Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling

OBJECTIVE: The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations. METHODS AND RESULTS: In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE(-/-)Irs2(+/-)) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs. CONCLUSIONS: Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states

Word Recognition of Digit Triplets and Monosyllabic Words in Multitalker Babble by Listeners With Sensorineural Hearing Loss

In an initial experiment (Wilson and Weakley, 2004), word recognition was assessed with six digit triplets presented at 14 signal-to-babble ratios (S/B) in 2 dB steps. An abbreviated version of the protocol was developed for clinic use involving three digit triplets at 7 S/Bs in 4 dB steps. The purpose of this experiment was to examine the relationship between the two digit protocols with comparisons made with other variables including age, pure-tone thresholds, subjective measures of understanding speech in quiet and in noise, and word recognition of monosyllabic words in quiet and in babble. Ninety-six listeners with sensorineural hearing loss participated. For equivalent performance, the short version of the digit triplets required (1) a 2.6 dB more favorable S/B than the long version and (2) a 15.1 dB less favorable S/B than the words. Age, hearing loss, and subjective evaluation of the ability to understand speech in quiet and in noise were not related to performance on digits or words in multitalker babble

A Comparison of Word-Recognition Abilities Assessed With Digit Pairs and Digit Triplets in Multitalker Babble

This study compares, for listeners with normal hearing and listeners with hearing loss, the recognition performances obtained with digit-pair and digit-triplet stimulus sets presented in multitalker babble. Digits 1 through 10 (excluding 7) were mixed in approximately 1,000 ms segments of babble from 4 to -20 dB signal-to-babble (S/B) ratios, concatenated to form the pairs and triplets, and recorded on compact disc. Nine and eight digits were presented at each level for the digit-triplet and digit-pair paradigms, respectively. For the listeners with normal hearing and the listeners with hearing loss, the recognition performances were 3 dB and 1.2 dB better, respectively, on digit pairs than on digit triplets. For equal intelligibility, the listeners with hearing loss required an approximately 10 dB more favorable S/B than the listeners with normal hearing. The distributions of the 50% points for the two groups had no overlap

Word Recognition in Multitalker Babble Measured With Two Psychophysical Methods

The purpose of this experiment was to determine the relationship between psychometric functions for words presented in multitalker babble using a descending presentation level protocol and a random presentation level protocol. Forty veterans (mean = 63.5 years) with mild-to-moderate sensorineural hearing losses were enrolled. Seventy of the Northwestern University Auditory Test No. 6 words spoken by the VA female speaker were presented at seven signal-to-babble ratios from 24 to 0 dB (10 words/step). Although the random procedure required 69 sec longer to administer than the descending protocol, there was no significant difference between the results obtained with the two psychophysical methods. There was almost no relation between the perceived ability of the listeners to understand speech in background noise and their measured ability to understand speech in multitalker babble. Likewise, there was a tenuous relation between pure-tone thresholds and performance on the words in babble and between recognition performance in quiet and performance on the words in babble

The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine

Signal transduction by insulin and IGF-1, severa