Spatial Release From Masking With Bilateral Bone Conduction Stimulation at Mastoid for Normal Hearing Subjects.

This study investigates the effect of spatial release from masking (SRM) in bilateral bone conduction (BC) stimulation at the mastoid. Nine adults with normal hearing were tested to determine SRM based on speech recognition thresholds (SRTs) in simulated spatial configurations ranging from 0 to 180 degrees. These configurations were based on nonindividualized head-related transfer functions. The participants were subjected to sound stimulation through either air conduction (AC) via headphones or BC. The results indicated that both the angular separation between the target and the masker, and the modality of sound stimulation, significantly influenced speech recognition performance. As the angular separation between the target and the masker increased up to 150°, both BC and AC SRTs decreased, indicating improved performance. However, performance slightly deteriorated when the angular separation exceeded 150°. For spatial separations less than 75°, BC stimulation provided greater spatial benefits than AC, although this difference was not statistically significant. For separations greater than 75°, AC stimulation offered significantly more spatial benefits than BC. When speech and noise originated from the same side of the head, the "better ear effect" did not significantly contribute to SRM. However, when speech and noise were located on opposite sides of the head, this effect became dominant in SRM.

The Chinese Zodiac-in-Noise Test: An Internet-Based Speech-in-Noise Test for Large-Scale Hearing Screening.

OBJECTIVES: Motivated by the growing need for hearing screening in China, the present study has two objectives. First, to develop and validate a new test, called the Chinese Zodiac-in-noise (ZIN) test, for large-scale hearing screening in China. Second, to conduct a large-scale remote hearing screening in China, using the ZIN test developed. DESIGN: The ZIN test was developed following a similar procedure as the digits-in-noise test but emphasizes the importance of consonant recognition by employing the 12 zodiac animals in traditional Chinese culture as speech materials. It measures the speech reception threshold (SRT) using triplets of Chinese zodiac animals in speech-shaped noise with an adaptive procedure. RESULTS: Normative data of the test were obtained in a group of 140 normal-hearing listeners, and the performance of the test was validated by comparisons with pure-tone audiometry in 116 listeners with various hearing abilities. The ZIN test has a reference SRT of -11.0 ± 1.6 dB in normal-hearing listeners with a test-retest variability of 1.7 dB and can be completed in 3 minutes. The ZIN SRT is highly correlated with the better-ear pure-tone threshold ( r = 0.82). With a cutoff value of -7.7 dB, the ZIN test has a sensitivity of 0.85 and a specificity of 0.94 for detecting a hearing loss of 25 dB HL or more at the better ear.A large-scale remote hearing screening involving 30,552 participants was performed using the ZIN test. The large-scale study found a hearing loss proportion of 21.0% across the study sample, with a high proportion of 57.1% in the elderly study sample aged over 60 years. Age and gender were also observed to have associations with hearing loss, with older individuals and males being more likely to have hearing loss. CONCLUSIONS: The Chinese ZIN test is a valid and efficient solution for large-scale hearing screening in China. Its remote applications may improve access to hearing screening and enhance public awareness of hearing health.

Comparable Encoding, Comparable Perceptual Pattern: Acoustic and Electric Hearing.

Perception with electric neuroprostheses is sometimes expected to be simulated using properly designed physical stimuli. Here, we examined a new acoustic vocoder model for electric hearing with cochlear implants (CIs) and hypothesized that comparable speech encoding can lead to comparable perceptual patterns for CI and normal hearing (NH) listeners. Speech signals were encoded using FFT-based signal processing stages including band-pass filtering, temporal envelope extraction, maxima selection, and amplitude compression and quantization. These stages were specifically implemented in the same manner by an Advanced Combination Encoder (ACE) strategy in CI processors and Gaussian-enveloped Tones (GET) or Noise (GEN) vocoders for NH. Adaptive speech reception thresholds (SRTs) in noise were measured using four Mandarin sentence corpora. Initial consonant (11 monosyllables) and final vowel (20 monosyllables) recognition were also measured. NaÏve NH listeners were tested using vocoded speech with the proposed GET/GEN vocoders as well as conventional vocoders (controls). Experienced CI listeners were tested using their daily-used processors. Results showed that: 1) there was a significant training effect on GET vocoded speech perception; 2) the GEN vocoded scores (SRTs with four corpora and consonant and vowel recognition scores) as well as the phoneme-level confusion pattern matched with the CI scores better than controls. The findings suggest that the same signal encoding implementations may lead to similar perceptual patterns simultaneously in multiple perception tasks. This study highlights the importance of faithfully replicating all signal processing stages in the modeling of perceptual patterns in sensory neuroprostheses. This approach has the potential to enhance our understanding of CI perception and accelerate the engineering of prosthetic interventions. The GET/GEN MATLAB program is freely available athttps://github.com/BetterCI/GETVocoder.

