Advertisement

Diabetologia

pp 1–15 | Cite as

DOC2B promotes insulin sensitivity in mice via a novel KLC1-dependent mechanism in skeletal muscle

  • Jing Zhang
  • Eunjin Oh
  • Karla E. Merz
  • Arianne Aslamy
  • Rajakrishnan Veluthakal
  • Vishal A. Salunkhe
  • Miwon Ahn
  • Ragadeepthi Tunduguru
  • Debbie C. ThurmondEmail author
Article

Abstract

Aims/hypothesis

Skeletal muscle accounts for >80% of insulin-stimulated glucose uptake; dysfunction of this process underlies insulin resistance and type 2 diabetes. Insulin sensitivity is impaired in mice deficient in the double C2 domain β (DOC2B) protein, while whole-body overexpression of DOC2B enhances insulin sensitivity. Whether insulin sensitivity in the skeletal muscle is affected directly by DOC2B or is secondary to an effect on other tissues is unknown; the underlying molecular mechanisms also remain unclear.

Methods

Human skeletal muscle samples from non-diabetic or type 2 diabetic donors were evaluated for loss of DOC2B during diabetes development. For in vivo analysis, new doxycycline-inducible skeletal-muscle-specific Doc2b-overexpressing mice fed standard or high-fat diets were evaluated for insulin and glucose tolerance, and insulin-stimulated GLUT4 accumulation at the plasma membrane (PM). For in vitro analyses, a DOC2B-overexpressing L6-GLUT4-myc myoblast/myotube culture system was coupled with an insulin resistance paradigm. Biochemical and molecular biology methods such as site-directed mutagenesis, co-immunoprecipitation and mass spectrometry were used to identify the molecular mechanisms linking insulin stimulation to DOC2B.

Results

We identified loss of DOC2B (55% reduction in RNA and 40% reduction in protein) in the skeletal muscle of human donors with type 2 diabetes. Furthermore, inducible enrichment of DOC2B in skeletal muscle of transgenic mice enhanced whole-body glucose tolerance (AUC decreased by 25% for female mice) and peripheral insulin sensitivity (area over the curve increased by 20% and 26% for female and male mice, respectively) in vivo, underpinned by enhanced insulin-stimulated GLUT4 accumulation at the PM. Moreover, DOC2B enrichment in skeletal muscle protected mice from high-fat-diet-induced peripheral insulin resistance, despite the persistence of obesity. In L6-GLUT4-myc myoblasts, DOC2B enrichment was sufficient to preserve normal insulin-stimulated GLUT4 accumulation at the PM in cells exposed to diabetogenic stimuli. We further identified that DOC2B is phosphorylated on insulin stimulation, enhancing its interaction with a microtubule motor protein, kinesin light chain 1 (KLC1). Mutation of Y301 in DOC2B blocked the insulin-stimulated phosphorylation of DOC2B and interaction with KLC1, and it blunted the ability of DOC2B to enhance insulin-stimulated GLUT4 accumulation at the PM.

Conclusions/interpretation

These results suggest that DOC2B collaborates with KLC1 to regulate insulin-stimulated GLUT4 accumulation at the PM and regulates insulin sensitivity. Our observation provides a basis for pursuing DOC2B as a novel drug target in the muscle to prevent/treat type 2 diabetes.

Keywords

DOC2B Glucose homeostasis GLUT4 Insulin sensitivity KLC1 Obesity Skeletal muscle Type 2 diabetes 

Abbreviations

2-DG

2-Deoxyglucose

DOC2B

Double C2 domain β

Dox

Doxycycline

GFP

Green fluorescent protein

HFD

High-fat diet

InsRes

Insulin resistance (as experimentally induced in vitro)

