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Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. J Clin Invest 2015 Nov 02;125(11):4026-41

Date

09/29/2015

Pubmed ID

26413867

Pubmed Central ID

PMC4639984

DOI

10.1172/JCI80652

Scopus ID

2-s2.0-84946760942 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

Alterations in insulin granule exocytosis and endocytosis are paramount to pancreatic β cell dysfunction in diabetes mellitus. Here, using temporally controlled gene ablation specifically in β cells in mice, we identified an essential role of dynamin 2 GTPase in preserving normal biphasic insulin secretion and blood glucose homeostasis. Dynamin 2 deletion in β cells caused glucose intolerance and substantial reduction of the second phase of glucose-stimulated insulin secretion (GSIS); however, mutant β cells still maintained abundant insulin granules, with no signs of cell surface expansion. Compared with control β cells, real-time capacitance measurements demonstrated that exocytosis-endocytosis coupling was less efficient but not abolished; clathrin-mediated endocytosis (CME) was severely impaired at the step of membrane fission, which resulted in accumulation of clathrin-coated endocytic intermediates on the plasma membrane. Moreover, dynamin 2 ablation in β cells led to striking reorganization and enhancement of actin filaments, and insulin granule recruitment and mobilization were impaired at the later stage of GSIS. Together, our results demonstrate that dynamin 2 regulates insulin secretory capacity and dynamics in vivo through a mechanism depending on CME and F-actin remodeling. Moreover, this study indicates a potential pathophysiological link between endocytosis and diabetes mellitus.

Author List

Fan F, Ji C, Wu Y, Ferguson SM, Tamarina N, Philipson LH, 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

Actin Cytoskeleton
Actins
Animals
Blood Glucose
Clathrin-Coated Vesicles
Cytoplasmic Granules
Dynamin II
Endocytosis
Exocytosis
Homeostasis
Insulin
Insulin-Secreting Cells
Mice
Mice, Knockout