Cochlear-implant Mandarin tone recognition with a disyllabic word corpus.

Despite pitch being considered the primary cue for discriminating lexical tones, there are secondary cues such as loudness contour and duration, which may allow some cochlear implant (CI) tone discrimination even with severely degraded pitch cues. To isolate pitch cues from other cues, we developed a new disyllabic word stimulus set (Di) whose primary (pitch) and secondary (loudness) cue varied independently. This Di set consists of 270 disyllabic words, each having a distinct meaning depending on the perceived tone. Thus, listeners who hear the primary pitch cue clearly may hear a different meaning from listeners who struggle with the pitch cue and must rely on the secondary loudness contour. A lexical tone recognition experiment was conducted, which compared Di with a monosyllabic set of natural recordings. Seventeen CI users and eight normal-hearing (NH) listeners took part in the experiment. Results showed that CI users had poorer pitch cues encoding and their tone recognition performance was significantly influenced by the "missing" or "confusing" secondary cues with the Di corpus. The pitch-contour-based tone recognition is still far from satisfactory for CI users compared to NH listeners, even if some appear to integrate multiple cues to achieve high scores. This disyllabic corpus could be used to examine the performance of pitch recognition of CI users and the effectiveness of pitch cue enhancement based Mandarin tone enhancement strategies. The Di corpus is freely available online: https://github.com/BetterCI/DiTone.

Pitch Perception With the Temporal Limits Encoder for Cochlear Implants.

The temporal-limits-encoder (TLE) strategy has been proposed to enhance the representation of temporal fine structure (TFS) in cochlear implants (CIs), which is vital for many aspects of sound perception but is typically discarded by most modern CI strategies. TLE works by computing an envelope modulator that is within the temporal pitch limits of CI electric hearing. This paper examines the TFS information encoded by TLE and evaluates the salience and usefulness of this information in CI users. Two experiments were conducted to compare pitch perception performance of TLE versus the widely-used Advanced Combinational Encoder (ACE) strategy. Experiment 1 investigated whether TLE processing improved pitch discrimination compared to ACE. Experiment 2 parametrically examined the effect of changing the lower frequency limit of the TLE modulator on pitch ranking. In both experiments, F0 difference limens were measured with synthetic harmonic complex tones using an adaptive procedure. Signal analysis of the outputs of TLE and ACE strategies showed that TLE introduces important temporal pitch cues that are not available with ACE. Results showed an improvement in pitch discrimination with TLE when the acoustic input had a lower F0 frequency. No significant effect of lower frequency limit was observed for pitch ranking, though a lower limit did tend to provide better outcomes. These results suggest that the envelope modulation introduced by TLE can improve pitch perception for CI listeners.

Utilizing True Wireless Stereo Earbuds in Automated Pure-Tone Audiometry.

