12.017ISI: 000424465200021PubMedID: 29414688OAI: oai:DiVA.org:uu-341518DiVA, id: diva2:1181839
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Society for Medical Research (SSMF)The Swedish Brain FoundationNovo NordiskErnfors FoundationAvailable from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-03-22Bibliographically approved
In thesis
1. Architecture and function of the insulin granule secretion machinery
Open this publication in new window or tab >>Architecture and function of the insulin granule secretion machinery
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin is released into the blood stream to normalize elevated blood glucose, for example after a meal. The hormone is synthesized by β-cells in the endocrine pancreas, and stored in small vesicles, known as secretory granules, until required. When glucose is elevated, these granules undergo regulated exocytosis and thereby secrete the hormone. The primary trigger for this is a glucose-dependent elevation in cytosolic Ca2+, which enters the cell through voltage-gated Ca2+ channels. Glucose-stimulated insulin secretion follows a biphasic timecourse, with a rapid 1st phase that lasts for a few minutes, followed by a slowly developing sustained 2nd phase. Compromised 1st phase secretion is an early sign of developing type-2 diabetes. Biphasic secretion is thought reflect the vastly different probabilities of individual insulin granules, but direct evidence for this is still lacking. In this thesis, high resolution TIRF microscopy was used to identify rate limiting steps for insulin granule exocytosis in health and in type-2 diabetes, and to understand these steps at the molecular level. It is shown that granule docking is critical for sustained insulin secretion. In β-cells from type-2 diabetic donors, docking is compromised and no longer responsive to glucose. Expression analysis in a large donor cohort suggests that this is due to decreased expression of proteins involved in the docking step. One of these proteins, the SNARE protein syntaxin-1, is well-known to cluster at the site of docked granules, which initiates the formation of functional release sites. Analysis using a series of syntaxin-1 mutations indicates that this clustering depends on specific features in its N-terminal Habc domain and involves binding of the S/M protein munc-18. The data suggest that the closed conformation of syntaxin-1 mediates the interaction between granule and plasma membrane. Finally, it is shown that voltage-gated L-type Ca2+ channels are slowly recruited to the sites of docked granules, which depends on interaction with the granule priming factor Munc13. This arrangement leads to localized the Ca2+ influx near a subset of the docked granules, which dramatically increases their release probability. Importantly, the interaction between Ca2+ channels and granules fails in type-2 diabetic β cells. In summary, the thesis highlights the importance of the spatial organization of the secretory machinery for adequate insulin secretion, and suggests that defects in this process partly underlie the disturbed blood glucose regulation in type-2 diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 34
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1440
Keywords
Docking, Syntaxin-1A, Voltage-gated Ca2+ Channels, Exocytosis, Type-2 Diabetes
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-344789 (URN)978-91-513-0264-5 (ISBN)
Public defence
2018-04-23, A3:117a, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2018-03-26 Created: 2018-03-11 Last updated: 2018-04-24

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Gandasi, Nikhil RYin, PengOmar-Hmeadi, MuhmmadBarg, Sebastian

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