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Expression of insulin signalling components in the sensory epithelium of the human saccule

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Abstract

Several studies have demonstrated a link between diabetes and the dysfunction of the inner ear. Few studies, however, have reported the signalling mechanisms involved in metabolic control in human inner ear cells. Knowledge of the expression and role of the insulin receptor and downstream signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. Thus, the insulin receptor, insulin signalling components and selected cAMP signalling components are expressed in the human saccule. In addition to well-known mechanisms of diabetes complications, such as neuropathy and vascular lesions, the expression of these proteins in the saccule could have a role in the observed link between diabetes and balance/hearing disorders.

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Abbreviations

IRS1:

Insulin receptor substrate 1

PKB:

Protein kinase B

GLUT4:

Glucose-sensitive transporter 4

PDE:

Phosphodiesterase

V2R:

Vasopressin type 2 receptor

GFAP:

Glial fibrillary acidic protein

Aqp:

Aquaporin

PDE1C:

Calcium-sensitive cAMP/cGMP phosphodiesterase

References

  • Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203:1007–1019

    Article  PubMed  CAS  Google Scholar 

  • Agrawal Y, Carey JP, Della Santina CC, Schubert MC, Minor LB (2010) Diabetes, vestibular dysfunction, and falls: analyses from the National Health and Nutrition Examination Survey. Otol Neurotol 31:1445–1450

    Article  PubMed  Google Scholar 

  • Angunsri N, Taura A, Nakagawa T, Hayashi Y, Kitajiri S, Omi E, Ishikawa K, Ito J (2011) Insulin-like growth factor 1 protects vestibular hair cells from aminoglycosides. Neuroreport 22:38–43

    Article  PubMed  CAS  Google Scholar 

  • Bainbridge KE, Hoffman HJ, Cowie CC (2008) Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004. Ann Intern Med 149:1–10

    Article  PubMed  Google Scholar 

  • Bartolami S, Gaboyard S, Quentin J, Travo C, Cavalier M, Barhanin J, Chabbert C (2011) Critical roles of transitional cells and Na/K-ATPase in the formation of vestibular endolymph. J Neurosci 31:16541–16549

    Article  PubMed  CAS  Google Scholar 

  • Brand Y, Setz C, Levano S, Listyo A, Chavez E, Pak K, Sung M, Radojevic V, Ryan AF, Bodmer D (2011) Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro. BMC Neurosci 12:114

    Article  PubMed  CAS  Google Scholar 

  • Cediel R, Riquelme R, Contreras J, Díaz A, Varela-Nieto I (2006) Sensorineural hearing loss in insulin-like growth factor I-null mice: a new model of human deafness. Eur J Neurosci 23:587–590

    Article  PubMed  CAS  Google Scholar 

  • Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511

    Article  PubMed  CAS  Google Scholar 

  • Degerman E, Rauch U, Göransson O, Lindberg S, Hultgårdh A, Magnusson M (2011a) Identification of new signaling components in the sensory epithelium of human saccule. Front Neurol 2:48

    Article  PubMed  Google Scholar 

  • Degerman E, Ahmad F, Chung YW, Guirguis E, Omar B, Stenson L, Manganiello V (2011b) From PDE3B to the regulation of energy homeostasis. Curr Opin Pharmacol 11:676–682

    Article  PubMed  CAS  Google Scholar 

  • Edamatsu M, Kondo Y, Ando M (2011) Multiple expression of glucose transporters in the lateral wall of the cochlear duct studied by quantitative real-time PCR assay. Neurosci Lett 490:72–77

    Article  PubMed  CAS  Google Scholar 

  • Fauser C, Schimanski S, Wangemann P (2004) Localization of beta1-adrenergic receptors in the cochlea and the vestibular labyrinth. J Membr Biol 201:25–32

    Article  PubMed  CAS  Google Scholar 

  • Féraille E, Rousselot M, Rajerison R, Favre H (1995) Effect of insulin on Na+,K+-ATPase in rat collecting duct. J Physiol (Lond) 488:171–180

    Google Scholar 

  • Fernández C, Goldberg JM (1976) Physiology of peripheral neurons innervating otolith organs of the squirrel monkey. I. Response to static tilts and to long-duration centrifugal force. J Neurophysiol 39:970–984

    PubMed  Google Scholar 

  • Fernández C, Goldberg JM (1976) Physiology of peripheral neurons innervating otolith organs of the squirrel monkey. II. Directional selectivity and force-response relations.J Neurophysiol 39:985–995

    PubMed  Google Scholar 

  • Fernández C, Goldberg JM (1976) Physiology of peripheral neurons innervating otolith organs of the squirrel monkey. III. Response dynamics.J Neurophysiol 39:996–1008

    PubMed  Google Scholar 

  • Frisina ST, Mapes F, Kim S, Frisina DR, Frisina RD (2006) Characterization of hearing loss in aged type II diabetics. Hear Res 211:103–113