True wireless stereo (TWS) earbuds have become popular and widespread in recent years, and numerous automated pure-tone audiometer applications have been developed for portable devices. However, most of these applications require specifically designed earphones to which the public may not have access. Therefore, the present study investigates the accuracy of automated pure-tone audiometry based on TWS earbuds (Honor FlyPods). The procedure for developing an automated pure-tone audiometer is reported. Calibration of the TWS earbuds was accomplished by electroacoustic measurements and establishing corrected reference equivalent threshold sound pressure levels. The developed audiometer was then compared with a clinical audiometer using 20 hearing-impaired participants. The average signed and absolute deviations between hearing thresholds measured using the two audiometers were 3.1 dB and 6.7 dB, respectively. The overall accuracy rate in determining the presence/absence of hearing loss was 81%. The results show that the proposed procedure for an automated air-conduction audiometer based on TWS earbuds is feasible, and the system gives accurate hearing level estimation using the reported calibration framework.

A New Approach for Noise Suppression in Cochlear Implants: A Single-Channel Noise Reduction Algorithm.

The cochlea "translates" the in-air vibrational acoustic "language" into the spikes of neural "language" that are then transmitted to the brain for auditory understanding and/or perception. During this intracochlear "translation" process, high resolution in time-frequency-intensity domains guarantees the high quality of the input neural information for the brain, which is vital for our outstanding hearing abilities. However, cochlear implants (CIs) have coarse artificial coding and interfaces, and CI users experience more challenges in common acoustic environments than their normal-hearing (NH) peers. Noise from sound sources that a listener has no interest in may be neglected by NH listeners, but they may distract a CI user. We discuss the CI noise-suppression techniques and introduce noise management for a new implant system. The monaural signal-to-noise ratio estimation-based noise suppression algorithm "eVoice," which is incorporated in the processors of Nurotron® EnduroTM, was evaluated in two speech perception experiments. The results show that speech intelligibility in stationary speech-shaped noise can be significantly improved with eVoice. Similar results have been observed in other CI devices with single-channel noise reduction techniques. Specifically, the mean speech reception threshold decrease in the present study was 2.2 dB. The Nurotron society already has more than 10,000 users, and eVoice is a start for noise management in the new system. Future steps on non-stationary-noise suppression, spatial-source separation, bilateral hearing, microphone configuration, and environment specification are warranted. The existing evidence, including our research, suggests that noise-suppression techniques should be applied in CI systems. The artificial hearing of CI listeners requires more advanced signal processing techniques to reduce brain effort and increase intelligibility in noisy settings.

ABCA1 and ABCG1 expression in the small intestine of type 2 diabetic rats.

OBJECTIVE: Inflammation of the small intestine may occur in type 2 diabetes. This study aimed to investigate whether ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) were altered in chronic inflammation of the small intestine of type 2 diabetic rats. METHODS: Thirty-two male Sprague-Dawley rats were used. Eight rats in the control group were fed with regular chow, and 24 rats were fed a high-fat diet and injected with a single low dose of streptozotocin. All of the control rats and diabetic rats were bred for 10 months. Immunohistochemistry detected ABCA1 and ABCG1 in the small intestine in all the rats. RESULTS: Hematoxylin-eosin staining showed chronic inflammation in the small intestine of the diabetic rats. Immunohistochemistry staining showed that alteration of ABCA1 and ABCG1 was different in the inflammatory and epithelial cells. Quantitative analysis showed that the overall expression of ABCA1 and ABCG1 increased in the diabetic rats compared to the control rats. Both ABCA1 and ABCG1 were enriched in the inflammatory cells of the small intestine in diabetic rats. In the epithelial cells, ABCA1, but not ABCG1, was detected in significantly more diabetic rats than control rats. CONCLUSION: Both ABCA1 and ABCG1 are enriched in chronic inflammation of the small intestine of type 2 diabetic rats. ABCA1, but not ABCG1, is activated in the intestinal epithelial cells of type 2 diabetic rats.

A Chinese patient with KBG syndrome and a 9q31.2-33.1 microdeletion.

KBG syndrome is characterized by postnatal short stature, macrodontia, facial and hand anomalies, delayed bone age and intellectual disability. KBG syndrome is an infrequently reported autosomal dominant condition caused by a mutation or haploinsufficiency of ANKRD11 at 16q24.3. We report on a patient, who showed many manifestations of KBG syndrome and was found to harbor a de novo ANKRD11 mutation, c.362T > A (p.Met121Lys). As the patient showed additional characteristics not occurring in KBG syndrome, a CGH array was performed which showed a de novo microdeletion of 9q31.2-q33.1. The majority of findings in our patient can be explained by the combined ANKRD11 mutation and 9q31.2-33.1 deletion. The case demonstrates well the need for comparing an abnormal genotype with a detailed phenotype analysis and the need for further studies in case the phenotype is unusual for the genotype.

