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Dynamin deficiency causes insulin secretion failure and hyperglycemia. Proc Natl Acad Sci U S A 2021 Aug 10;118(32)

Date

08/08/2021

Pubmed ID

34362840

Pubmed Central ID

PMC8364113

DOI

10.1073/pnas.2021764118

Scopus ID

2-s2.0-85112629945 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Pancreatic β cells operate with a high rate of membrane recycling for insulin secretion, yet endocytosis in these cells is not fully understood. We investigate this process in mature mouse β cells by genetically deleting dynamin GTPase, the membrane fission machinery essential for clathrin-mediated endocytosis. Unexpectedly, the mice lacking all three dynamin genes (DNM1, DNM2, DNM3) in their β cells are viable, and their β cells still contain numerous insulin granules. Endocytosis in these β cells is severely impaired, resulting in abnormal endocytic intermediates on the plasma membrane. Although insulin granules are abundant, their release upon glucose stimulation is blunted in both the first and second phases, leading to hyperglycemia and glucose intolerance in mice. Dynamin triple deletion impairs insulin granule exocytosis and decreases intracellular Ca2+ responses and granule docking. The docking defect is correlated with reduced expression of Munc13-1 and RIM1 and reorganization of cortical F-actin in β cells. Collectively, these findings uncover the role of dynamin in dense-core vesicle endocytosis and secretory capacity. Insulin secretion deficiency in the absence of dynamin-mediated endocytosis highlights the risk of impaired membrane trafficking in endocrine failure and diabetes pathogenesis.

Author List

Fan F, Wu Y, Hara M, Rizk A, Ji C, Nerad D, Tamarina N, Lou X

Author

Xuelin Lou PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Glucose
Calcium Signaling
Dynamin II
Dynamins
Endocytosis
Female
GTP-Binding Proteins
Hyperglycemia
Insulin-Secreting Cells
Male
Mice, Knockout
Mice, Transgenic
Nerve Tissue Proteins