INSR

Insulin receptor

IPGTT

Intraperitoneal glucose tolerance test

IPITT

Intraperitoneal insulin tolerance test

KLC1

Kinesin light chain 1

MID

Munc13-interacting domain

MOI

Multiplicity of infection

NDRI

National Disease Research Interchange

PM

Plasma membrane

pV

Pervanadate

rtTA

Reverse tetracycline transactivator

skmDoc2b-dTg

Doxycycline-inducible skeletal-muscle-specific Doc2b overexpression

SNARE

Soluble N-ethylmaleimide-sensitive factor-attachment protein receptor

STX4

Syntaxin 4

STXBP

Syntaxin binding protein

TPR

Tetratricopeptide repeats

TRE

Tetracycline-responsive element

t-SNARE

Target-associated SNARE

WT

Wild type

Notes

Acknowledgements

We are grateful to E. Olson (Department of Cellular and Molecular Endocrinology, City of Hope, Duarte, CA, USA) for technical support and to N. Linford (Department of Cellular and Molecular Endocrinology, City of Hope, Duarte, CA, USA) for editing assistance. Research reported in this publication also includes work performed in the Multi-omics Mass Spectrometry & Biomarker Discovery Core, Integrative Genomics and Bioinformatics Core, Drug Discovery and Structural Biology Core, the Light Microscopy/Digital Imaging Core and the Comprehensive Metabolic Phenotyping Core at City of Hope (Duarte, CA, USA), all supported by a Cancer Center Support Grant from the National Cancer Institute to City of Hope. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Parts of this work were presented at the Federation of American Societies for Experimental Biology (FASEB) science research conference, Glucose Transport: Gateway for Metabolic Systems Biology, July 2017.

Contribution statement

JZ performed the majority of the studies, contributed to discussion and wrote and edited the manuscript. EO designed and generated the TRE-Doc2b+/− mice and contributed to the analysis of serum analytes and to the manuscript revision and discussion. KEM assisted with the design of the myotube viral transduction paradigm, the co-immunoprecipitation experiments and IPGTT studies of the obese mice and contributed to the manuscript revision and discussion. AA, RV and VAS assisted with in vivo studies and contributed to manuscript revision and discussion. RT assisted with L6-mycGLUT4 cell culture and manuscript revision and discussion. MA generated the Doc2b adenovirus and contributed to manuscript revision and discussion. DCT conceived the study, contributed to the discussion and wrote, reviewed and edited the manuscript. All authors read and approved the final version of the manuscript. DCT is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was supported by grants from: the National Institutes of Health, including from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK067912; R01 DK102233; R01 DK112917 to DCT); the American Heart Association (17POST33661194, to JZ; 15PRE21970002 to RT); and the National Cancer Institute (P30CA33572). This work was also supported by the Indiana Clinical and Translational Science Institute (predoctoral fellowship to AA). Additional financial support was provided to DCT through City of Hope: the Ruth and Robert Lanman Endowment, the George Schaeffer award and an Excellence award.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4824_MOESM1_ESM.pdf (522 kb)
ESM 1 (PDF 521 kb)