The transcription levels of ABCA1, ABCG1 and SR-BI are negatively associated with plasma CRP in Chinese populations with various risk factors for atherosclerosis.

ATP binding cassette transporters (ABCA1, ABCG1) and scavenger receptor class B type I (SR-BI) are the three most important cellular cholesterol transporters that may prevent atherogenesis. The aim of this study was to investigate whether they were altered in Chinese populations with various risk factors for atherosclerosis and their potential associations with C-reactive protein (CRP). Healthy female controls (n = 30) and populations with various risk factors for atherosclerosis, such as type 2 diabetes (n = 17), hypertension (n = 12), overweight/obesity (n = 10), incipient nephropathy (n = 10), postmenopausal women (n = 9), male (n = 19), ageing male (n = 22), or smoking (n = 16), were recruited. ABCA1, ABCG1 and SR-BI mRNA levels in peripheral monocytes was determined. ABCG1 was decreased in all the risk populations except ageing. ABCA1 was decreased in all the risk populations except diabetes and male. SR-BI was decreased in those with overweight/obesity and incipient nephropathy. Circulating CRP was increased almost in all the risk populations except in males. The levels of ABCA1, ABCG1 and SR-BI were reduced in those with subclinically high CRP, and negatively associated with CRP level. These data indicates that ABCA1, ABCG1, and SR-BI are reduced in various populations under subclinically inflammatory conditions, which may potentially lead to impairing reverse cholesterol transport and developing atherosclerosis.

Associations of ATP-binding cassette transporter A1 and G1 with insulin secretion in human insulinomas.

OBJECTIVES: Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) are 2 important cholesterol transporters in human pancreatic ß-cells. The aim of this study was to investigate their alteration in insulinomas and their potential associations with abnormal insulin secretion in these patients. METHODS: Six patients with insulinoma and 6 healthy controls were recruited. Lipid profiles and glucose metabolism were measured. Insulin content, ABCA1, and ABCG1 in insulinomas and the adjacent islets of the 6 patients with insulinoma were detected by immunohistochemistry or immunofluorescence. RESULTS: Plasma total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride were comparable between the controls and the patients with insulinoma. Fasting glucose was less than 2.8 mmol/L, and insulin release index was greater than 0.3 in each patient. Serum insulin fell extremely, and blood glucose reached the reference range within an hour after the cutting of the tumors in 2 patients with insulinoma. Adenosine triphosphate-binding cassette transporter G1 increased in insulinomas compared with the adjacent islets. However, ABCA1 was detected neither in the adjacent islets nor in insulinomas. Adenosine triphosphate-binding cassette transporter G1 expression in insulinomas was significantly associated with fasting insulin level and insulin release index. CONCLUSIONS: Increased ABCG1 may contribute to insulin hypersecretion in insulinomas. In contrast, the undetectable ABCA1 in insulinomas may reflect a negative feedback in insulin secretion in these patients.

Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma.

BACKGROUND: Sulfonylurea receptor 1 (SUR1) and multidrug resistance protein 1 (MRP1) are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS: Fasting glucose, insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients. Insulin content, SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS: Insulinoma patients presented the typical demonstrations of Whipple's triad. Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L, and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose. Immunohistochemistry and immunofluorescence staining showed that SUR1 increased, but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS: The hypersecretion of insulin in insulinomas might be, at least partially, due to the enrichment of SUR1. In contrast, MRP1, which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

Familial syndrome resembling Aarskog syndrome.

