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Moriya T.,Kitasato University | Tanaka S.,Kyoto University | Kawasaki R.,Kyoto University | Ohashi Y.,University of Tokyo | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To examine the interactive relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetic patients and to elucidate the role of DR and microalbuminuria on the onset of macroalbuminuria and renal function decline. RESEARCH DESIGN AND METHODS-We explored the effects of DR and microalbuminuria on the progression of DN from normoalbuminuria and low microalbuminuria (<150 mg/gCr) to macroalbuminuria or renal function decline in the Japan Diabetes Complications Study (JDCS), which is a nationwide randomized controlled study of type 2 diabetic patients focusing on lifestyle modification. Patients were divided into four groups according to presence or absence of DR and MA: normoalbuminuria without DR [NA(DR-)] (n = 773), normoalbuminuria with DR [NA(DR+)] (n = 279), microalbuminuria without DR [MA(DR2)] (n = 277), and microalbuminuria with DR [MA(DR+)] (n = 146). Basal urinary albumin-to-creatinine ratio and DR status were determined at baseline and followed for a median of 8.0 years. RESULTS-Annual incidence rates of macroalbuminuria were 1.6/1,000 person-years (9 incidences), 3.9/1,000 person-years (8 incidences), 18.4/1,000 person-years (34 incidences), and 22.1/1,000 person-years (22 incidences) in the four groups, respectively. Multivariate-adjusted hazard ratios of the progression to macroalbuminuria were 2.48 (95% CI 0.94-6.50; P = 0.07), 10.40 (4.91-22.03; P< 0.01), and 11.55 (5.24-25.45; P < 0.01) in NA(DR+), MA(DR-), and MA(DR+), respectively, in comparison with NA(DR-). Decline in estimated glomerular filtration rate (GFR) per year was two to three times faster in MA(DR+) (-1.92 mL/min/1.73m2/year) than in the other groups. CONCLUSIONS-In normo- and low microalbuminuric Japanese type 2 diabetic patients, presence ofmicroalbuminuria at baseline was associated with higher risk ofmacroalbuminuria in 8 years. Patients with microalbuminuria and DR showed the fastest GFR decline. Albuminuria and DR should be considered as risk factors of renal prognosis in type 2 diabetic patients. An open sharing of information will benefit both ophthalmologists and diabetologists. ©2013 by the American Diabetes Association. Source

Nakatsu Y.,Hiroshima University | Seno Y.,Hiroshima University | Kushiyama A.,Institute for Adult Disease | Sakoda H.,University of Miyazaki | And 9 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2015

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnelpositive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. © 2015 the American Physiological Society. Source

Shinjo T.,Kyushu University | Nakatsu Y.,Hiroshima University | Iwashita M.,Kyushu University | Sano T.,Hiroshima University | And 9 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2015

Dipeptidyl peptidase IV (DPPIV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitateinduced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF- κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF- κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF- κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events. © 2015 the American Physiological Society. Source

Katayama S.,Saitama University | Moriya T.,Kitasato University | Tanaka S.,Kyoto University | Tanaka S.,Tokyo University of Science | And 6 more authors.
Diabetologia | Year: 2011

Aims/hypothesis: The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria). Methods: For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year. Results: Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p<0.01). The hazard ratio for an HbA 1c of 7-9% or ≥9% was 2.72 (p<0.01) or 5.81 (p<0.01) relative to HbA1c <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or ≥140 mmHg were 2.31 (p=0.06) and 3.54 (p<0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p<0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission). Conclusions/interpretation: These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful. © The Author(s) 2011. Source

Ohno H.,Hiroshima University | Nakatsu Y.,Hiroshima University | Sakoda H.,University of Tokyo | Kushiyama A.,Institute for Adult Disease | And 13 more authors.
American Journal of Physiology - Cell Physiology | Year: 2011

Glucose transporter 1 (GLUT1) is widely distributed throughout various tissues and contributes to insulin- independent basal glucose uptake. Using a split-ubiquitin membrane yeast two-hybrid system, we newly identified 4F2 heavy chain (4F2hc) as a membrane protein interacting with GLUT1. Though 4F2hc reportedly forms heterodimeric complexes between amino acid transporters, such as LAT1 and LAT2, and regulates amino acid uptake, we investigated the effects of 4F2hc on GLUT1 expression and the associated glucose uptake. First, FLAG-tagged 4F2hc and hemagglutinin-tagged GLUT1 were overexpressed in human embryonic kidney 293 cells and their association was confirmed by coimmunoprecipitation. The green fluorescent protein-tagged 4F2hc and DsRed-tagged GLUT1 showed significant, but incomplete, colocalization at the plasma membrane. In addition, an endogenous association between GLUT1 and 4F2hc was demonstrated using mouse brain tissue and HeLa cells. Interestingly, overexpression of 4F2hc increased the amount of GLUT1 protein in HeLa and HepG2 cells with increased glucose uptake. In contrast, small interfering RNA (siRNA)-mediated 4F2hc gene suppression markedly reduced GLUT1 protein in both cell types, with reduced glucose uptake. While GLUT1 mRNA levels were not affected by overexpression or gene silencing of 4F2hc, GLUT1 degradation after the addition of cycloheximide was significantly suppressed by 4F2hc overexpression and increased by 4F2hc siRNA treatment. Taken together, these observations indicate that 4F2hc is likely to be involved in GLUT1 stabilization and to contribute to the regulation of not only amino acid but also glucose metabolism. © 2011 the American Physiological Society. Source

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