References

  1. 1.
    Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46(1):3–19.  https://doi.org/10.1007/s00125-002-1009-0 CrossRefPubMedGoogle Scholar
  2. 2.
    DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(Suppl 2):S157–S163.  https://doi.org/10.2337/dc09-S302 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jaldin-Fincati JR, Pavarotti M, Frendo-Cumbo S, Bilan PJ, Klip A (2017) Update on GLUT4 vesicle traffic: a cornerstone of insulin action. Trends Endocrinol Metab 28(8):597–611.  https://doi.org/10.1016/j.tem.2017.05.002 CrossRefPubMedGoogle Scholar
  4. 4.
    Fukuda N, Emoto M, Nakamori Y et al (2009) DOC2B: a novel syntaxin-4 binding protein mediating insulin-regulated GLUT4 vesicle fusion in adipocytes. Diabetes 58(2):377–384.  https://doi.org/10.2337/db08-0303 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Miyazaki M, Emoto M, Fukuda N et al (2009) DOC2b is a SNARE regulator of glucose-stimulated delayed insulin secretion. Biochem Biophys Res Commun 384(4):461–465.  https://doi.org/10.1016/j.bbrc.2009.04.133 CrossRefPubMedGoogle Scholar
  6. 6.
    Ke B, Oh E, Thurmond DC (2007) Doc2β is a novel Munc18c-interacting partner and positive effector of syntaxin 4-mediated exocytosis. J Biol Chem 282(30):21786–21797.  https://doi.org/10.1074/jbc.M701661200 CrossRefPubMedGoogle Scholar
  7. 7.
    Groffen AJ, Martens S, Diez Arazola R et al (2010) Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science 327(5973):1614–1618.  https://doi.org/10.1126/science.1183765 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yao J, Gaffaney JD, Kwon SE, Chapman ER (2011) Doc2 is a Ca2+ sensor required for asynchronous neurotransmitter release. Cell 147(3):666–677.  https://doi.org/10.1016/j.cell.2011.09.046 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ramalingam L, Oh E, Yoder SM et al (2012) Doc2b is a key effector of insulin secretion and skeletal muscle insulin sensitivity. Diabetes 61(10):2424–2432.  https://doi.org/10.2337/db11-1525 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Li J, Cantley J, Burchfield JG et al (2014) DOC2 isoforms play dual roles in insulin secretion and insulin-stimulated glucose uptake. Diabetologia 57(10):2173–2182.  https://doi.org/10.1007/s00125-014-3312-y CrossRefPubMedGoogle Scholar
  11. 11.
    Ramalingam L, Oh E, Thurmond DC (2014) Doc2b enrichment enhances glucose homeostasis in mice via potentiation of insulin secretion and peripheral insulin sensitivity. Diabetologia 57(7):1476–1484.  https://doi.org/10.1007/s00125-014-3227-7 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Keller MP, Choi Y, Wang P et al (2008) A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res 18(5):706–716.  https://doi.org/10.1101/gr.074914.107 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Aslamy A, Thurmond DC (2017) Exocytosis proteins as novel targets for diabetes prevention and/or remediation? Am J Physiol Regul Integr Comp Physiol 312(5):R739–R752.  https://doi.org/10.1152/ajpregu.00002.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chang L, Chiang SH, Saltiel AR (2004) Insulin signaling and the regulation of glucose transport. Mol Med 10:65–71PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kiraly-Borri CE, Morgan A, Burgoyne RD, Weller U, Wollheim CB, Lang J (1996) Soluble N-ethylmaleimide-sensitive-factor attachment protein and N-ethylmaleimide-insensitive factors are required for Ca2+-stimulated exocytosis of insulin. Biochem J 314(1):199–203.  https://doi.org/10.1042/bj3140199 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lang J (1999) Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Biochem 259(1-2):3–17.  https://doi.org/10.1046/j.1432-1327.1999.00043.x CrossRefPubMedGoogle Scholar
  17. 17.
    Sollner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE (1993) A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75(3):409–418.  https://doi.org/10.1016/0092-8674(93)90376-2 CrossRefPubMedGoogle Scholar
  18. 18.
    Michaeli L, Gottfried I, Bykhovskaia M, Ashery U (2017) Phosphatidylinositol (4, 5)-bisphosphate targets double C2 domain protein B to the plasma membrane. Traffic 18(12):825–839.  https://doi.org/10.1111/tra.12528 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Martens S, McMahon HT (2011) C2 domains and membrane fusion. Curr Top Membr 68:141–159CrossRefGoogle Scholar
  20. 20.
    Yu H, Rathore SS, Davis EM, Ouyang Y, Shen J (2013) Doc2b promotes GLUT4 exocytosis by activating the SNARE-mediated fusion reaction in a calcium- and membrane bending-dependent manner. Mol Biol Cell 24(8):1176–1184.  https://doi.org/10.1091/mbc.e12-11-0810 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Friedrich R, Yeheskel A, Ashery U (2010) DOC2B, C2 domains, and calcium: a tale of intricate interactions. Mol Neurobiol 41(1):42–51.  https://doi.org/10.1007/s12035-009-8094-8 CrossRefPubMedGoogle Scholar