Aarskog(-Scott) syndrome (AAS) is characterized by short stature, and facial, limb, and genital anomalies. AAS can be an X-linked condition caused by mutations in the FGD1 gene, but there is evidence that an autosomal dominant or recessive form also exists. We report on a Chinese family in whom several members have manifestations of AAS, but differ in limb anomalies and show additional characteristics. FGD1 sequencing and linkage analysis excluded FGD1 as the cause in this family. A common known submicroscopic chromosome imbalance is less likely. Both autosomal dominant and recessive patterns of inheritance remain possible.

Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus.

UNLABELLED: Aims/Introduction: Endothelial lipase (EL) plays an important role in high-density lipoprotein (HDL) metabolism and experimental data suggest that EL might be proatherogenic. We have investigated whether serum EL concentration is associated with changes in serum capacity to induce cholesterol efflux and arterial stiffness in type 2 diabetes. MATERIALS AND METHODS: Serum EL was assayed by ELISA in 172 diabetic patients and 175 controls. The ability of serum to induce cholesterol efflux was measured using a cell culture system and arterial stiffness was determined by measuring pulse wave velocity (PWV) between carotid and femoral arteries. RESULTS: Diabetic patients had significantly higher C-reactive protein (CRP) and EL (27.7 ± 16.6 ng/mL vs 24.0 ± 11.3, P < 0.05). Cholesterol efflux to serum mediated through scavenger receptor class B type I was impaired (15.1 ± 2.5%vs 16.7 ± 3.1, respectively, P < 0.01). In controls, serum EL correlated with cholesterol efflux to serum (r = -0.16, P = 0.025), but only a trend was seen in the diabetic patients. Linear regression showed that in controls, HDL, serum EL and waist circumference were major independent determinants of cholesterol efflux; whereas in the diabetic cohort, the major independent determinants of cholesterol efflux were HDL, CRP and age. PWV was increased in the diabetic patients (P < 0.01), but no association between serum EL and PWV was seen in either groups. CONCLUSIONS: Serum EL was increased in diabetic patients, but impaired serum capacity to induce cholesterol efflux in these patients was mainly related to low HDL and subclinical inflammation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00016.x, 2010).

ABCG1 mediated oxidized LDL-derived oxysterol efflux from macrophages.

OBJECTIVES: The uptake of oxidized LDL (oxLDL) by macrophages is a key initial event in atherogenesis, and the removal of oxidized lipids from artery wall via reverse cholesterol transport is considered antiatherogenic. The aims of this study were to investigate the pathways mediating the removal of oxysterols from oxLDL-loaded macrophages, and the subsequent uptake of the oxysterols by hepatocytes. METHODS: LDL was labeled with [3H]cholesterol, and LDL-[3H]cholesterol was oxidized by copper using a standard method. [3H]oxysterol formation in oxLDL was analyzed by thin layer chromatography. oxLDL-[3H]sterol was incubated with macrophages, allowing the uptake of [3H]sterol by macrophages. [3H]sterol efflux from macrophages mediated by ATP binding cassette transporters (ABCA1, ABCG1), or scavenger receptor class B type I (SR-BI) was measured. The subsequent uptake of the [3H]sterol by hepatocytes was also determined. RESULTS: 7-Ketocholesterol was the major oxysterol formed in oxLDL, and it was significantly higher in oxLDL compared with that in native LDL (naLDL). oxLDL-derived sterol efflux to HDL from macrophages was significantly increased compared with naLDL-derived sterol, and it was mainly mediated by ABCG1, but not by ABCA1 or SR-BI. Moreover, although HDL dose-dependently induced sterol efflux from macrophages, only the exported sterol by ABCG1 pathway was efficiently taken up by hepatocytes. CONCLUSIONS: ABCG1 mediates oxysterol efflux from oxLDL-loaded macrophages, and the exported oxysterol by ABCG1 pathway can be selectively taken up by hepatocytes.

The expression of ATP-binding cassette transporters in hypertensive patients.

