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Tohru Funahashi - One of the best experts on this subject based on the ideXlab platform.
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Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin.
Endocrine metabolic & immune disorders drug targets, 2012Co-Authors: Ken Kishida, Tohru Funahashi, Iichiro ShimomuraAbstract:Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta-cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially Hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that Hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve Hypoadiponectinemia and thus prevent the development of life style-related diseases including T2DM and ACVD.
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Hypercholesterolemia and Hypoadiponectinemia are associated with necrotic core-rich coronary plaque
International journal of cardiology, 2009Co-Authors: Shinobu Kojima, Tohru Funahashi, Sunao Kojima, Hidetomo Maruyoshi, Yasuhiro Nagayoshi, Koichi Kaikita, Hitoshi Sumida, Seigo Sugiyama, Hisao OgawaAbstract:Abstract Background Hypercholesterolemia is a risk factor for coronary artery disease and closely linked to unstable plaque. Hypoadiponectinemia is frequently observed in patients with metabolic syndrome complicated with macroangiopathy and predicts poor clinical outcome. Spectral analysis of intravascular ultrasonography radiofrequency (IVUS-Virtual Histology [VH]) allows quantitative analysis of plaque composition. The purpose of this study was to verify the effects of low-density lipoprotein (LDL) cholesterol level on plaque morphology, and test the hypothesis that adiponectin influences coronary plaque volume and composition. Methods Preintervention IVUS-VH using a continuous pullback was performed in 92 coronary vessels in 92 patients with coronary artery disease. The morphological distribution of plaque was evaluated prospectively in a 60-mm segment of coronary vessels containing the culprit lesion. Results Serum LDL cholesterol levels correlated positively with necrotic core volume ( r =0.217, P =0.037) and percent necrotic core tissue ( r =0.308, P =0.003), while plasma adiponectin levels correlated negatively with plaque volume ( r =−0.297, P =0.004) and necrotic core volume ( r =−0.306, P =0.003). Multiple regression analyses showed close association between necrotic core volume and statin-use ( β =−21.68, P =0.004) and adiponectin levels ( β =−31.25, P =0.038), and that percent necrotic core tissue was influenced by statin-use ( β =−4.595, P =0.026) and LDL cholesterol levels ( β =0.092, P =0.031). Conclusions Adiponectin is closely linked to coronary plaque volume. Hypercholesterolemia and Hypoadiponectinemia correlate with necrotic core lesions and may contribute to increased risk of coronary plaque vulnerability. Statins can affectively prevent necrotic core plaque formation associated with hypercholesterolemia and Hypoadiponectinemia.
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Visceral obesity and Hypoadiponectinemia are significant determinants of hepatic dysfunction: An epidemiologic study of 3827 Japanese subjects.
Journal of clinical gastroenterology, 2009Co-Authors: Yoshihiro Kamada, Tohru Funahashi, Hitoshi Nishizawa, Yukiyoshi Okauchi, Tadashi Nakamura, Miwa Ryo, Juichi Fukushima, Yuichi Yoshida, Shinichi Kiso, Iichiro ShimomuraAbstract:BACKGROUND AND AIM Adiponectin is an anti-inflammatory and insulin-sensitizing adipocytokine, and its serum concentrations are reduced in obesity with visceral fat accumulation. Visceral fat accumulation is an independent determinant of elevated serum liver enzymes. Hypoadiponectinemia plays important roles in the clinical progression of nonalcoholic steatohepatitis. The aim of this study was to evaluate the relation between visceral fat area (VFA), serum adiponectin concentration, and biochemical liver tests, such as aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) in normal subjects. METHODS The study group comprised 3827 Japanese subjects [mean age+/-SD; 47.6+/-10.7 y: 2854 males (48.4+/-10.7 y), 973 females (45.3+/-10.1 y)], who underwent annual health checkup in 2004. In addition to parameters measured in the annual health checkup, VFA and serum adiponectin concentration were measured by the bioelectrical impedance analysis method and a latex particle-enhanced turbidimetric assay system, respectively. RESULTS Pearson's correlation analysis showed a significant correlation between VFA and the levels of the above 3 liver enzymes in both sexes, and a significant negative correlation between adiponectin and all biochemical liver tests in men and with ALT and GGT in women. Stepwise multiple regression analysis showed that VFA was a significant determinant of serum liver tests in both sexes. Moreover, serum adiponectin concentration significantly and negatively influenced male ALT and GGT and female GGT. CONCLUSIONS Both visceral obesity and Hypoadiponectinemia are significant determinants of subtle and asymptomatic hepatic dysfunction in normal Japanese subjects.