    Article  PubMed  Google Scholar 

  • Fujita T, Yamashita D, Katsunuma S, Hasegawa S, Tanimoto H, Nibu KI (2012) Increased inner ear susceptibility to noise injury in mice with streptozotocin-induced diabetes. Diabetes 61:2980–2986

    Article  PubMed  CAS  Google Scholar 

  • Fukushima H, Cureoglu S, Schachern PA, Kusunoki T, Oktay MF, Fukushima N, Paparella MM, Harada T (2005) Cochlear changes in patients with type 1 diabetes mellitus. Otolaryngol Head Neck Surg 133:100–106

    Article  PubMed  Google Scholar 

  • Fukushima H, Cureoglu S, Schachern PA, Paparella MM, Harada T, Oktay MF (2006) Effects of type 2 diabetes mellitus on cochlear structure in humans. Arch Otolaryngol Head Neck Surg 132:934–938

    Article  PubMed  Google Scholar 

  • Han JW, Zhan XR, Li XY, Xia B, Wang YY, Zhang J, Li BX (2010) Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats. World J Gastroenterol 16:6111–6118

    Article  PubMed  CAS  Google Scholar 

  • Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, Stolz DB, Land SR, Marconcini LA, Kliment CR, Jenkins KM, Beaulieu KA, Mouded M, Frank SJ, Wong KK, Shapiro SD (2010) Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 16:219–212

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa T, Naito Y, Taniguchi K (1995) Hearing impairment in WBN/Kob rats with spontaneous diabetes mellitus. Diabetologia 38:649–655

    Article  PubMed  CAS  Google Scholar 

  • Ishiyama A, Mowry SE, Lopez IA, Ishiyama G (2009) Immunohistochemical distribution of basement membrane proteins in the human inner ear from older subjects. Hear Res 254:1–14

    Article  PubMed  CAS  Google Scholar 

  • Ishiyama G, Lopez IA, Beltran-Parrazal L, Ishiyama A (2010) Immunohistochemical localization and mRNA expression of aquaporins in the macula utriculi of patients with Meniere’s disease and acoustic neuroma. Cell Tissue Res 340:407–419

    Article  PubMed  CAS  Google Scholar 

  • Kakarlapudi V, Sawyer R, Staecker H (2003) The effect of diabetes on sensorineural hearing loss. Otol Neurotol 24:382–386

    Article  PubMed  Google Scholar 

  • Khan KM, Drescher MJ, Hatfield JS, Ramakrishnan NA, Drescher DG (2007) Immunohistochemical localization of adrenergic receptors in the rat organ of Corti and spiral ganglion. J Neurosci Res 85:3000–3012

    Article  PubMed  CAS  Google Scholar 

  • Klagenberg KF, Zeigelboim BS, Jurkiewicz AL, Martins-Bassetto J (2007) Vestibulocochlear manifestations in patients with type I diabetes mellitus. Braz J Otorhinolaryngol 73:353–358

    PubMed  Google Scholar 

  • Knight LC, Saeed SR, Hradek GT, Schindler RA (1995) Insulin receptors on the endolymphatic sac: an autoradiographic study. Laryngoscope 105:635–638

    Article  PubMed  CAS  Google Scholar 

  • Lee HS, Kim KR, Chung WH, Cho YS, Hong SH (2008) Early sensorineural hearing loss in ob/ob mouse, an animal model of type 2 diabetes. Clin Exp Otorhinolaryngol 1:211–216

    Article  PubMed  Google Scholar 

  • Lerman-Garber I, Cuevas-Ramos D, Valdés S, Enríquez L, Lobato M, Osornio M, Escobedo AR, Pascual-Ramos V, Mehta R, Ramírez-Anguiano J, Gómez-Pérez FJ (2012) Sensorineural hearing loss—a common finding in early-onset type 2 diabetes mellitus. Endocr Pract 18:549–557

    Article  PubMed  Google Scholar 

  • Leto D, Saltiel AR (2012) Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 13:383–396

    Article  PubMed  CAS  Google Scholar 

  • Lisowska G, Namysłowski G, Morawski K, Strojek K (2001) Early identification of hearing impairment in patients with type 1 diabetes mellitus. Otol Neurotol 22:316–320

    Article  PubMed  CAS  Google Scholar 

  • Lopez IA, Ishiyama G, Lee M, Baloh RW, Ishiyama A (2007) Immunohistochemical localization of aquaporins in the human inner ear. Cell Tissue Res 328:453–460

    Article  PubMed  CAS  Google Scholar 

  • Maekawa C, Kitahara T, Kizawa K, Okazaki S, Kamakura T, Horii A, Imai T, Doi K, Inohara H, Kiyama H (2010) Expression and translocation of aquaporin-2 in the endolymphatic sac in patients with Meniere’s disease. J Neuroendocrinol 22:1157–1164

    Article  PubMed  CAS  Google Scholar 

  • Murillo-Cuesta S, Rodríguez-de la Rosa L, Cediel R, Lassaletta L, Varela-Nieto I (2011) The role of insulin-like growth factor-I in the physiopathology of hearing. Front Mol Neurosci 4:11

