Diabetes mellitus (DM) is a prevalent metabolic disease of middle age and older adults worldwide (about 7.0% and rising). There are two major types of diabetes: Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). It is estimated that 5-10% of Americans who are diagnosed with diabetes have T1DM. Most common is T2DM, affecting more than 20% of people over age 60 (American Diabetes Association 2006
). Both types of DM can cause serious health complications that involve multiple organs and physiological systems. Many T2DM complications in older people are associated with natural aging, but they appear earlier in diabetic patients (Biessels et al. 2002
Studies that have attempted to characterize hearing loss in diabetics show inconsistent results (for reviews see Tay et al. 1995
; Fowler and Jones 1999
; Maia and Campos 2005
). Specifically, some studies find bilateral hearing loss at high frequencies for children with T1DM (Elamin et al. 2005
), while others did not find hearing loss (Dalton et al. 1998
; de Espana et al.
Kudelska et al. 1995), or found hearing loss in middle age and older T2DM patients (Rózańska 2002
; Diaz de Leon-Morales et al. 2005
; Sakuta et al. 2007
). However, Tay et al. (1995)
showed hearing impairment at low and middle frequencies in diabetics. In contrast, Salvinelli et al. (2004)
found no effect on hearing for either type of diabetes, and evoked otoacoustic emissions (OAEs) were not affected at most frequencies in T2DM subjects (de Leo et al., 1997; Erdem et al., 2003
). However, Sasso et al. (1999)
reported a significant drop in OAE amplitudes for diabetic subjects. To evaluate brainstem auditory function, auditory brainstem response (ABR) latencies were used (de Leo et al. 1997; Sasso et al. 1999
), to show prolonged activation of central auditory pathways. Except for the ABR latency experiments, these human studies used simple, limited auditory measures that evaluated peripheral hearing.
Recently, we showed a significant effect on both peripheral and central hearing functions in older T2DM subjects by using a comprehensive test battery (Frisina et al. 2006
). Peripheral hearing function was assayed by pure tones, otoacoustic emissions (transient and distortion product), and speech thresholds, revealing more significant losses in the T2DM group compared to age-matched controls. For the first time, effects of T2DM on hearing tests involving central auditory processing in aged human subjects were evaluated by measuring hearing in-noise (HINT) and suprathreshold gap detection thresholds. As for the inner ear findings, the T2DM group showed significantly worse performance on these tests compared to age matched non-diabetic controls, suggesting that the CNS is susceptible to the damaging effects of the diabetes conditions.
There are several animal models of diabetes: animals that develop diabetes by specific experimental procedures and animals that develop diabetes spontaneously, owing to a genetic predisposition (Mordes et al. 1981; Shafrir 1997
.). Streptozotocin (STZ) induced diabetes is a T1DM model and is widely used for longer (6 months) duration studies of diabetes. For example, this T1DM model has been used to evaluate alteration of auditory function with ABRs. Threshold elevations and first-peak latency prolongation appeared in rodents (Biessels et al., 2001
; Manschot et al. 2003
; Biessels et al. 2005
). Also, significant prolongation of auditory evoked potentials was reported for STZ-treated rats by 3 months of diabetes duration, suggesting changes in central auditory regions (Biessels et al. 1999
). In genetically predisposed young adult rats (T2DM, 13 months of age) evaluation of auditory function showed elevation of ABR thresholds (Ishikawa et al. 1995
) as compared to non-susceptible strains. A main limitation of these previous studies that attempted to identify the effect of diabetes on hearing function was that hearing ability of the rodent strains were not well characterized initially, making it difficult to identify effects of hearing impairment, diabetes, and chemical side effects (those induced by streptozotocin, alloxan).
The necessity of utilizing an appropriate mouse model for studying effects of diabetes (prevalent in older populations) on age related hearing loss is obvious from scientific and clinical perspectives. The most commonly used animal model of T1DM, STZ injection, may interfere with metabolism of inner ear hair cells as well as with auditory neurons in the brain. Another, important aspect of evaluating mouse models of diabetes is selection of an appropriate mouse strain to avoid genetic effects on presbycusis. For example, C57Bl/6 and DBA strains of mice have the ahl allele, inducing a rapid, high-frequency hearing loss (Willott and Carlson 1995
; Willott et al. 2001
), making them unsuitable for studies in middle age and old animals of the interaction of diabetes and presbycusis. Much evidence suggests that the CBA/CaJ serves as an excellent model for many cases of human presbycusis since it shows hearing loss that progresses on a time frame similar to human’s, when one corrects for the different absolute lifespans of mice and men. The age related hearing loss of the CBA/CaJ strain most likely corresponds to the sensory-neural type of human presbycusis (high-tone frequency loss with changes in central auditory regions) (e.g., Spongr et al. 1998; Frisina et al. 1998
; Parham et al. 1999
; Willott 2001
; Jacobson et al. 2003
The aim of the present investigation was to induce two types of diabetes in middle age CBA/CaJ mice and evaluate effects on age-related hearing loss using different hearing tests. The effect of a long duration (6 months) metabolic stress on the progression and time course of age-related hearing loss - presbycusis, was characterized by hearing assessments for both peripheral (cochlea) and central (inferior colliculus - IC) portions of the auditory pathway. Age-matched non-diabetic control mice were utilized for comparison with hyperglycemic T1DM mice (STZ induced) and for T2DM (high fat diet) to maximize effects for future studies of possible anatomical, genetic and neurochemical mechanisms of diabetes on hearing ability with age.