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relationship between the serum uric acid level visceral fat accumulation and serum adiponectin concentration in japanese men
Internal Medicine, 2008Co-Authors: Sachiko Tamba, Tohru Funahashi, Shinji Kihara, Hitoshi Nishizawa, Yukiyoshi Okauchi, Tomoko Ogawa, Midori Noguchi, Koichi Fujita, Hiromi Iwahashi, Kazuya YamagataAbstract:Objective Visceral fat accumulation is an underlying component of the metabolic syndrome (MetS). Hypoadiponectinemia is one of the key molecules of the MetS. In the present study, we investigated the relationship between the serum uric acid level, visceral fat accumulation and serum adiponectin concentration in Japanese men. Patients and Methods The study group comprised 1,520 Japanese employed men (mean age: 45.6±10.4 years, ± SD), who had undergone an annual health check-up both in 2004 and 2005. In addition to parameters measured in the annual health check-up, visceral fat area (VFA) and serum adiponectin concentration were measured by the bioelectrical impedance analysis method and a sandwich enzyme-linked immunosorbent assay (ELISA) system, respectively. Results Visceral fat accumulation was identified in 56.1% of the subjects with hyperuricemia. There was significant positive correlation between visceral fat area and serum uric acid levels (r=0.223, p<0.0001), and negative correlation between serum adiponectin concentration and serum uric acid levels (r=-0.198, p<0.0001). The one-year change in VFA was associated with the one-year change in serum uric acid levels. Stepwise multiple regression analysis showed that VFA and the serum adiponectin concentration were significant explanatory variables for serum uric acid levels. Conclusion Hyperuricemia is significantly associated with visceral fat accumulation and Hypoadiponectinemia in Japanese men.
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adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice
World Journal of Gastroenterology, 2008Co-Authors: Tamao Nishihara, Tohru Funahashi, Shinji Kihara, Miyako Baba, Morihiro Matsuda, Masahiro Inoue, Yasuko Nishizawa, Atsunori Fukuhara, Hiroshi Araki, Shinji TamuraAbstract:AIM: To investigate the causal relationship between Hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model, and to determine the contribution of adiponectin deficiency to colorectal cancer development and proliferation. METHODS: We examined the influence of adiponectin deficiency on colorectal carcinogenesis induced by the administration of azoxymethane (AOM) (7.5 mg/kg, intraperitoneal injection once a week for 8 wk), by using adiponectin-knockout (KO) mice. RESULTS: At 53 wk after the first AOM treatment, KO mice developed larger and histologically more progressive colorectal tumors with greater frequency compared with wild-type (WT) mice, although the tumor incidence was not different between WT and KO mice. KO mice showed increased cell proliferation of colorectal tumor cells, which correlated with the expression levels of cyclooxygenase-2 (COX-2) in the colorectal tumors. In addition, KO mice showed higher incidence and frequency of liver tumors after AOM treatment. Thirteen percent of WT mice developed liver tumors, and these WT mice had only a single tumor. In contrast, 50% of KO mice developed liver tumors, and 58% of these KO mice had multiple tumors. CONCLUSION: Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice. This study strongly suggests that Hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.
Feng Gao - One of the best experts on this subject based on the ideXlab platform.