    Article  PubMed  CAS  Google Scholar 

  • Murillo-Cuesta S, Camarero G, González-Rodríguez A, De La Rosa LR, Burks DJ, Avendaño C, Valverde AM, Varela-Nieto I (2012) Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function. Mol Med 18:260–269

    Article  PubMed  CAS  Google Scholar 

  • Nakou M, Bertsias G, Stagakis I, Centola M, Tassiulas I, Hatziapostolou M, Kritikos I, Goulielmos G, Boumpas DT, Iliopoulos D (2010) Gene network analysis of bone marrow mononuclear cells reveals activation of multiple kinase pathways in human systemic lupus erythematosus. PLoS One 5:e13351

    Article  PubMed  Google Scholar 

  • Palacios S, Lalioti V, Martinez-Arca S, Chattopadhyay S, Sandoval IV (2001) Recycling of the insulin-sensitive glucose transporter GLUT4. Access of surface internalized GLUT4 molecules to the perinuclear storage compartment is mediated by the Phe5-Gln6-Gln7-Ile8 motif. J Biol Chem 276(5):3371–3383

    Article  PubMed  CAS  Google Scholar 

  • Perez R, Ziv E, Freeman S, Sichel JY, Sohmer H (2001) Vestibular end-organ impairment in an animal model of type 2 diabetes mellitus. Laryngoscope 111:110–113

    Article  PubMed  CAS  Google Scholar 

  • Sanes JR, Engvall E, Butkowski R, Hunter DD (1990) Molecular heterogeneity of basal laminae: isoforms of laminin and collagen IV at the neuromuscular junction and elsewhere. J Cell Biol 111:1685–1699

    Article  PubMed  CAS  Google Scholar 

  • Sha SH, Chen FQ, Schacht J (2010) PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse. Hear Res 264:86–92

    Article  PubMed  CAS  Google Scholar 

  • Taguchi D, Takeda T, Kakigi A, Takumida M, Nishioka R, Kitano H (2007) Expressions of aquaporin-2, vasopressin type 2 receptor, transient receptor potential channel vanilloid (TRPV)1, and TRPV4 in the human endolymphatic sac. Laryngoscope 117:695–698

    Article  PubMed  CAS  Google Scholar 

  • Takeda T, Takeda S, Kakigi A, Okada T, Nishioka R, Taguchi D, Nishimura M, Nakatani H (2010) Hormonal aspects of Ménière’s disease on the basis of clinical and experimental studies. ORL J Otorhinolaryngol Relat Spec 71 (Suppl 1):1–9

    PubMed  Google Scholar 

  • Takumida M, Anniko M (2011) Localization of prostanoid receptors in the mouse inner ear. Acta Otolaryngol 131:142–148

    Article  PubMed  Google Scholar 

  • Takumida M, Kakigi A, Egami N, Nishioka R, Anniko M (2012) Localization of aquaporins 1, 2, and 3 and vasopressin type 2 receptor in the mouse inner ear. Acta Otolaryngol 132:807–813

    PubMed  CAS  Google Scholar 

  • Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    Article  PubMed  CAS  Google Scholar 

  • Vasilyeva ON, Frisina ST, Zhu X, Walton JP, Frisina RD (2009) Interactions of hearing loss and diabetes mellitus in the middle age CBA/CaJ mouse model of presbycusis. Hear Res 249:44–53

    Article  PubMed  Google Scholar 

  • Wangemann P (2002) Adrenergic and muscarinic control of cochlear endolymph production. Adv Otorhinolaryngol 59:42–50

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Gunnel Roos and Ann-Kristin Holmén-Pålbrink for excellent technical assistance and to the staff on the Surgical Ward at the Department of Neurosurgery.

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Authors and Affiliations

  1. Department of Experimental Medical Sciences, Section for Diabetes, Metabolism and Endocrinology, Lund University, Biomedical Center, C11, 221 84, Lund, Sweden

    Eva Degerman

  2. Section for Vascular Wall Biology, Lund University, Lund, Sweden

    Uwe Rauch & Anna Hultgårdh

  3. Department of Clinical Sciences, Section for Otorhinolaryngology, Lund University & Skåne University Hospital, Lund, Sweden

    Sven Lindberg & Måns Magnusson

  4. Department of Otorhinolaryngology, Head and Neck Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Per Caye-Thomasen

  5. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Per Caye-Thomasen

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  1. Eva Degerman
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  2. Uwe Rauch
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Corresponding author

Correspondence to Eva Degerman.

Additional information

This work was supported by the Swedish Research Council Project 3362 (to E.D.) and 2611 (to M.M.), the Crafoord Foundation, the Swedish Society of Medicine, the A. Påhlsson Foundation and the NovoNordisk Foundation, Denmark.

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Degerman, E., Rauch, U., Lindberg, S. et al. Expression of insulin signalling components in the sensory epithelium of the human saccule. Cell Tissue Res 352, 469–478 (2013). https://doi.org/10.1007/s00441-013-1614-x

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