title: A Critical Role for β-Catenin in Modulating Levels of Insulin Secretion from β-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization.
abstract: The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases β-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that β-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of β-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating β-catenin from the plasma membrane pool to the nucleus. We show that β-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that β-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that β-catenin levels modulate Ca2+-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion.
authors: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.|the Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors: Brie
authors: B
authors: Sorrenson
authors: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors: Emmanuelle
authors: E
authors: Cognard
authors: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors: Kathryn L
authors: KL
authors: Lee
authors: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors: Waruni C
authors: WC
authors: Dissanayake
authors: the Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore 138667.
authors: Yanyun
authors: Y
authors: Fu
authors: the Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore 138667.
authors: Weiping
authors: W
authors: Han
authors: the Department of Medicine, St. Vincent's Hospital, Victoria Street, Sydney, New South Wales 2010, Australia, and.|the Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
authors: William E
authors: WE
authors: Hughes
authors: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand, peter.shepherd@auckland.ac.nz.|the Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors: Peter R
authors: PR
authors: Shepherd
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D052216:Glucagon-Like Peptide 1
keywords: Type 2 diabetes; Wnt signaling; beta cell (B-cell); beta-catenin (B-catenin); incretin; insulin secretion; islet