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GW24-e1276 Hypoadiponectinemia induces vascular insulin resistance in normotensive young spontaneously hypertensive rats and the underlying mechanisms
Heart, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Objectives Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. However, the mechanism responsible for inducing vascular insulin resistance in prehypertension remains elusive. The present study aimed to determine whether Hypoadiponectinemia causes vascular insulin resistance in prehypertension and to investigate the involved mechanisms. Methods Four-week-age prehypertensive spontaneously hypertensive rats (ySHRs) and adiponectin knockout mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. Mesenteric arterioles were isolated from rats and mice (anaesthetised with 30 mg/kg pentobarbital sodium, i.p.), cut into 3∼4 ring segments with 1 mm long, and subjected to functional assessments. Results Mesenteric arteriole segments of ySHRs showed a markedly reduced vasorelaxation response to insulin compared with those of age-matched Wistar-Kyoto controls (WKY) (21.6 % ± 3.2% vs. 41.6% ± 4.4% to 10 -6 mol/L insulin, n = 8-10 arteriole segments from 6-8 rats, P P in vivo with the globular domain of adiponectin (gAd) for 1 week increased insulin-induced vasorelaxant effect (32.5% ± 2.5% vs. 21.6% ± 3.2 %, P P Conclusions Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by reciprocally modulating the Akt/eNOS/NO and ERK1/2/ET-1 pathways in vascular endothelium in prehypertensive SHRs. Therefore, restoration of endogenous adiponectin production, supplementation with exogenous adiponectin and treatment targeting APPL1 may have potential therapeutic value in the prevention and alleviation of endothelial dysfunction and hypertension.
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a novel mechanism for vascular insulin resistance in normotensive young shrsnovelty and significance Hypoadiponectinemia and resultant appl1 downregulation
Hypertension, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN -/- ) mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN -/- mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.
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a novel mechanism for vascular insulin resistance in normotensive young shrs Hypoadiponectinemia and resultant appl1 downregulation
Hypertension, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN(-/-)) mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN(-/-) mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.
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Response to Hypoadiponectinemia and Endogenous Nitric Oxide Synthase Inhibitor in Hypertension
Hypertension (Dallas Tex. : 1979), 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Feng Gao, Haifeng ZhangAbstract:We thank Dr Tsuda1 for his interest in our work and his insightful comments. We agree with Dr Tsuda1 that it is interesting and important to elucidate the role of nitric oxide (NO) bioavailability, including asymmetric dimethyl arginine (ADMA, an endogenous NO synthase inhibitor) levels in the development of vascular insulin resistance and hypertension. Insulin-induced vasorelaxation contributes to the maintenance of microvascular tone and vascular resistance. Therefore, vascular insulin resistance plays a role in elevated peripheral vascular resistance and subsequent hypertension. However, mechanisms responsible for vascular insulin resistance during the prehypertensive stage remain elusive. Recently, we found that Hypoadiponectinemia induces low APPL1 (an adaptor protein that mediates adiponectin signaling) expression …
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Abstract 13009: A Novel Mechanism for Vascular Insulin Resistance in Normotensive Young SHRs: Hypoadiponectinemia and Resultant APPL1 Downregulation
Circulation, 2012Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Aims: Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation has revealed that a low plasma adiponectin concentration is significantly associated with hypertension. The present study aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance in prehypertension and to investigate the involved mechanisms. Methods: Four-week-age prehypertensive spontaneously hypertensive rats (ySHRs) and adiponectin knockout mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. Results: Mesenteric arteriole segments of ySHRs showed a markedly reduced vasorelaxation response to insulin compared with those of age-matched Wistar-Kyoto controls (WKY) (21.6 % ± 3.2 % vs. 41.6 % ± 4.4 % to 10 -6 mol/L insulin, n=8-10 arteriole segments from 6-8 rats, P vs. 4.89 ± 0.49 μ g/ml, P in vivo with the globular domain of adiponectin (gAd) for 1 week increased insulin-induced vasorelaxant effect (32.5 % ± 2.5 % vs. 21.6 % ± 3.2 %, P P Conclusion: Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by reciprocally modulating the Akt/eNOS/NO and ERK1/2/ET-1 pathways in vascular endothelium in prehypertensive SHRs.
