Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins

Abstract

. Rac1 regulates glucose-induced insulin secretion through modulation of cytoskeleton organization in beta cells. Diabetes 57, Suppl. 1, A55. Balczon, R., Overstreet, K. A., Zinkowski, R. P., Haynes, A. and Appel, M. (1992).The identification, purification, and characterization of a pancreatic beta-cell form of the microtubule adenosine triphosphatase kinesin. Endocrinology 131, 331-336. Barg, S., Huang, P., Eliasson, L., Nelson, D. J., Obermuller, S., Rorsman, P., Thevenod, F. and Renstrom, E. (2001). Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification. J. Cell Sci. 114, 2145-2154. Barg, S., Eliasson, L., Renstrom, E. and Rorsman, P. (2002). A subset of 50 secretory granules in close contact with L-type Ca(2+) channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 51, S74-S82. Berglund, O. (1980). Different dynamics of insulin secretion in the perfused pancreas of mouse and rat. Acta Endocrinol. 93, 54-60. Journal of Cell Science 122 (7)Journal of Cell Science Journal of Cell Science

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…This study is the first demonstration to our knowledge that dynamin 2-mediated endocytosis regulates plasma glucose homeostasis through changing the insulin secretion capacity of β The molecular mechanisms underlying actin regulation of biphasic insulin secretion (10,61) are poorly understood. One possibility is that the reorganized F-actin inhibits insulin release as a physical barrier by impeding granule access to the PM or decrease RRP size, as proposed in chromaffin cells (62,63).…”

“…In patients with T2D, the second phase is strongly reduced and the first phase is nearly abolished (7). Multiple factors contribute to the biphasic nature of glucose-stimulated insulin secretion (GSIS), including distinct pools of insulin granules, metabolic signaling, and actin cytoskeleton remodeling (8)(9)(10)(11)(12). The granules docked to the PM, also known as the readily releasable pool (RRP) granules, mainly contribute to the first phase.…”

“…Direct total internal reflection fluorescence (TIRF) imaging suggests that the granules near the PM participate in the first phase and the "newcomer" granules mobilized from a reserve pool located a distance away from the PM produce the second phase of GSIS (12). Moreover, increasing evidence supports an emerging model in which the actin cytoskeleton plays a critical role in biphasic GSIS (10,11) through granule mobilization and recruitment from the reserve pool to the PM. Many actin remodeling molecules, such as the Rho GTPase family proteins Cdc42 (13) and RAC1 (14), PAK1 (15), N-WASP (16), and PPARβ/δ (17), selectively regulate the second phase of GSIS, and perturbations of microtubules (18) and kinesin-1 (19) disrupt the second phase.…”

Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton

“…However, in these cells the reinforcement of the Ca 2+ -dependent exocytosis depends on Rac2 (Abdel-Latif et al, 2005;Stratmann et al, 2010). In pancreatic b-cells, Cdc42 potentiates only the second, prolonged phase of insulin release in response to high glucose levels, and not the first phase (Wang and Thurmond, 2009). In HeLa cells, GTP hydrolysis by the Rho GTPase TC10, which is accelerated by the p190 Rho GAP, triggers regulated exocytosis (Kawase et al, 2006).…”

“…In PC12 cells, RhoA and Cdc42, respectively, induce inhibition and stimulation of actin remodeling and exocytosis of dense-core vesicles (Ory and Gasman, 2011). In pancreatic b-cells, Cdc42 binds directly to syntaxin 1 and VAMP2 (Wang and Thurmond, 2009). Phospholipids are also relevant in the modulation of exocytic events.…”