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Cited by 103Pancreatic function and diabetesCellular transport and secretionProtein Kinase Regulation and GTPase Signaling

Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin

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Asahara, S., Shibutani, Y., Teruyama, K., Inoue, H. Y., Kawada, Y., Etoh, H., Matsuda, T., Kimura-Koyanagi, M. +12 more·2013·Diabetologia
DOI 10.1007/s00125-013-2849-5PMC PMC3622740
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Abstract

AIMS/HYPOTHESIS: The small G-protein ras-related C3 botulinum toxin substrate 1 (RAC1) plays various roles in mammalian cells, such as in the regulation of cytoskeletal organisation, cell adhesion, migration and morphological changes. The present study examines the effects of RAC1 ablation on pancreatic beta cell function. METHODS: Isolated islets from pancreatic beta cell-specific Rac1-knockout (betaRac1(-/-)) mice and RAC1 knockdown INS-1 insulinoma cells treated with small interfering RNA were used to investigate insulin secretion and cytoskeletal organisation in pancreatic beta cells. RESULTS: BetaRac1(-/-) mice showed decreased glucose-stimulated insulin secretion, while there were no apparent differences in islet morphology. Isolated islets from the mice had blunted insulin secretion in response to high glucose levels. In RAC1 knockdown INS-1 cells, insulin secretion was also decreased in response to high glucose levels, consistent with the phenotype of betaRac1(-/-) mice. Even under high glucose levels, RAC1 knockdown INS-1 cells remained intact with F-actin, which inhibits the recruitment of the insulin granules, resulting in an inhibition of insulin secretion. CONCLUSIONS/INTERPRETATION: In RAC1-deficient pancreatic beta cells, F-actin acts as a barrier for insulin granules and reduces glucose-stimulated insulin secretion.

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  • Genetic knockdown of PAK1 and Rac1 leads to impaired 2nd phase insulin secretion.

    “Genetic knockdown of PAK1 and Rac1 leads to impaired 2nd phase insulin secretion (24, 720).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [24]

    The Results report reduced glucose-stimulated insulin secretion after RAC1 knockdown in INS-1 cells, and the Discussion states that only second-phase secretion was significantly reduced in beta-cell-specific Rac1-knockout mice. The paper mentions PAK1 as a RAC1 effector but does not report PAK1 knockdown or show that it impairs second-phase secretion. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Glucose-induced remodeling of the submembrane actin network depends on glucose metabolism and is controlled by small GTPases such as Cdc42.

    “It depends on glucose metabolism and is controlled by small GTPases such as Cdc42 (24, 720).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [24]

    The Results section reports that glucose stimulation depolymerises F-actin in INS-1 cells, and the Discussion says CDC42 has been reported to regulate F-actin remodelling in pancreatic beta-cell lines. Neither passage establishes that the remodelling depends on glucose metabolism, rather than glucose stimulation. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Glucose-induced remodeling of the submembrane actin network is required for the full insulin secretory response.

    “Glucose-induced remodeling of the submembrane actin network is required for the full insulin secretory response.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [24]

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Research works printed but not linked: 42

