Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.
Morphological measurements of the nasal and paranasal cavities were conducted to investigate their relevance to the acoustic properties of the human nasal tract. The magnetic resonance imaging (MRI) technique was used to measure the three-dimensional geometry of the vocal tract. The area function of the nasal tract was calculated for seven subjects based on data obtained during natural breathing. The entire vocal tract was measured for five subjects during sustained production of nasal consonants. A marked morphological difference was observed between our data and previously published data [A. S. House and K. N. Stevens, J. Speech Hear. Disord. 21, 218-232 (1956); G. Fant, Acoustic Theory of Speech Production (Mouton, The Hague, 1970), 2nd ed., p. 139] particularly in the middle portion of the nasal tract. Previous data derived from cadaver specimens showed a large cavity in the middle portion possibly due to an absent or dehydrated mucous membrane, while our data showed narrow passages due to thickly layered mucosa. It has been confirmed by an additional experiment that the wide cavity is reproducible by applying an adrenergic agent to the nasal mucosa. Transfer functions of the vocal tract and the nasal tract were calculated from measured data, and compared to spectra of real speech signals recorded subsequent to the MRI experiment. The results indicate that asymmetry between the two nasal passages can cause extra pole-zero pairs, and suggest that the paranasal cavities play an important role in shaping the spectral characteristics of human nasal sounds.
Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-γ agonist, reportedly has more beneficial effects on insulin sensitivity than other angiotensin II type 1 receptor blockers. In this study, we studied the effects of telmisartan on the adipose tissue macrophage phenotype in high-fat-fed mice. Telmisartan was administered for 5 wk to high-fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in visceral adipose tissues were then examined. An insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight, and adipocyte size without affecting the amount of energy intake. Telmisartan reduced the mRNA expression of CD11c and TNF-α, M1 macrophage markers, and significantly increased the expressions of M2 markers, such as CD163, CD209, and macrophage galactose N-acetyl-galactosamine specific lectin (Mgl2), in a quantitative RT-PCR analysis. A flow cytometry analysis showed that telmisartan decreased the number of M1 macrophages in visceral adipose tissues. In conclusion, telmisartan improves insulin sensitivity and modulates adipose tissue macrophage polarization to an antiinflammatory M2 state in high-fat-fed mice.
AimsTo evaluate the effect of multifaceted interventions using the Achievable Benchmark of Care (ABC) method for improving the technical quality of diabetes care in primary care settings.MethodsWe conducted a 1‐year cluster randomized controlled trial in 22 regions divided into an intervention group (IG) or control group (CG). Physicians in the IG received a monthly report of their care quality, with the top 10% quality of diabetes care scores for all physicians being the achievable benchmark. The change in quality‐of‐care scores between the IG and CG during follow‐up was analysed using a generalized linear model considering clustering.ResultsA total of 2199 patients were included. Their mean (sd) age was 56.5 ± 5.9 years and the mean (sd) HbA1c level was 56.4 ± 13.3 mmol/mol (7.4 ± 1.2%). The quality‐of‐care score in the CG changed from 50.2%‐point at baseline to 51%‐point at 12 months, whereas the IG score changed from 49.9%‐point to 69.6%‐point, with statistically significant differences between the two groups during follow‐up [the effect of intervention was 19.0%‐point (95% confidence interval 16.7%‐ to 21.3%‐point; P < 0.001)].ConclusionsMultifaceted intervention, measuring quality‐of‐care indicators and providing feedback regarding the quality of diabetes care to physicians with ABC, was effective for improving the technical quality of care in patients with Type 2 diabetes in primary care settings. (Trial Registration: umin.ac.jp/ctr as UMIN000002186)
Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFalpha-induced insulin resistance in 3T3-L1 adipocytes. TNFalpha transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFalpha treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFalpha. TNFalpha stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFalpha treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFalpha. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFalpha or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFalpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.
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