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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

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 6

Impaired exocytosis-endocytosis coupling in β cells in the absence of dynamin 2.

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Impaired exocytosis-endocytosis coupling in β cells in the absence of dy...
(A–E) Real-time Cm recordings showed endocytosis heterogeneity in amplitude and kinetics in different wild-type β cells. Arrows indicate the depolarizing pulse (0 mV, 1-second pulse in A–D; 0.5-second pulse in E); arrowheads in E indicate the large, stepwise Cm decreases. (F) Average Cm traces triggered by a single depolarization (0 mV, 1 second) from control (n = 15 cells) and Dnm2 KO cells (n = 14). The time constants of Cm decays are 2.7 seconds and 4.3 seconds for control and KO cells, respectively. The right panel shows the normalized Cm traces. Note the slower Cm decay and incomplete Cm recovery in KO cells. (G) The amplitude and speed of Cm decay at 2 seconds (P < 0.01) and 10 seconds (P < 0.005) after the depolarization (n = 15 and 14 for control and KO, respectively, unpaired 2-tailed t test). (H) Exocytosis-dominant (type-1) and endocytosis-dominant (type-2) Cm changes elicited by a train of pulses (ten 500-ms pulses, 0 mV, 1 Hz) in different β cells from wild-type mice. (I) The average Cm traces from control (n = 16) and Dnm2 KO (n = 21) groups. (J–L) Cumulative exocytosis and endocytosis and endocytosis rate during the train stimulation. **P < 0.01, ***P < 0.005.

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

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