American Diabetes Association
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Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Version 3 2020-11-10, 16:42
Version 2 2020-11-10, 15:56
Version 1 2020-11-10, 15:29
posted on 2020-11-10, 16:42 authored by Ada AdminAda Admin, Christian H. Burns, Belinda Yau, Anjelica Rodriguez, Jenna Triplett, Drew Maslar, You Sun An, Reini E.N. van der Welle, Ross G. Kossina, Max R. Fisher, Gregory W. Strout, Peter O. Bayguinov, Tineke Veenendaal, David Chitayat, James A.J. Fitzpatrick, Judith Klumperman, Melkam A. Kebede, Cedric S. Asensio
Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.


The Washington University Center for Cellular Imaging (WUCCI) gratefully acknowledges support from Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813 to JAJF), the Foundation for Barnes-Jewish Hospital (3770 to JAJF) and the Washington University Diabetes Research Center (DRC) (P30 DK020579). MAK is supported by a Jennie Mackenzie Philanthropic Fellowship, University of Sydney. Y.A. is a recipient of the Australian Postgraduate Scholarship. JK and RvdW are supported by the Deutsche Forschungs Gemeinshaft (DFG) FOR2625. This work was supported by American Diabetes Association grant #1-17-JDF-064 and by NIH grants R01 GM124035 and R15 GM116096 to CSA.