  1. [1]Orci L Gabbay KH Malaisse WJ Pancreatic beta-cell web: its possible role in insulin secretion Science 1972 175 1128 1130 10.1126/science.175.4026.1128 4551150 · DOI
  2. [2]Konstantinova I Nikolova G Ohara-Imaizumi M EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets Cell 2007 129 359 370 10.1016/j.cell.2007.02.044 17448994 · DOI
  3. [3]Wang Z Oh E Thurmond DC Glucose-stimulated Cdc42 signaling is essential for the second phase of insulin secretion J Biol Chem 2007 282 9536 9546 10.1074/jbc.M610553200 17289663 PMC2396332 · DOI · Paper page
  4. [4]Kasai K Ohara-Imaizumi M Takahashi N Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation J Clin Invest 2005 115 388 396 15690086 PMC546426
  5. [5]Kowluru A Small G proteins in islet beta-cell function Endocr Rev 2010 31 52 78 10.1210/er.2009-0022 19890090 PMC2852207 · DOI
  6. [6]Kowluru A Friendly, and not so friendly, roles of Rac1 in islet beta-cell function: lessons learnt from pharmacological and molecular biological approaches Biochem Pharmacol 2011 81 965 975 10.1016/j.bcp.2011.01.013 21300027 PMC3073707 · DOI
  7. [7]Veluthakal R Kaur H Goalstone M Kowluru A Dominant-negative alpha-subunit of farnesyl- and geranyltransferase inhibits glucose-stimulated, but not KCl-stimulated, insulin secretion in INS 832/13 cells Diabetes 2007 56 204 210 10.2337/db06-0668 17192483 · DOI
  8. [8]Li J Luo R Kowluru A Li G Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 beta-cells Am J Physiol Endocrinol Metab 2004 286 E818 E827 10.1152/ajpendo.00307.2003 14736704 · DOI
  9. [9]Kassai H Terashima T Fukaya M Rac1 in cortical projection neurons is selectively required for midline crossing of commissural axonal formation Eur J Neurosci 2008 28 257 267 10.1111/j.1460-9568.2008.06343.x 18702697 · DOI
  10. [10]Herrera PL Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages Development 2000 127 2317 2322 10804174
  11. [11]Inoue H Ogawa W Ozaki M Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo Nat Med 2004 10 168 174 10.1038/nm980 14716305 · DOI · Paper page
  12. [12]Kido Y Burks DJ Withers D Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2 J Clin Invest 2000 105 199 205 10.1172/JCI7917 10642598 PMC377430 · DOI
  13. [13]Hashimoto N Kido Y Uchida T PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells J Clin Invest 2005 115 138 145 15630453 PMC539193
  14. [14]Shigeyama Y Kobayashi T Kido Y Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice Mol Cell Biol 2008 28 2971 2979 10.1128/MCB.01695-07 18316403 PMC2293082 · DOI
  15. [15]Kitamura T Kido Y Nef S Merenmies J Parada LF Accili D Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor Mol Cell Biol 2001 21 5624 5630 10.1128/MCB.21.16.5624-5630.2001 11463843 PMC87283 · DOI
  16. [16]Matsumoto M Ogawa W Akimoto K PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity J Clin Invest 2003 112 935 944 12975478 PMC193669
  17. [17]Miki T Minami K Shinozaki H Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility Diabetes 2005 54 1056 1063 10.2337/diabetes.54.4.1056 15793244 · DOI
  18. [18]Shibasaki T Takahashi H Miki T Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP Proc Natl Acad Sci USA 2007 104 19333 19338 10.1073/pnas.0707054104 18040047 PMC2148290 · DOI · Paper page
  19. [19]Yasuda T Shibasaki T Minami K Rim2alpha determines docking and priming states in insulin granule exocytosis Cell Metab 2010 12 117 129 10.1016/j.cmet.2010.05.017 20674857 · DOI · Paper page
  20. [20]Sugihara K Nakatsuji N Nakamura K Rac1 is required for the formation of three germ layers during gastrulation Oncogene 1998 17 3427 3433 10.1038/sj.onc.1202595 10030666 · DOI
  21. [21]Wicksteed B Brissova M Yan W Conditional gene targeting in mouse pancreatic beta-cells: analysis of ectopic Cre transgene expression in the brain Diabetes 2010 59 3090 3098 10.2337/db10-0624 20802254 PMC2992770 · DOI
  22. [22]Hashimoto N Kido Y Uchida T Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass Nat Genet 2006 38 589 593 10.1038/ng1774 16642023 · DOI
  23. [23]Pigeau GM Kolic J Ball BJ Insulin granule recruitment and exocytosis is dependent on p110gamma in insulinoma and human beta-cells Diabetes 2009 58 2084 2092 10.2337/db08-1371 19549714 PMC2731529 · DOI
  24. [24]Howell SL Tyhurst M Regulation of actin polymerization in rat islets of Langerhans Biochem J 1980 192 381 383 6171248 PMC1162347
  25. [25]Wang Z Pedersen E Basse A Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo Oncogene 2010 29 3362 3373 10.1038/onc.2010.95 20383193 · DOI
  26. [26]Sosa MS Lopez-Haber C Yang C Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer Mol Cell 2010 40 877 892 10.1016/j.molcel.2010.11.029 21172654 PMC3038344 · DOI
  27. [27]Hayashi-Takagi A Takaki M Graziane N Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1 Nat Neurosci 2010 13 327 332 10.1038/nn.2487 20139976 PMC2846623 · DOI · Paper page
  28. [28]JeBailey L Wanono O Niu W Roessler J Rudich A Klip A Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells Diabetes 2007 56 394 403 10.2337/db06-0823 17259384 · DOI
  29. [29]Ueda S Kitazawa S Ishida K Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma FASEB J 2010 24 2254 2261 10.1096/fj.09-137380 20203090 PMC4183928 · DOI
  30. [30]Benitah SA Frye M Glogauer M Watt FM Stem cell depletion through epidermal deletion of Rac1 Science 2005 309 933 935 10.1126/science.1113579 16081735 · DOI
  31. [31]Jayaram B Syed I Singh A Isoprenylcysteine carboxyl methyltransferase facilitates glucose-induced Rac1 activation, ROS generation and insulin secretion in INS 832/13 beta-cells Islets 2011 3 48 57 10.4161/isl.3.2.15016 21346419 PMC3092562 · DOI
  32. [33]Rorsman P Eliasson L Renstrom E Gromada J Barg S Gopel S The cell physiology of biphasic insulin secretion News Physiol Sci 2000 15 72 77 11390882
  33. [35]Rorsman P Renstrom E Insulin granule dynamics in pancreatic beta cells Diabetologia 2003 45 1029 1045 10.1007/s00125-003-1153-1 12879249 · DOI · Paper page
  34. [36]Howell SL Tyhurst M Interaction between insulin-granules and F-actin in vitro Biochem J 1979 178 367 371 220962 PMC1186524
  35. [37]Thurmond DC Gonelle-Gispert C Furukawa M Halban PA Pessin JE Glucose-stimulated insulin secretion is coupled to the interaction of actin with the t-SNARE (target membrane soluble N-ethymaleimide-sensitive factor attachment protein receptor protein) complex Mol Endocrinol 2003 17 732 742 10.1210/me.2002-0333 12554769 · DOI
  36. [38]Tomas A Yermen B Min L Pessin JE Halban PA Regulation of pancreatic beta-cell insulin secretion by actin cytoskeleton remodelling: role of gelsolin and cooperation with the MAPK signalling pathway J Cell Sci 2006 119 2156 2167 10.1242/jcs.02942 16638805 · DOI
  37. [39]Hammar E Tomas A Bosco D Halban PA Role of the Rho-ROCK (Rho-associated kinase) signaling pathway in the regulation of pancreatic beta-cell function Endocrinology 2009 150 2072 2079 10.1210/en.2008-1135 19106222 · DOI
  38. [40]Nie J Sun C Faruque O Synapses of Amphids Defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-cells J Biol Chem 2012 287 26435 26444 10.1074/jbc.M112.378372 22669945 PMC3406726 · DOI
  39. [41]Nevins AK Thurmond DC Glucose regulates the cortical actin network through modulation of Cdc42 cycling to stimulate insulin secretion Am J Physiol Cell Physiol 2003 285 C698 C710 12760905
  40. [43]Lim GE Xu M Sun J Jin T Brubaker PL The rho guanosine 5'-triphosphatase, cell division cycle 42, is required for insulin-induced actin remodeling and glucagon-like peptide-1 secretion in the intestinal endocrine L cell Endocrinology 2009 150 5249 5261 10.1210/en.2009-0508 19819966 · DOI
  41. [44]Toft-Nielsen MB Damholt MB Madsbad S Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients J Clin Endocrinol Metab 2001 86 3717 3723 10.1210/jc.86.8.3717 11502801 · DOI · Paper page
  42. [45]Lugari R Dei Cas A Ugolotti D Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes Horm Metab Res 2002 34 150 154 10.1055/s-2002-23199 11972305 · DOI

