Diabetes and Hearing Loss. Mohammed Al Sofiani Internal Medicine Department University at Buffalo Catholic Health System

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1 Diabetes and Hearing Loss Mohammed Al Sofiani Internal Medicine Department University at Buffalo Catholic Health System

2 Diabetes and Hearing Loss Background: We have clear evidence that diabetes has pathologic effects on many systems in the body (micro and macrovascular complications) The association between diabetes and the auditory system is still controversial. It seems logical that micro vascular complications would have an impact on the extensive vascularity of the cochlea. Copyright A.K. Vats

3 Diabetes and Hearing Loss Animal studies: Changes consistent with diabetic micro vascular complications were found in cochlear capillaries of rats in which diabetes was induced by streptozotocin injections. Loss of the outer hair cells was found in 5 month old genetically diabetic rats and increased loss was noted at 10.5 months of age, suggesting increasing damage with increased duration of diabetes. *Smith TL, et al. Insulin dependent diabetic microangiopathy in the inner ear. Laryngoscope *Rust KR, Prazma J, Triana RJ, et al. Inner ear damage secondary to diabetes mellitus: II. Changes in aging SHR/Ncp rats. Arch Otolaryngol Head Neck Surg 1992;118:

4 Diabetes and Hearing Loss Molecular studies: Manigrasso, et al. Unlocking the biology of RAGE in diabetic microvascular complications. January Figure: Interaction between Advanced Glycation End products (AGEs) and Receptors for AGE (RAGEs) contributes to the micro and macrovascular complications of DM.

5 Diabetes and Hearing Loss Molecular studies: Figure: Cleavage of srage from the cell surface by ADAM10 and by expression of a splice variant of srage. Ramasamy, et al. RAGE: therapeutic target and biomarker of the inflammatory response the evidence mounts. Journal of Leukocyte Biology. September 2009.

6 Diabetes and Hearing Loss Human studies: There is insufficient evidence of a significant relationship between diabetes and hearing impairment in human. NHANES showed that over two thirds of diabetics (self reported DM) are affected by some degree of hearing impairment (about twofold higher than that of the non diabetic population) Bainbridge KE, Hoffman HJ, Cowie CC. Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Exam ination Survey, 1999 to Ann Intern Med 2008;149:1 10

7 The Hearing Handicap Inventory for the Elderly Screening Version (HHIE S) HHIE S Score <10: No self perceived handicap 10: Self perceived handicap f No handicap Self perceived handicap Proportion of patients with self perceived hearing handicap using the HHIE S questionnaire.

8 No Hearing Handicap Hearing Handicap P value Age (years) 56.32± ± Gender Male Duration of DM (years) 5.73± ± Diabetic complications (%) P= Retinopathy Nephropathy Neuropathy CAD Stroke/TIA A1c (%) 7.2± ± HTN (%) On insulin (%) Demographic and health characteristics of diabetic patients stratified by hearing handicap. Percentage of patients with and without hearing handicap stratified by duration of DM

9 Type 1 Diabetes Mellitus (T1DM) and Hearing Loss: Audiometric Assessment Hypothesis: Hearing loss is more prevalent in type 1 diabetics with a longer duration of diabetes compared to those with a shorter duration of DM.

10 Type 1 DM and hearing loss Primary endpoints: To evaluate the hearing function in type 1 diabetic subjects. To evaluate the impact of duration of DM on hearing function in T1DM. Secondary endpoints: To evaluate the correlation between hearing loss and the development of other micro and macrovascular complications of T1DM. To evaluate the correlation of metabolic control with hearing impairment in T1DM. To evaluate the correlation between serum levels of CRP, VEGF, and srage and hearing function in T1DM. To evaluate the correlation between urinary levels of oxidative stress markers (isoprostane) and hearing function in T1DM

11 Type 1 DM and hearing loss Methods: Approved by UB IRB. A written informed consent was obtained from all study subjects prior to their enrolment in the study. Patients were interviewed at the time of their regular visits to the endocrinology office at R&B Medical Group. Levels of CRP, VEGF, srage and isoprostane were measured by ELISA.

12 Type 1 DM and hearing loss Inclusion criteria: Adults (aged years old) at start of screening. Type 1 DM. Exclusion criteria: History of recurrent otitis media. History of Meniere's disease Noise exposure (Occupational, recreational, or military) Use of toxic drugs: High dose aspirin (6 8 g/day) Recurrent exposure to aminoglycoside, erythromycin, tetracycline. Cisplatin Loop diuretic 5 Fluorouracil Bleomycin Congenital diseases associated with hearing Cocaine abuse. impairment such as Arnold Chiari malformation.

13 Screening Phase 42 Type 1 diabetics (20 60 Y.O) (n=42) Eligible patients (n=30) Excluded (n=12) Had one or more of the exclusion criteria (n=10) Refused to participate (n=2) Data collection History (comorbidities, medication list, etc.) Physical exam (including MNSI*) Results of most recent labs (A1c, BMP, urinalysis for proteinuria) Data analysis Audiometric test Collection of blood and urine samples *MNSI: Michigan Neuropathy Screening Instrument Storage of samples ( 80⁰c) until the time of lab analysis.