Katsuhiro Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123i metaiodobenzylguanidine scintigraphy
Metabolism-clinical and Experimental, 2007Co-Authors: Naohiko Takahashi, Futoshi Anan, Mikiko Nakagawa, Kunio Yufu, Tetsuji Shinohara, Tetsuo Tsubone, Koro Goto, Takayuki Masaki, Isao Katsuragi, Katsuhiro TanakaAbstract:Hypoadiponectinemia is associated with insulin resistance. However, there is very limited information about the relationship between plasma adiponectin and cardiac autonomic nervous function. We tested the hypothesis that Hypoadiponectinemia is associated with cardiac sympathetic overactivity in patients with type 2 diabetes mellitus. Thirty-three male type 2 diabetic patients not on insulin treatment were classified into a Hypoadiponectinemia group (plasma adiponectin concentration, <4.0 μg/mL; age, 58.6 ± 8.6 years [mean ± SD]; n = 14) and an age-matched normoadiponectinemia group (serum adiponectin concentration, ≥4.0 μg/mL; age, 58.2 ± 8.1 years; n = 19). In each patient, baroreflex sensitivity, heart rate variability, plasma norepinephrine concentration, and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings were assessed. Compared with the normoadiponectinemia group, the Hypoadiponectinemia group had a higher body mass index (P < .01), higher plasma concentrations of glucose and insulin (P < .05 and P < .01, respectively), higher homeostasis model assessment of insulin resistance (HOMA-IR) values (P < .005), higher plasma triglyceride levels (P < .05), and lower plasma high-density lipoprotein cholesterol levels (P < .05). In the Hypoadiponectinemia group, the autonomic function measurements included a lower baroreflex sensitivity (P< .05) and a lower delayed myocardial uptake of 123I-MIBG (P < .01) with a higher washout rate (P < .05). Multiple regression analysis revealed that the plasma adiponectin level was independently associated with HOMA-IR (F = 9.916) and the percent washout rate of 123I-MIBG (F = 5.985). Our results suggest that in middle-aged men with type 2 diabetes mellitus, Hypoadiponectinemia is associated with cardiac sympathetic overactivity as determined by 123I-MIBG scintigraphy.
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Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy.
Metabolism: clinical and experimental, 2007Co-Authors: Naohiko Takahashi, Futoshi Anan, Mikiko Nakagawa, Kunio Yufu, Tetsuji Shinohara, Tetsuo Tsubone, Koro Goto, Takayuki Masaki, Isao Katsuragi, Katsuhiro TanakaAbstract:Hypoadiponectinemia is associated with insulin resistance. However, there is very limited information about the relationship between plasma adiponectin and cardiac autonomic nervous function. We tested the hypothesis that Hypoadiponectinemia is associated with cardiac sympathetic overactivity in patients with type 2 diabetes mellitus. Thirty-three male type 2 diabetic patients not on insulin treatment were classified into a Hypoadiponectinemia group (plasma adiponectin concentration,
Yasuo Terauchi - One of the best experts on this subject based on the ideXlab platform.