  22. 22.
    Jewell JL, Oh E, Ramalingam L et al (2011) Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis. J Cell Biol 193(1):185–199.  https://doi.org/10.1083/jcb.201007176 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Orita S, Sasaki T, Naito A et al (1995) Doc2: a novel brain protein having two repeated C2-like domains. Biochem Biophys Res Commun 206(2):439–448.  https://doi.org/10.1006/bbrc.1995.1062 CrossRefPubMedGoogle Scholar
  24. 24.
    Sakaguchi G, Orita S, Maeda M, Igarashi H, Takai Y (1995) Molecular cloning of an isoform of Doc2 having two C2-like domains. Biochem Biophys Res Commun 217(3):1053–1061.  https://doi.org/10.1006/bbrc.1995.2876 CrossRefPubMedGoogle Scholar
  25. 25.
    Naito A, Orita S, Wanaka A et al (1997) Molecular cloning of mouse Doc2α and distribution of its mRNA in adult mouse brain. Brain Res Mol Brain Res 44(2):198–204.  https://doi.org/10.1016/S0169-328X(96)00198-2 CrossRefPubMedGoogle Scholar
  26. 26.
    Lundby A, Secher A, Lage K et al (2012) Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun 3(1):876.  https://doi.org/10.1038/ncomms1871 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Luo W, Slebos RJ, Hill S et al (2008) Global impact of oncogenic Src on a phosphotyrosine proteome. J Proteome Res 7(8):3447–3460.  https://doi.org/10.1021/pr800187n CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hornbeck PV, Kornhauser JM, Tkachev S et al (2012) PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res 40(D1):D261–D270.  https://doi.org/10.1093/nar/gkr1122 CrossRefPubMedGoogle Scholar
  29. 29.
    Shimoda Y, Okada S, Yamada E, Pessin JE, Yamada M (2015) Tctex1d2 is a negative regulator of GLUT4 translocation and glucose uptake. Endocrinology 156(10):3548–3558.  https://doi.org/10.1210/en.2015-1120 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nagano F, Orita S, Sasaki T et al (1998) Interaction of Doc2 with tctex-1, a light chain of cytoplasmic dynein. Implication in dynein-dependent vesicle transport. J Biol Chem 273(46):30065–30068.  https://doi.org/10.1074/jbc.273.46.30065 CrossRefPubMedGoogle Scholar
  31. 31.
    Ramalingam L, Lu J, Hudmon A, Thurmond DC (2014) Doc2b serves as a scaffolding platform for concurrent binding of multiple Munc18 isoforms in pancreatic islet beta-cells. Biochem J 464(2):251–258.  https://doi.org/10.1042/BJ20140845 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Aslamy A, Oh E, Olson EM et al (2018) Doc2b protects β-cells against inflammatory damage and enhances function. Diabetes 67(7):1332–1344.  https://doi.org/10.2337/db17-1352 CrossRefPubMedGoogle Scholar
  33. 33.
    Ueyama A, Yaworsky KL, Wang Q, Ebina Y, Klip A (1999) GLUT-4myc ectopic expression in L6 myoblasts generates a GLUT-4-specific pool conferring insulin sensitivity. Am J Phys 277:E572–E578CrossRefGoogle Scholar
  34. 34.
    McCarthy AM, Spisak KO, Brozinick JT, Elmendorf JS (2006) Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport. Am J Physiol Cell Physiol 291(5):C860–C868.  https://doi.org/10.1152/ajpcell.00107.2006 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chen G, Raman P, Bhonagiri P, Strawbridge AB, Pattar GR, Elmendorf JS (2004) Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J Biol Chem 279(38):39705–39709.  https://doi.org/10.1074/jbc.C400171200 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Tunduguru R, Zhang J, Aslamy A et al (2017) The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells. J Biol Chem 292(46):19034–19043.  https://doi.org/10.1074/jbc.M117.801340 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhou M, Sevilla L, Vallega G et al (1998) Insulin-dependent protein trafficking in skeletal muscle cells. Am J Phys 275:E187–E196Google Scholar
  38. 38.
    Grill MA, Bales MA, Fought AN, Rosburg KC, Munger SJ, Antin PB (2003) Tetracycline-inducible system for regulation of skeletal muscle-specific gene expression in transgenic mice. Transgenic Res 12(1):33–43.  https://doi.org/10.1023/A:1022119005836 CrossRefPubMedGoogle Scholar
  39. 39.
    Spurlin BA, Park SY, Nevins AK, Kim JK, Thurmond DC (2004) Syntaxin 4 transgenic mice exhibit enhanced insulin-mediated glucose uptake in skeletal muscle. Diabetes 53(9):2223–2231.  https://doi.org/10.2337/diabetes.53.9.2223 CrossRefPubMedGoogle Scholar
  40. 40.
    Morley TS, Xia JY, Scherer PE (2015) Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements. Nat Commun 6(1):7906.  https://doi.org/10.1038/ncomms8906 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P (2009) Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 150(5):2109–2117.  https://doi.org/10.1210/en.2008-0971 CrossRefPubMedGoogle Scholar