14 Type 1 DM and hearing loss Normal Hearing Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Normal MILD Profound Hearing Loss The Welch Allyn AM282 Audiometer The World Health Organization MODERATE (WHO) classification of hearing loss (HL) SEVERE PROFOUND

15 Type 1 DM and hearing loss: n Mean/Percentage Age (mean +- SD) ±11.4 Race (%) White African American Others Gender (%) 27 90% 0 0% 3 10% Male 15 50% Duration of DM (mean +- SD) ±10.8 BMI (mean +- SD) ± % A1c (mean +- SD) ± % Retinopathy (%) % Nephropathy (%) 3 10% Neuropathy (%) % CAD (%) 2 6.7% Stroke/TIA (%) 0 0% PAD (%) 1 3.3% History of HTN (%) 3 10% Table 1: Baseline characteristics of the study subjects. Figure 1: Proportion of patients with high frequency hearing loss.

16 Type 1 DM and hearing loss High Frequencies No Hearing Impairment (n=11) Hearing Impaired (n=19) P value Age (years) 36.2 ± ± Gender Male 63.6% 42.1% 0.45 Race 0.54 White African American Others 81.8% 94.7% % 5.3% Duration of DM (years) 21.2 ± ± BMI 27.28± ± Most recent A1c (%) 7.6 ± ± Average A1c (%) 7.8 ± ± Table 2: Demographic and health characteristics of diabetic patients stratified by hearing function at high frequency sounds.

17 Type 1 DM and hearing loss High Frequencies No Hearing Impairment (n=11) Hearing Impaired (n=19) P value Retinopathy 36.4% 31.6% 1 Nephropathy 0% 15.8% 0.28 CAD % 0.52 Stroke/TIA 0 0 NA PAD 0 5.3% 1 Abnormal MNSI* 9.1% 57.9% 0.02 History of HTN % 0.28 Insulin Pump 90.9% 78.9% 0.63 ASA 18.2% 42.1% 0.25 Cont. Table 2: Demographic and health characteristics of diabetic patients stratified by hearing function at high frequency sounds. * MNSI: Michigan Neuropathy Screening Instrument.

18 Type 1 DM and hearing loss Duration of Diabetes (years) Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Profound Hearing Loss Figure 2: Average pure tone thresholds in both ears among type 1 diabetic subjects by duration of diabetes.

19 Type 1 DM and hearing loss Duration of Diabetes (years) Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Profound Hearing Loss Figure 3: Average pure tone thresholds in the right ear among type 1 diabetic subjects by duration of diabetes.

20 Type 1 DM and hearing loss Duration of Diabetes (years) Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Profound Hearing Loss Figure 4: Average pure tone thresholds in the left ear among type 1 diabetic subjects by duration of diabetes.

21 Type 1 DM and hearing loss Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Profound Hearing Loss Figure 5: Average pure tone thresholds in both ears among type 1 diabetics stratified by presence of diabetic neuropathy.

22 Type 1 DM and hearing loss Mild Hearing Loss Moderate Hearing Loss Severe Hearing Loss Profound Hearing Loss Figure 6: Average pure tone thresholds in both ears among type 1 diabetics (diabetes for 35 years) and non diabetic subjects (40 59 years old).

23 Type 1 DM and hearing loss P value= 0.41 Figure 7: Serum levels of VEGF in diabetic patients with hearing loss compared to diabetic patients with normal hearing at high frequency sounds.

24 Type 1 DM and hearing loss P value= 0.68 Figure 8: Serum levels of CRP in diabetic patients with hearing loss compared to diabetic patients with normal hearing at high frequency sounds.

25 P value= 0.82 Figure 9: Urine levels of isoprostane in diabetic patients with hearing loss compared to diabetic patients with normal hearing at high frequency sounds.

26 Type 1 DM and hearing loss *P value= 0.03 Figure 10: Serum levels of srage in diabetic patients with hearing loss compared to diabetic patients with normal hearing at high frequency sounds.

27 Diabetes and Hearing Loss Conclusion: Type 1 diabetic patients 60 years old or younger may show early highfrequency hearing loss similar to early presbycusis. High frequency hearing loss is significantly and positively associated with age, duration of DM, and presence of peripheral neuropathy. Diabetic patients between 40 and 60 years old with duration of DM 35 years have significantly higher hearing thresholds at 6000 and 8000 Hz compared to age matched non diabetic control subjects.

28 Diabetes and Hearing Loss Conclusion: srage blood levels are significantly lower in type 1 diabetic patients who have hearing loss compared with diabetic patients with normal hearing. This may support the hypothesis that srage, by limiting the interaction of AGE with cell membrane RAGE, can provide protection against AGE toxicity.

29 Acknowledgment R&B Medical Group Howard Lippes, MD, FACP John Hall, MD, FACP Kara Brenton, RN Hannan Imam, PA Sisters of Charity Hospital Henry Woodman, MD, FACP James Stephen, MD Sara MacLeod, MD Department of Communicative Disorders and Sciences/ UB Nancy A. Stecker, Ph.D Clinical and Translational Research Center (CTRC) Husam Ghanim, Ph.D