Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. J Clin Invest 2015 Nov 02;125(11):4026-41
Date
09/29/2015Pubmed ID
26413867Pubmed Central ID
PMC4639984DOI
10.1172/JCI80652Scopus ID
2-s2.0-84946760942 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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 XAuthor
Xuelin Lou PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Actin CytoskeletonActins
Animals
Blood Glucose
Clathrin-Coated Vesicles
Cytoplasmic Granules
Dynamin II
Endocytosis
Exocytosis
Homeostasis
Insulin
Insulin-Secreting Cells
Mice
Mice, Knockout