  42. 42.
    Winzell MS, Ahren B (2004) The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53(Suppl 3):S215–S219.  https://doi.org/10.2337/diabetes.53.suppl_3.S215 CrossRefPubMedGoogle Scholar
  43. 43.
    Williams LM, Campbell FM, Drew JE et al (2014) The development of diet-induced obesity and glucose intolerance in C57BL/6 mice on a high-fat diet consists of distinct phases. PLoS One 9(8):e106159.  https://doi.org/10.1371/journal.pone.0106159 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A 100(13):7569–7574.  https://doi.org/10.1073/pnas.1332633100 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sano H, Kane S, Sano E et al (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278(17):14599–14602.  https://doi.org/10.1074/jbc.C300063200 CrossRefPubMedGoogle Scholar
  46. 46.
    Pham K, Langlais P, Zhang X, Chao A, Zingsheim M, Yi Z (2012) Insulin-stimulated phosphorylation of protein phosphatase 1 regulatory subunit 12B revealed by HPLC-ESI-MS/MS. Proteome Sci 10(1):52.  https://doi.org/10.1186/1477-5956-10-52 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rodriguez E, Pulido N, Romero R, Arrieta F, Panadero A, Rovira A (2004) Phosphatidylinositol 3-kinase activation is required for sulfonylurea stimulation of glucose transport in rat skeletal muscle. Endocrinology 145(2):679–685.  https://doi.org/10.1210/en.2003-0755 CrossRefPubMedGoogle Scholar
  48. 48.
    Strommer L, Permert J, Arnelo U et al (1998) Skeletal muscle insulin resistance after trauma: insulin signaling and glucose transport. Am J Phys 275:E351–E358Google Scholar
  49. 49.
    Semiz S, Park JG, Nicoloro SM et al (2003) Conventional kinesin KIF5B mediates insulin-stimulated GLUT4 movements on microtubules. EMBO J 22(10):2387–2399.  https://doi.org/10.1093/emboj/cdg237 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Xiao Q, Miao B, Bi J, Wang Z, Li Y (2016) Prioritizing functional phosphorylation sites based on multiple feature integration. Sci Rep 6(1):24735.  https://doi.org/10.1038/srep24735 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Mertins P, Mani DR, Ruggles KV et al (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534(7605):55–62.  https://doi.org/10.1038/nature18003 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Zhu H, Lee HY, Tong Y et al (2012) Crystal structures of the tetratricopeptide repeat domains of kinesin light chains: insight into cargo recognition mechanisms. PLoS One 7(3):e33943.  https://doi.org/10.1371/journal.pone.0033943 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jewell JL, Oh E, Bennett SM, Meroueh SO, Thurmond DC (2008) The tyrosine phosphorylation of Munc18c induces a switch in binding specificity from syntaxin 4 to Doc2beta. J Biol Chem 283(31):21734–21746.  https://doi.org/10.1074/jbc.M710445200 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ramalingam L, Yoder SM, Oh E, Thurmond DC (2014) Munc18c: a controversial regulator of peripheral insulin action. Trends Endocrinol Metab 25(11):601–608.  https://doi.org/10.1016/j.tem.2014.06.010 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Takazawa K, Noguchi T, Hosooka T, Yoshioka T, Tobimatsu K, Kasuga M (2008) Insulin-induced GLUT4 movements in C2C12 myoblasts: evidence against a role of conventional kinesin motor proteins. Kobe J Med Sci 54:E14–E22PubMedGoogle Scholar
  56. 56.
    Guilherme A, Emoto M, Buxton JM et al (2000) Perinuclear localization and insulin responsiveness of GLUT4 requires cytoskeletal integrity in 3T3-L1 adipocytes. J Biol Chem 275(49):38151–38159.  https://doi.org/10.1074/jbc.M003432200 CrossRefPubMedGoogle Scholar
  57. 57.
    Fletcher LM, Welsh GI, Oatey PB, Tavare JM (2000) Role for the microtubule cytoskeleton in GLUT4 vesicle trafficking and in the regulation of insulin-stimulated glucose uptake. Biochem J 352(2):267–276.  https://doi.org/10.1042/bj3520267 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jing Zhang
    • 1
    • 2
  • Eunjin Oh
    • 1
  • Karla E. Merz
    • 1
  • Arianne Aslamy
    • 1
    • 3
  • Rajakrishnan Veluthakal
    • 1
  • Vishal A. Salunkhe
    • 1
  • Miwon Ahn
    • 1
  • Ragadeepthi Tunduguru
    • 1
    • 4
  • Debbie C. Thurmond
    • 1
    Email author
  1. 1.Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research InstituteBeckman Research Institute of City of HopeDuarteUSA
  2. 2.Anwita Biosciences IncSan CarlosUSA
  3. 3.Department of Cellular and Integrative PhysiologyIndiana University School of MedicineIndianapolisUSA
  4. 4.Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research InstituteBeckman Research Institute of City of HopeDuarteUSA

Personalised recommendations