Cholesterol efflux is regulated by cholesterol transporters, including adenosine triphosphate-binding cassette transporters, A1, G1 (ABCA1, ABCG1), and scavenger receptor class B type I (SR-BI). We have investigated whether the expression of these transporters/receptor is altered in patients with hypertension and also studied their functional effects in cholesterol efflux. The newly diagnosed hypertensive patients, as well as age- and gender-matched healthy controls were recruited. mRNA of ABCA1, ABCG1 and SR-BI in monocytes was measured. The functional effects of the three transporters/receptor and cholesterol efflux from monocyte-derived macrophages ex vivo were also determined. The expression of ABCA1 and ABCG1 was significantly decreased in the newly diagnosed untreated hypertensive patients compared with that in healthy controls. The levels of ABCA1 and ABCG1 were negatively associated with blood pressure, and the reduction of ABCA1 and ABCG1 could be reversed by anti-hypertensive therapy. No significant associations between plasma lipids, oxidized low-density lipoprotein (LDL) and the expression of ABCA1 or ABCG1 were found. Cholesterol efflux from monocyte-derived macrophages to autologous serum, apolipoprotein AI (apoAI) or high-density lipoprotein (HDL) was impaired in hypertensive patients. Cholesterol efflux to autologous serum or apoAI was associated with the expression of ABCA1, whereas cholesterol efflux to autologous serum or HDL was associated with the expression of ABCG1. The expression of ABCA1 and ABCG1 in monocytes is reduced in hypertensive patients, which could be reversed by anti-hypertensive therapy. The reduction in ABCA1/ABCG1 is associated with the impairment of cholesterol efflux from monocyte-derived macrophages.

Impaired serum capacity to induce cholesterol efflux is associated with endothelial dysfunction in type 2 diabetes mellitus.

OBJECTIVE: Reverse cholesterol transport (RCT) plays a protective role against atherosclerosis and cholesterol efflux from cells is an early step in the RCT pathway. We investigated whether the capacity of serum to induce cholesterol efflux was associated with endothelial dysfunction in type 2 diabetes. METHODS: Endothelium-dependent and -independent vasodilation of the brachial artery was measured by high-resolution vascular ultrasound and serum cholesterol efflux capacity was determined by measuring the transfer of [3H]cholesterol from Fu5AH cells to serum in 137 patients with type 2 diabetes and 75 controls. RESULTS: Serum cholesterol efflux capacity was lower in diabetic patients than in the controls (13.6+/-2.5% vs. 14.6+/-3.4%, respectively, p=0.02), and both endothelium-dependent vasodilation (4.9+/-2.2% vs. 8.8+/-4.1%, respectively, p<0.01) and endothelium-independent vasodilation were impaired (13.4+/-4.3% vs. 16.3+/-5.5%. respectively, p<0.01). Endothelium-dependent vasodilation correlated with serum cholesterol efflux capacity (r=0.26, p=0.003) in diabetic patients and controls (r=0.24, p=0.037). On general linear model analysis, the presence of diabetes, brachial artery diameter and serum cholesterol efflux capacity were significant independent determinants of endothelium-dependent vasodilation. CONCLUSION: Impaired serum cholesterol efflux capacity was associated with endothelial dysfunction independent of other cardiovascular risk factors.

Cellular cholesterol efflux to serum is impaired in diabetic nephropathy.

BACKGROUND: Cholesterol efflux from cells is an early step of reverse cholesterol transport (RCT) and the capacity of serum to induce cellular cholesterol efflux has recently been shown to be an independent predictor of coronary artery atherosclerosis. Our aim is to evaluate the capacity of serum to induce ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) mediated cholesterol efflux in type 2 diabetic patients with nephropathy. METHODS: Diabetic patients were recruited according to their urinary albumin excretion rate (normoalbuminuria, microalbuminuria and proteinuria) with 20 subjects in each group and compared with 20 age-matched controls. The ability of the serum to induce cholesterol efflux was measured using a cell culture system. RESULTS: Serum capacity to induce ABCA1-mediated cholesterol efflux was decreased in patients with microalbuminuria or proteinuria (p < 0.05) whereas SR-BI-mediated cholesterol efflux was impaired in all three groups of diabetic patients (p < 0.05). Plasma high-density lipoprotein (HDL) cholesterol and apoAI were reduced in all groups of diabetic patients, but pre-beta-HDL was only significantly decreased in those with microalbuminuria or proteinuria. Serum advanced glycation end products (AGEs) were significantly increased in diabetic patients with microalbuminuria or proteinuria. Serum AGEs and pre-beta-HDL were the significant independent determinants of ABCA1-mediated cholesterol efflux, whereas plasma HDL and log (creatinine) were the significant determinants of SR-BI-mediated cholesterol efflux. CONCLUSION: The capacity of serum to induce ABCA1- and SR-BI-mediated cholesterol efflux was impaired in diabetic patients with incipient or overt nephropathy. These abnormalities may contribute to the accelerated development of atherosclerotic vascular disease in these patients.