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Hypoadiponectinemia plays a crucial role in the development of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus independent of visceral adipose tissue
Alcoholism: Clinical and Experimental Research, 2007Co-Authors: Masato Yoneda, Tomoyuki Iwasaki, Koji Fujita, Hiroyuki Kirikoshi, Masahiko Inamori, Yuichi Nozaki, Shiro Maeyama, Koichiro Wada, Satoru Saito, Yasuo TerauchiAbstract:Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Insulin resistance has been found to increase the risk of NASH, and obesity, and decreased levels of adiponectin are important factors in determining the severity of insulin resistance. Recent evidence has indicated that Hypoadiponectinemia is involved in hepatic steatosis and NASH. Methods: To investigate whether Hypoadiponectinemia causes hepatic steatosis in type 2 diabetes mellitus (DM) patients independently of visceral adipose tissue, we measured the plasma adiponectin concentration, hepatic fat content based on the liver-to-spleen ratio (L/S ratio) according to computed tomography (CT) attenuation values, and the amount of visceral adipose tissue and subcutaneous adipose tissue by CT in 248 type 2 DM patients. We also investigated the relationship between the serum level of adiponectin and hepatic fibrosis. Results: Significant correlations were observed between the L/S ratios and aspartate aminotransferase, alanine aminotransferase, visceral adipose tissue, subcutaneous adipose tissue, and serum adiponectin values (r=0.300, p=0.0007), and there was a highly significant inverse correlation between the visceral adipose tissue values and the serum adiponectin levels (r=−0.327, p<0.0002). The subcutaneous adipose tissue values, however, were not correlated with the serum adiponectin levels. Multiple regression analysis was used to quantify the impact of measured variables on the L/S ratio. After adjustment for age, gender, and visceral adipose tissue, the serum adiponectin levels were still significantly correlated with the L/S ratios (p=0.0064). And there was a stepwise decrease in the serum adiponectin in parallel to the severity of hepatic fibrosis. Conclusions: Hypoadiponectinemia is concluded to be involved in the etiology of hepatic steatosis independently of visceral adipose tissue content, and is considered to be an important factor in the progression of fibrosis; further studies will be necessary to elucidate the exact physiological role of adiponectin and its contribution to the progression of NASH.
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Hypoadiponectinemia plays a crucial role in the development of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus independent of visceral adipose tissue.
Alcoholism clinical and experimental research, 2007Co-Authors: Masato Yoneda, Tomoyuki Iwasaki, Koji Fujita, Hiroyuki Kirikoshi, Masahiko Inamori, Yuichi Nozaki, Shiro Maeyama, Koichiro Wada, Satoru Saito, Yasuo TerauchiAbstract:Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Insulin resistance has been found to increase the risk of NASH, and obesity, and decreased levels of adiponectin are important factors in determining the severity of insulin resistance. Recent evidence has indicated that Hypoadiponectinemia is involved in hepatic steatosis and NASH. Methods: To investigate whether Hypoadiponectinemia causes hepatic steatosis in type 2 diabetes mellitus (DM) patients independently of visceral adipose tissue, we measured the plasma adiponectin concentration, hepatic fat content based on the liver-to-spleen ratio (L/S ratio) according to computed tomography (CT) attenuation values, and the amount of visceral adipose tissue and subcutaneous adipose tissue by CT in 248 type 2 DM patients. We also investigated the relationship between the serum level of adiponectin and hepatic fibrosis. Results: Significant correlations were observed between the L/S ratios and aspartate aminotransferase, alanine aminotransferase, visceral adipose tissue, subcutaneous adipose tissue, and serum adiponectin values (r=0.300, p=0.0007), and there was a highly significant inverse correlation between the visceral adipose tissue values and the serum adiponectin levels (r=−0.327, p
Wenjuan Xing - One of the best experts on this subject based on the ideXlab platform.
