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Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis
Fan Fan, … , Louis H. Philipson, Xuelin Lou
Fan Fan, … , Louis H. Philipson, Xuelin Lou
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4026-4041. https://doi.org/10.1172/JCI80652.
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Research Article Endocrinology Article has an altmetric score of 2

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

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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

Fan Fan, Chen Ji, Yumei Wu, Shawn M. Ferguson, Natalia Tamarina, Louis H. Philipson, Xuelin Lou

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Figure 7

Strong defect in CME and abnormal accumulation of endocytic intermediates in Dnm2 KO β cells.

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Strong defect in CME and abnormal accumulation of endocytic intermediate...
(A) Impaired transferrin uptake in Dnm2 KO β cells. Representative images after 10 minutes of transferrin uptake. (B) Relative changes of fluorescence intensity (n = 3 independent experiments, 6–12 β cells were analyzed from each group in each experiment; P < 0.01, 2-tailed t test). (C) Accumulated endocytic intermediates (arrows) adjacent to the PM in KO cells. Two clathrin-coated vesicles interlinked together through a narrow membrane tubule (arrowhead) are shown in the inset. (D and E) A gallery of endocytic intermediates from Dnm2 KO and control cells. Note the CCPs with elongated necks/tubules in KO. (F) Significant increase of CCPs in Dnm2 KO cells at rest (n = 22 and 36 EM sections for control and KO) and after 20 mM glucose stimulation (n = 29 and 20 for control and KO cells, respectively) (P < 0.005, 2-tailed t test). (G) 3D reconstruction of endocytic profiles in a Dnm2 KO β cell using EM tomography. Cells were stimulated with 20 mM glucose for 20 minutes at 37°C before fixation. Note the abundant CCPs (red) and the elongated, narrow tubules (light green) that connected the CCPs to the PM (dark green) directly or through a membrane expansion. (H and I) Simple CCPs with elongated tubules connected to the cell surface. (J–M) Complex structures of endocytic intermediates that connected to PM with large, branched membrane vacuoles. Scale bars: 2 μm (A); 200 nm (C and G); 100 nm (C, inset, D, and E); 50 nm (H–M). **P < 0.01, ***P < 0.005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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