title: Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis.
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.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Chen
authors.initials: C
authors.lastname: Ji
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ferguson
authors.forename: Natalia
authors.initials: N
authors.lastname: Tamarina
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Xuelin
authors.initials: X
authors.lastname: Lou
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D022163:Clathrin-Coated Vesicles / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000378:metabolism; D034285:Dynamin II / Q000172:deficiency / Q000502:physiology*; D004705:Endocytosis; D005089:Exocytosis; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000199:Actins; D001786:Blood Glucose; D007328:Insulin; D034285:Dynamin II