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GW24-e1276 Hypoadiponectinemia induces vascular insulin resistance in normotensive young spontaneously hypertensive rats and the underlying mechanisms
Heart, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Objectives Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. However, the mechanism responsible for inducing vascular insulin resistance in prehypertension remains elusive. The present study aimed to determine whether Hypoadiponectinemia causes vascular insulin resistance in prehypertension and to investigate the involved mechanisms. Methods Four-week-age prehypertensive spontaneously hypertensive rats (ySHRs) and adiponectin knockout mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. Mesenteric arterioles were isolated from rats and mice (anaesthetised with 30 mg/kg pentobarbital sodium, i.p.), cut into 3∼4 ring segments with 1 mm long, and subjected to functional assessments. Results Mesenteric arteriole segments of ySHRs showed a markedly reduced vasorelaxation response to insulin compared with those of age-matched Wistar-Kyoto controls (WKY) (21.6 % ± 3.2% vs. 41.6% ± 4.4% to 10 -6 mol/L insulin, n = 8-10 arteriole segments from 6-8 rats, P P in vivo with the globular domain of adiponectin (gAd) for 1 week increased insulin-induced vasorelaxant effect (32.5% ± 2.5% vs. 21.6% ± 3.2 %, P P Conclusions Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by reciprocally modulating the Akt/eNOS/NO and ERK1/2/ET-1 pathways in vascular endothelium in prehypertensive SHRs. Therefore, restoration of endogenous adiponectin production, supplementation with exogenous adiponectin and treatment targeting APPL1 may have potential therapeutic value in the prevention and alleviation of endothelial dysfunction and hypertension.
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a novel mechanism for vascular insulin resistance in normotensive young shrsnovelty and significance Hypoadiponectinemia and resultant appl1 downregulation
Hypertension, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN -/- ) mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN -/- mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.
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a novel mechanism for vascular insulin resistance in normotensive young shrs Hypoadiponectinemia and resultant appl1 downregulation
Hypertension, 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN(-/-)) mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN(-/-) mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.
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Response to Hypoadiponectinemia and Endogenous Nitric Oxide Synthase Inhibitor in Hypertension
Hypertension (Dallas Tex. : 1979), 2013Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Feng Gao, Haifeng ZhangAbstract:We thank Dr Tsuda1 for his interest in our work and his insightful comments. We agree with Dr Tsuda1 that it is interesting and important to elucidate the role of nitric oxide (NO) bioavailability, including asymmetric dimethyl arginine (ADMA, an endogenous NO synthase inhibitor) levels in the development of vascular insulin resistance and hypertension. Insulin-induced vasorelaxation contributes to the maintenance of microvascular tone and vascular resistance. Therefore, vascular insulin resistance plays a role in elevated peripheral vascular resistance and subsequent hypertension. However, mechanisms responsible for vascular insulin resistance during the prehypertensive stage remain elusive. Recently, we found that Hypoadiponectinemia induces low APPL1 (an adaptor protein that mediates adiponectin signaling) expression …
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Abstract 13009: A Novel Mechanism for Vascular Insulin Resistance in Normotensive Young SHRs: Hypoadiponectinemia and Resultant APPL1 Downregulation
Circulation, 2012Co-Authors: Wenjuan Xing, Wenjun Yan, Peilin Liu, Lu Sun, Ling Tao, Haifeng Zhang, Feng GaoAbstract:Aims: Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation has revealed that a low plasma adiponectin concentration is significantly associated with hypertension. The present study aimed to determine whether Hypoadiponectinemia induces vascular insulin resistance in prehypertension and to investigate the involved mechanisms. Methods: Four-week-age prehypertensive spontaneously hypertensive rats (ySHRs) and adiponectin knockout mice were used to evaluate the role of Hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. Results: Mesenteric arteriole segments of ySHRs showed a markedly reduced vasorelaxation response to insulin compared with those of age-matched Wistar-Kyoto controls (WKY) (21.6 % ± 3.2 % vs. 41.6 % ± 4.4 % to 10 -6 mol/L insulin, n=8-10 arteriole segments from 6-8 rats, P vs. 4.89 ± 0.49 μ g/ml, P in vivo with the globular domain of adiponectin (gAd) for 1 week increased insulin-induced vasorelaxant effect (32.5 % ± 2.5 % vs. 21.6 % ± 3.2 %, P P Conclusion: Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by reciprocally modulating the Akt/eNOS/NO and ERK1/2/ET-1 pathways in vascular endothelium in prehypertensive SHRs.