High-carb or low-carb, that is a question

Embargo Period 12 month

スルフォニル尿素剤およびビグアナイド剤の脂肪細胞分化に及ぼす影響: 培養3T3-L1前脂肪細胞を用いての検討

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1055号, 学位授与年月日：平成4年7月31日,学位授与年：199

[学会開催報告]

[学会開催報告

2型糖尿病患者の肝臓における酸化的リン酸化を制御するマスター遺伝子の同定

本研究では、2型糖尿病患者の肝臓で発現変動する遺伝子および代謝パスウェイを抽出し、それらの病態生理学的意義を遺伝子発現-臨床連関から明らかにするとともに,代謝パスウェイの協調的発現制御機構解明を試みた。1)2型糖尿病患者および健常者の肝に発現する遺伝子のSAGE解析およびDNAチップ解析:糖尿病肝および正常肝の間で差異のある遺伝子と代謝パスウェイを抽出した。2)病態形成分泌タンパク候補遺伝子の抽出:SAGEおよびDNAチップ解析で抽出した機能未解明の分泌蛋白コード遺伝子のうち、BMI、インスリン抵抗性、血糖コントロールなどの病態と発現量が関連している遺伝子を同定し、特許出願した(出願番号2005-125689)。3)代謝パスウェイの抽出:2型糖尿病の肝臓ではミトコンドリア酸化的リン酸化に関与するOXPHOS遺伝子が協調的に発現亢進していることを明らかにした。4)肝臓におけるOXPHOS遺伝子群の病態生理学的意義の解明:OXPHOS遺伝子群各遺伝子の標準化スコア平均値をOXPHOS mean centroid として算出し,2型糖尿病の病態との関連を検索した.その結果OXPHOS mean centroidは空腹時血糖値およびインスリン抵抗性指数と相関した。5)肝臓におけるOXPHOS遺伝子群の協調的発現を制御する病態・因子:肝発現遺伝子相互の関連を解析したところ、OXPHOS mean centroidは糖新生関連遺伝子群、活性酸素産生系およびredox系遺伝子群と有意に正相関した。したがって、糖尿病患者の肝臓では、糖代謝・脂質代謝の結果生じる基質の過剰供給によりOXPHOSおよび活性酸素産生系遺伝子群が発現亢進し、酸化ストレスが生じて肝臓におけるインスリン抵抗性がもたらされる可能性がある。さらに、転写因子・転写補助因子の中でも、PPARG,ESRRA,NCOA1,THRA,NCOA2などのエネルギー代謝に関わる遺伝子と正相関した。これらの中に、肝と骨格筋における組織特異的OXPHOS遺伝子発現を制御する因子が存在する可能性がある。Mitochondrial oxidative phosphorylation (OXPHOS) plays an important role in the pathophysiology of type 2 diabetes. Genes for OXPHOS have been reported to be down-regulated in the skeletal muscle from patients with type 2 diabetes; however, hepatic regulation is unknown.In the present study, I analyzed gene expression for OXPHOS from the livers of 14 patients with type 2 diabetes and 14 subjects with normal glucose tolerance (NGT) using serial analysis of gene expression (SAGE) and DNA chip analysis. I evaluated the correlation between gene expression levels for OXPHOS and clinical parameters of individuals with type 2 diabetes and NGT.Both gene analyses showed that genes for OXPHOS were significantly up-regulated in the type 2 diabetic liver.In the SAGE analysis, tag count comparisons of mitochondrial transcripts showed that rRNAs were 3.5-fold over-expressed, and mRNAs were 1.2-fold over-expressed in the type 2 diabetes library. DNA chip analysis revealed that gene expression for OXPHOS, which correlated with several nuclear factors, including estrogen-related receptor-a (ERR-α) or peroxisome proliferator-activated receptor-y (PPAR-y), was a predictor of fasting plasma glucose levels, independent of age, body mass index, insulin resistance, and fasting insulin levels (P=0.04). Surprisingly, genes for OXPHOS did not correlate with either peroxisome proliferator-activated receptor-γ coactivator-la (PGC-1α) or nuclear respiratory factor 1 (NRF-1).These results indicate that up-regulated genes for OXPHOS in the liver, which are regulated by different mechanisms from genes in the skeletal muscle, are associated with fasting hyperglycemia in patients with type 2 diabetes.研究課題/領域番号:17590920, 研究期間(年度):2005-2006出典：「2型糖尿病患者の肝臓における酸化的リン酸化を制御するマスター遺伝子の同定」研究成果報告書　課題番号17590920 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