Determinants of leukocyte adenosine triphosphate-binding cassette transporter G1 gene expression in type 2 diabetes mellitus.

Cellular cholesterol efflux is regulated by cholesterol transporters including adenosine triphosphate-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI). We have investigated whether the expression of these transporters is affected by type 2 diabetes mellitus and the association with glycemic indexes and oxidized low-density lipoprotein (oxLDL). Messenger RNA of ABCA1, ABCG1, and SR-BI in peripheral monocytes was measured in 30 diabetic patients and 30 matched controls. Plasma oxLDL and advanced glycation end products (AGEs) were assayed by enzyme-linked immunosorbent assay. Cellular cholesterol efflux from monocytes to serum was determined in a subgroup chosen randomly. The expression of ABCG1 was decreased in diabetic patients (P < .05), whereas the levels of ABCA1 and SR-BI were comparable between the 2 groups. Fasting glucose, hemoglobin A(1c), AGEs, and oxLDL were all significantly increased in diabetic patients. There was an inverse correlation between serum AGEs and ABCG1 (r = -0.44, P < .05) that remained significant after adjusting for potential confounding factors. No associations between fasting glucose, hemoglobin A(1c), plasma lipids, or oxLDL and the expression of ABCG1, ABCA1, or SR-BI were found. Cholesterol efflux from monocytes to standard serum or autologous serum was significantly impaired in diabetic patients, and the reduction in efflux to autologous serum correlated with the expression of ABCG1 (r = 0.60, P < .05). The expression of ABCG1 in monocytes is reduced in type 2 diabetes mellitus and is partly related to serum AGEs concentration. The reduction in ABCG1 is associated with impairment in cholesterol efflux and may contribute to accelerated foam cell formation in diabetic patients.

Increased serum advanced glycation end products are associated with impairment in HDL antioxidative capacity in diabetic nephropathy.

BACKGROUND: Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications. Recent data suggest that AGEs may also interfere with the function of HDL and the reverse cholesterol transport pathway. We have investigated whether serum AGE level is associated with impairment in the antioxidative capacity of HDL and in the ability of serum to induce cholesterol efflux in type 2 diabetic patients with and without nephropathy. METHODS: A total of 167 controls and 264 diabetic patients was recruited. The ability of serum to induce cellular cholesterol efflux and the capacity of HDL to inhibit LDL oxidation ex vivo was determined. Serum AGEs were assayed by competitive ELISA using a polyclonal rabbit antisera raised against AGE-RNase. RESULTS: Diabetic subjects were subdivided into three groups (normoalbuminuria, microalbuminuria and proteinuria). Serum AGEs were significantly increased in diabetic patients with microalbuminuria or proteinuria (P < 0.001). Cholesterol efflux was significantly decreased in all three groups of diabetic patients compared to controls (P < 0.001) whereas the antioxidative capacity of HDL was significantly impaired in patients with microalbuminuria or proteinuria (P < 0.01). No relationship between serum AGEs and cholesterol efflux was found. However, serum AGE concentration was significantly associated with the antioxidative capacity of HDL and this was partly due to the adverse effect of AGEs on paraoxonase-1 activity. CONCLUSION: In type 2 diabetic patients with incipient or overt nephropathy, increased serum concentration of AGEs was associated with impairment in the antioxidative capacity of HDL. Cholesterol efflux to serum was also reduced but was not related to serum AGEs.