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Authors
Asahara, S., Shibutani, Y., Teruyama, K., Inoue, H. Y., Kawada, Y., Etoh, H., Matsuda, T., Kimura-Koyanagi, M., Hashimoto, N., Sakahara, M., Fujimoto, W., Takahashi, H., Ueda, S., Hosooka, T., Satoh, T., Inoue, H., Matsumoto, M., Aiba, A., Kasuga, M., & Kido, Y.
Affiliations
  • Kobe University (JP)
  • Kanazawa University (JP)
  • Japanese Foundation For Cancer Research (JP)
  • National Center for Global Health and Medicine (JP)
  • Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
Corresponding author
Kido, Y.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2013-02-15
Volume
56
Issue
5
Pages
1088-1097
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-013-2849-5
PMC
PMC3622740
OpenAlex
W2062056640
Cited by
103
References
3
Citations by year
2026: 3 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 18 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 4 · 2013: 4
FWCI
6.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetologia (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (18GS0317, 22590981)
  • Japan Society for the Promotion of Science (24657140, 22300106, 25461351, 23700832, 23650214, 22790860)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Rac1, glucose-stimulated insulin secretion, pancreatic beta cells, F-actin, cytoskeleton, small GTPases, beta-cell-specific knockout mice, INS-1 cells, islets
MeSH terms
Insulin Secretion, Animals, Cell Line, Hyperglycemia, Insulin, Male, Actin Cytoskeleton, Neuropeptides, Pancreas, Perfusion, RNA, Messenger, Mice, Knockout, rac1 GTP-Binding Protein, RNA Interference, RNA, Small Interfering, Tissue Culture Techniques, Insulin-Secreting Cells, Mice, Rats, Secretory Pathway

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