Selenoprotein P as a diabetesassociated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

13301甲第4107号博士（医学）金沢大学博士論文本文Full 以下に掲載：Diabetologia 57(9) pp.1968-1976 2014.Springer. 共著者：Kazuhide Ishikura, Hirofumi Misu, Masafumi Kumazaki, Hiroaki Takayama, Naoto Matsuzawa-Nagata, Natsumi Tajima, Keita Chikamoto, Fei Lan, Hitoshi Ando, Tsuguhito Ota, Masaru Sakurai, Yumie Takeshita, Kenichiro Kato, Akio Fujimura, Ken-ichi Miyamoto, Yoshiro Saito, Satomi Kameo, Yasuo Okamoto, Yoh Takuwa, Kazuhiko Takahashi, Hiroyasu Kidoya, Nobuyuki Takakura, Shuichi Kaneko, Toshinari Takamur

Pharmacokinetics and pharmacodynamics of insulin aspart in patients with Type 2 diabetes: Assessment using a meal tolerance test under clinical conditions

Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, especially under clinical conditions. The aim of the present study was to assess both the pharmacokinetics and pharmacodynamics of insulin aspart in Type 2 diabetic patients who were being treated with the analogue alone. Meal tolerance tests with and without self-injection of a customary dose of insulin aspart (0.05-0.22 U/kg) were conducted in 20 patients in a randomized cross-over study. The dose of insulin aspart (per bodyweight) was significantly correlated with both the maximum concentration (r 2 = 0.59; P < 0.01) and area under the concentration-time curve for insulin aspart (r 2 = 0.53; P < 0.01). However, the time to maximum concentration (T max), which varied widely from < 60 to ≥ 120 min, was not associated with either dosage (r 2 = 0.02; P = 0.51) or body mass index (r 2 = 0.02; P = 0.57). Injection of insulin aspart exacerbated delayed hyperinsulinaemia after meal loading, mainly in patients with T max ≥ 120 min. With regard to pharmacodynamics, insulin aspart had favourable effects on postprandial hyperglycaemia, hyperglucagonaemia and hyperlipidaemia. The T max for this insulin analogue differed greatly between individuals and delayed hyperinsulinaemia was particularly exacerbated in patients with higher T max values. Identification of the factors contributing to interindividual variation in the absorption lag time is essential for improving the efficacy and safety of insulin aspart. © 2012 The Authors. Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd

Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects

金沢大学大学院医学系研究科金沢大学医薬保健研究域医学系Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis. © 2008 Elsevier B.V. All rights reserved

Inverse Correlation between Serum Levels of Selenoprotein P and Adiponectin in Patients with Type 2 Diabetes

Background: We recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resistance in the liver and skeletal muscle; however, it is unknown whether and, if so, how SeP acts on adipose tissue. The present study tested the hypothesis that SeP is related to hypoadiponectinemia in patients with type 2 diabetes. Methodology/Principal Findings: We compared serum levels of SeP with those of adiponectin and other clinical parameters in 36 patients with type 2 diabetes. We also measured levels of blood adiponectin in SeP knockout mice. Circulating SeP levels were positively correlated with fasting plasma glucose (r = 0.35, P = 0.037) and negatively associated with both total and high-molecular adiponectin in patients with type 2 diabetes (r = 20.355, P = 0.034; r = 20.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (b = 20.343, P = 0.022; b = 20.357, P = 0.017). SeP knockout mice exhibited an increase in blood adiponectin levels when fed regular chow or a high sucrose, high fat diet. Conclusions/Significance: These results suggest that overproduction of liver-derived secretory protein SeP is connected with hypoadiponectinemia in patients with type 2 diabetes

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg

A liver-derived secretory protein, selenoprotein P, causes insulin resistance

金沢大学医薬保健研究域医学系The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes. © 2010 Elsevier Inc

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection