Skip to main content

Advertisement

SpringerLink
Log in

Zucker diabetic fatty rats, a model for type 2 diabetes, develop an inner ear dysfunction that can be attenuated by losartan treatment

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Hearing loss secondary to diabetes remains under debate. In our study, we used Zucker Diabetic Fatty (ZDF) rats as an animal model of type 2 diabetes to investigate whether (1) hearing ability impairment and structural alterations of the inner ear occur in diabetes and (2) an angiotensin II receptor blocker (losartan) can protect rats from diabetic damage. Homozygous mutants were treated with a placebo or losartan and heterozygous animals served as non-diabetic controls. All animals underwent immunohistochemical and electronmicroscopical analysis. Functional testing of hearing ability was performed by click-evoked auditory brainstem responses. The present study showed significant sensorineural hearing impairment in placebo-treated diabetic rats (hearing threshold, 45.0 ± 2.1 dB SPL) compared to both non-diabetic controls (34.7 ± 4 dB SPL) and losartan-treated diabetic rats (36.1 ± 7.4 dB SPL). Concurrently, the functional decline in the placebo-treated rats was associated with significant morphological abnormalities, particularly in the intermediate cells of the stria vascularis and with strial dysfunction. These degenerative changes were indicated by the down-regulation of several pumps, ionic and cellular channels, which are involved in the cycling of K+ and the maintenance of the endocochlear potential essential for the hearing process. Thus, the inner ear can be regarded as a target organ during hyperglycemic disorders and a metabolically induced “diabetic otopathy” may be added to angiopathy, nephropathy and neuropathy as a specific complication of diabetes mellitus. Blockade of the angiotensin II receptor can prevent this “diabetic otopathy” despite hyperglycemic serum levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ABR:

Auditory brainstem responses

BC:

Basal cell

Cx:

Connexin

dB:

Decibel

EP:

Endocochlear potential

IMC:

Intermediate cell

MC:

Marginal cell

RAS:

Renin-angiotensin system

SV:

Stria vascularis

T2DM:

Type 2 diabetes mellitus

ZDF:

Zucker Diabetic Fatty Rats

References

  • Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, Smith BJ, Burks TN, Cohn RD, Fedarko NS, Carey RM, O’Rourke B, Walston JD (2011) Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A 108:14849–14854

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Akinpelu OV, Mujica-Mota M, Daniel SJ (2013) Is type 2 diabetes mellitus associated with alterations in hearing?: a systematic review and meta-analysis. Laryngoscope 133:767–776

    Google Scholar 

  • Aladag I, Eyibilen A, Güven M, Atis O, Erkorkmaz Ü (2009) Role of oxidative stress in hearing impairment in patients with type two diabetes mellitus. J Laryngol Otol 123:957–963

    Article  CAS  PubMed  Google Scholar 

  • Cao Z, Cooper ME (2011) Efficacy of renin-angiotensin system (RAS) blockers on cardiovascular and renal outcomes in patients with type 2 diabetes. Acta Diabetol 49:243–254

    Article  PubMed  Google Scholar 

  • Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578

    Article  CAS  PubMed  Google Scholar 

  • De Cavanagh EMV, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, Fraga CD (2003) Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J 17:1096–1098

    PubMed  Google Scholar 

  • Duman D, Tekin M (2012) Autosomal recessive nonsyndromic deafness genes: a review. Front Biosci 17:2213–2236

    Article  Google Scholar 

  • Eckhard A, Gleiser C, Rask-Andersen H, Arnold H, Liu W, Mack A, Müller M, Löwenheim H, Hirt B (2012) Co-localisation of Kir4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K+ recycling routes. Cell Tissue Res 350:27–43

    Article  CAS  PubMed  Google Scholar 

  • Forge A, Becker D, Casalotti S, Edwards J, Marziano N, Nevill G (2003) Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessement of connexin composition in mammals. J Comp Neurol 467:207–231

    Article  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 Central  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 

  • Gratton M, Smyth BJ, Schulte BA, Vincent DA Jr (1995) Na, K-ATPase activity decreases in the cochlear lateral wall of quiet-aged gerbils. Hear Res 83:43–50

    Article  CAS  PubMed  Google Scholar 

  • Hamelin R, Allagnat F, Haefliger JA, Meda P (2009) Connexins, diabetes and the metabolic syndrome. Curr Protein Pept Sci 10:18–29

    Article  CAS  PubMed  Google Scholar 

  • Hibino H, Kurach Y (2006) Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology 21:336–345

    Article  CAS  PubMed  Google Scholar 

  • Huh SK, Lipton JM, Batjer HH (1997) The protective effects of alpha-melanocyte stimulating hormone on canine brain stem ischemia. Neurosurgery 40:132–140

    CAS  PubMed  Google Scholar 

  • Jordao AMD (1857) Considérations sur un cas de diabéte. These, Faculte de Medicine de Paris

  • Leem J, Koh EH (2012) Interaction between mitochondria and the endoplasmic reticulum: Implications for the pathogenesis of Type 2 diabetes mellitus. Exp Diabetes Res 2012:242984

    Article  PubMed Central  PubMed  Google Scholar 

  • Maia CA, Campos CA (2005) Diabetes mellitus as etiological factor of hearing loss. Braz J Otorhinolaryngol 71:208–214

    Article  PubMed  Google Scholar 

  • Marcus DC, Wu T, Wangemann P, Kofuji P (2002) KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol Cell Physiol 282:C403–C407

    Article  CAS  PubMed  Google Scholar 

  • McQueen CT, Baxter A, Smith TL, Raynor E, Yoon SM, Prazma J, Pillsbury HC 3rd (1999) Non-insulin-dependent diabetic microangiopathy in the inner ear. J Laryngol Otol 113:13–18

    CAS  PubMed  Google Scholar 

  • Meyer zum Gottesberge AM (1988) Physiology and pathophysiology of inner ear melanin. Pigment Cell Res 1:238–249

    Article  CAS  PubMed  Google Scholar 

  • Meyer zum Gottesberge AM (2000) Hormonal regulation of the inner ear. In: Sterkers O, Ferrary E, Dauman R, Sauvage JP, Tran Ba Huy P (eds) Menière’s disease 1999–Update. Kugler, The Hague, pp 49–57

  • Meyer zum Gottesberge AM (2005) Alpha-MSH as an emergency hormone of the inner ear? ARO 1134 (Abstract)

  • Meyer zum Gottesberge AM, Massing T, Hansen S (2012) Missing mitochondrial Mpv17 gene function induces tissue-specific cell-death pathway in the degenerating inner ear. Cell Tissue Res 347:343–356

    Article  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Nakae S, Tachibana M (1986) The cochlea of the spontaneously diabetic mouse. II. Electron microscopic observations of non-obese diabetic mice. Arch Otorhinolaryngol 243:313–316

    Article  CAS  PubMed  Google Scholar 

  • Ohlemiller KK, Rice MER, Gagnon PM (2008) Strial microvascular pathology and age-associated endocochlear potential decline in NOD congenic mice. Hear Res 244:85–97

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Patuzzi R (2011) Ion flow in cochlear hair cells and the regulation of hearing sensitivity. Hear Res 280:3–20

    Article  CAS  PubMed  Google Scholar 

  • Raynor E, Robison WG, Garrett CG, McGuirt WT, Pillsbury HC, Prazma J (1995) Consumption of a high-galactose diet induces diabetic-like changes in the inner ear. Otolaryngol Head Neck Surg 113:748–754

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WW, Dos Santos RA, Simões e Silva AC (2008) The renin–angiotensin system and diabetes: an update. Vasc Health Risk Manag 4:787–803

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rozengurt N, Lopez I, Chiu CS, Kofuji P, Lester HA, Neusch C (2003) Time course of inner ear degeneration and deafness in mice lacking the Kir4.1 potassium channel subunit. Hear Res 177:71–80

    Article  CAS  PubMed  Google Scholar 

  • Rust KR, Prazma J, Triana RJ, Michaelis OE 4th, Pillsbury HC (1992) Inner Ear damage secondary to diabetes mellitus: II. Changes in aging SHR/N-cp rats. Arch Otolaryngol Head Neck Surg 118:397–400

    Article  CAS  PubMed  Google Scholar 

  • Ryan AF, Wattsm AG (1991) Expression of mRNAs encoding α and β subunit isoforms of the Na, K-ATPase in the rat cochlea. Mol Cell Neurosci 2:179–187

    Article  CAS  PubMed  Google Scholar 

  • Shafrir E (2010) Contribution of animal models to the research of the causes of diabetes. World J Diabetes 1:137–140

    Article  PubMed Central  PubMed  Google Scholar 

  • Silva KC, Rosales MAB, Biswas SK, Lopes de Faria JB, Lopes de Faria JM (2009) Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes. Diabetes 58:1382–1390

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith TL, Raynor E, Prazma J, Buenting JE, Pillsbury HC (1995) Insulin-dependent diabetic microangiopathy in the inner ear. Laryngoscope 105:236–240

    Article  CAS  PubMed  Google Scholar 

  • Spicer SS, Schulte BA (2005) Novel structures in marginal and intermediate cells presumably relate to functions of apical versus basal strial strata. Hear Res 200:87–101

    Article  PubMed  Google Scholar 

  • Spicer SS, Gratton MA, Schulte BA (1997) Expression patterns of ion transport enzymes in spiral ligament fibrocytes change in relation to strial atrophy in the aged gerbil cochlea. Hear Res 111:93–102

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan K, Ramarao P (2007) Animal models in type 2 diabetes research: an overview. Indian J Med Res 125:451–471

    CAS  PubMed  Google Scholar 

  • Tachibana M, Nakae S (1986) The cochlea of the spontaneously diabetic mouse. I. Electron microscopic observation of KK mice. Arch Otorhinolaryngol 243:238–241

    Article  CAS  PubMed  Google Scholar 

  • Tocci G, Volpe M (2011) End-organ protection in patients with hypertension. Drugs 71:1003–1017

    Article  CAS  PubMed  Google Scholar 

  • Tomisawa H (2000) Diabetic changes in the stria vascularis in humans–a study of PAS-stained temporal bone sections. Nihon Jibiinkoka Gakkai Kaiho 103:1227–1237

    Article  CAS  PubMed  Google Scholar 

  • Tóth F, Várkonyi TT, Kiss JG, Rovó L, Lengyel C, Légrády P, Jór J, Czigner J (2001) Brainstem auditory-evoked potential examinations in diabetic patients. Scand Audiol Suppl 52:156–159

    Article  PubMed  Google Scholar 

  • Triana RJ, Suits GW, Garrison S, Prazma J, Brechtelsbauer PB, Michaelis OE, Pillsbury HC (1991) Inner Ear damage secondary to diabetes mellitus: I. Changes in adolescent SHR/N-cp rats. Arch Otolaryngol Head Neck Surg 117:635–640

    Article  CAS  PubMed  Google Scholar 

  • Vague P, Coste TC, Jannot MF, Raccah D, Tsimaratos M (2004) C-peptide, Na+, K + -ATPase, and Diabetes. Exper Diabesity Res 5:37–50

    Article  CAS  Google Scholar 

  • Wolters FL, Klis SF, Hamers FP, de Groot JC, Smoorenburg GF (2004) Perilymphatic application of alpha-melanocyte stimulating hormone ameliorates hearing loss caused by systemic administration of cisplatin. Hear Res 189:31–40

    Article  CAS  PubMed  Google Scholar 

  • Wright JA, Richards T, Becker DL (2012) Connexins and diabetes. Cardiol Res Pract 2012:496904

    PubMed Central  PubMed  Google Scholar 

  • Xie B, Jiao Q, Cheng Y, Zhong Y, Shen X (2012) Effect of pigment epithelium-derived factor on glutamate uptake in retinal muller cells under high-glucose conditions. Invest Ophthalmol Vis Sci 53:1023–1032

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank Prof. S. Schäfer (Sanofi/Aventis) for initiating the study and providing the material and Mr. P. Hainz and G. Fischer (Sanofi/Aventis) and Mrs. U. Becker-Ledzian (Düsseldorf) for outstanding technical assistance.

Author information

Authors and Affiliations

  1. Department of Otorhinolaryngology, Division of Phoniatrics and Pediatric Audiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Thomas Massing

  2. Department of Otorhinolaryngology, Research Laboratory Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Anja Sasse

  3. Department of Otorhinolaryngology, Primary Care Department, Largo del Pozzo 71/b, 41100, Modena, Italy

    Silvia Palma

  4. Department of Otorhinolaryngology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Stefan Hansen

  5. Medical Faculty Department of Otorhinolaryngology, Research Laboratory Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany

    Angela-Maria Meyer zum Gottesberge

Authors
  1. Angela-Maria Meyer zum Gottesberge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Massing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anja Sasse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Palma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela-Maria Meyer zum Gottesberge.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meyer zum Gottesberge, AM., Massing, T., Sasse, A. et al. Zucker diabetic fatty rats, a model for type 2 diabetes, develop an inner ear dysfunction that can be attenuated by losartan treatment. Cell Tissue Res 362, 307–315 (2015). https://doi.org/10.1007/s00441-015-2215-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-015-2215-7

Keywords

Search

Navigation