Ectopic fat accumulation in the liver and glucose homeostasis

Liver fat is associated not only with enhanced hepatic glucose production but also with skeletal muscle insulin resistance, supporting a central role of fatty liver in systemic insulin resistance and existence of a network between the liver and skeletal muscle. Palmitate and cholesterol act as toxic lipids to cause hepatic insulin resistance via mitochondria-derived oxidative stress. Obesity-mediated disruption in crosstalk among protein-, glucose- and lipid-metabolism pathways results in hepatic insulin resistance, enhanced gluconeogenesis and liver steatosis by impairing proteasome function. The liver plays as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated skeletal muscle insulin resistance through unique mechanisms. Selenoprotein P is upregulated through FoxOs and hyperglycemia and causes resistance to insulin, angiogenesis and exercise through reductive stress. LECT2 is upregulated in satiety through AMPK inactivation and contributes to the development of muscle insulin resistance and obesity by activating JNK and by impairing myogenesis, respectively. Therefore, overnutrition evokes remodeling of nutrient homeostasis by toxic lipids and proteasome dysfunction in the liver. The remodeling also results in the overproduction of hepatokines that disrupt inter-organ network leading to pathology of diabetes. © Springer Japan 2016.Book Chapter / Embargo Period 12 month

Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-α stimulation, and effects of a phosphodiesterase inhibitor

大学院医学系研究科環境社会医学Diabetic nephropathy is a major complication of diabetes leading to end-stage renal disease, which requires hemodialysis. Although the mechanism by which it progresses is largely unknown, the role of hyperglycemia-derived oxidative stress has recently been the focus of attention as the cause of diabetic complications. Constituent cells of the renal glomeruli have the capacity to release reactive oxygen species (ROS) upon stimulation of NADPH oxidase activated by protein kinase C (PKC). Hyperglycemia and insulin resistance in the diabetic state are often associated with activation of PKC and tumor necrosis factor (TNF)-α, respectively. The aim of this study is to clarify the signaling pathway leading to ROS production by PKC and TNF-α in rat glomeruli. Isolated rat glomeruli were stimulated with phorbol 12-myristate 13-acetate (PMA) and TNF-α, and the amount of ROS was measured using a chemiluminescence method. Stimulation with PMA (10 ng/ml) generated ROS with a peak value of 136 ± 1.2 cpm/mg protein (mean ± SEM). The PKC inhibitor H-7, the NADPH oxidase inhibitor diphenylene iodonium and the phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin inhibited PMA-induced ROS production by 100%, 100% and 80%, respectively. In addition, TNF-α stimulated ROS production (283 ± 5.8/mg protein/20 min). The phosphodiesterase inhibitor cilostazol activates protein kinase A and is reported to improve albuminuria in diabetic rats. Cilostazol (100 μg/ml) inhibited PMA, and TNF-α-induced ROS production by 78 ± 1.8, and 19 ± 2.7%, respectively. The effects of cilostazol were not additive with wortmannin. Cilostazol arrests oxidative stress induced by PKC activation by inhibiting the PI-3 kinase-dependent pathway, and may thus prevent the development of diabetic nephropathy. © 2007 Elsevier Inc. All rights reserved

Pioglitazone in Nonalcoholic Steatohepatitis

金沢大学医薬保健研究域医学

Comment on: Nathan DM, Buse JB, Davidson MB et al. (2006) Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.

金沢大学大学院医学系研究科環境社会医

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

金沢大学医学部附属病院内科The relationship between the effect of aldose reductase inhibitors (ARIs) on the activation of the polyol pathway and on diabetic neuropathy has not been fully established. To address this issue, we investigated the effect of epalrestat (150 mg/day), an ARI, on erythrocyte sorbitol levels as an index of polyol activation and on nerve function test results in 43 patients with diabetic peripheral polyneuropathy. After 6 months of epalrestat administration, erythrocyte sorbitol levels did not decrease in patients as a whole. However, a decrease in erythrocyte sorbitol levels during epalrestat administration was significantly correlated with baseline erythrocyte sorbitol levels (ρ=-.47, P<.01): The higher the level at baseline, the greater the decrease after epalrestat treatment. Moreover, the mean sorbitol level during epalrestat treatment was associated with the beneficial effect of epalrestat on vibration sensitivity as measured with a C-128 tuning fork (ρ=-.66, P<.01) and/or a pallesthesiometer TM-31A (ρ=.53, P<.05). On the other hand, erythrocyte sorbitol levels did not reflect the prognosis of nerve conduction velocity. These findings at least partly suggest a causal relationship between polyol activation and the development of diabetic neuropathy. Aldose reductase inhibitor treatment may be clinically useful in the control of polyol activation, especially in patients with excessive accumulation of sorbitol. © 2006 Elsevier Inc. All rights reserved