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Pancreatic β-Cell-Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion.

Citation
Burns, C. H., et al. “Pancreatic Β-Cell-Specific Deletion Of Vps41 Causes Diabetes Due To Defects In Insulin Secretion.”. Diabetes, pp. 436-448.
Center Washington University in St Louis
Author 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
Abstract

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 determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (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 β-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.

Year of Publication
2021
Journal
Diabetes
Volume
70
Issue
2
Number of Pages
436-448
Date Published
02/2021
ISSN Number
1939-327X
DOI
10.2337/db20-0454
Alternate Journal
Diabetes
PMID
33168621
PMCID
PMC7881869
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