ナチュラルダイナミクスを使用した二足歩行ロボットの力学と制御

電気通信大学200

Insulin receptor cleavage induced by estrogen impairs insulin signaling

Introduction: Soluble insulin receptor (sIR), which is the ectodomain of insulin receptor (IR), is present in human plasma. Plasma sIR levels are positively correlated with blood glucose levels and negatively correlated with insulin sensitivity. An in vitro model of IR cleavage shows that extracellular calpain 2 directly cleaves IR, which generates sIR, and sequential cleavage of the IRβ subunit by γ-secretase impairs insulin signaling in a glucose concentration-dependent manner. Nevertheless, sIR levels vary among subjects with normal glucose levels. Research design and methods: We examined sIR levels of pregnant women throughout gestation. Using an in vitro model, we also investigated the molecular mechanisms of IR cleavage induced by estradiol. Results: In pregnant women, sIR levels were positively correlated with estrogen levels and significantly increased at late pregnancy independent of glucose levels. Using an in vitro model, estrogen elicited IR cleavage and impaired cellular insulin signaling. Estradiol-induced IR cleavage was inhibited by targeting of calpain 2 and γ-secretase. Estrogen exerted these biological effects via G protein-coupled estrogen receptor, and its selective ligand upregulated calpain 2 expression and promoted exosome secretion, which significantly increased extracellular calpain 2. Simultaneous stimulation of estrogen and high glucose levels had a synergic effect on IR cleavage. Metformin prevented calpain 2 release in exosomes and restored insulin signaling impaired by estrogen. Conclusions: Estradiol-induced IR cleavage causes cellular insulin resistance, and its molecular mechanisms are shared with those by high glucose levels. sIR levels at late pregnancy are significantly elevated along with estrogen levels. Therefore, estradiol-induced IR cleavage is preserved in pregnant women and could be part of the etiology of insulin resistance in gestational diabetes mellitus and overt diabetes during pregnancy

FMD and eGFR Slope in Males and Females

Aims: It is known that there are sex differences in vascular endothelial function and the development of chronic kidney diseases; however, it remains unclear whether sex differences influence the association between vascular endothelial function and renal prognosis. Methods: To clarify the relationship between vascular endothelial function and longitudinal eGFR changes in male and female patients with cardiovascular risk factors, we retrospectively evaluated 341 patients (176 males and 165 females) with cardiovascular risk factors in whom vascular function was assessed by flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) and in whom 24-month longitudinal eGFR values were recorded after the vascular function examinations. Associations of values of FMD and baPWV with values of eGFR slope were statistically analyzed. Results: Simple regression analysis showed that the value of FMD was positively associated with eGFR slope in females (p=0.001) and non-smoking males (p=0.033) but not in smoking males. Multiple regression analysis showed that the value of FMD remains a positive contributor for eGFR slope in females (p=0.001) and non-smoking males (p=0.045) but not in smoking males. In contrast, values of baPWV had no significant association with eGFR slope regardless of sex and cigarette smoking. Conclusions: In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males

Phase angle and extracellular water-to-total body water ratio estimated by bioelectrical impedance analysis are associated with levels of hemoglobin and hematocrit in patients with diabetes

Background: Anemia is one of the common complications of diabetes and is associated with mortality. Phase angle (PhA), ratio of extracellular water to total body water (ECW/TBW) and skeletal muscle mass index (SMI) estimated by bioelectrical impedance analysis (BIA) have been used as prognostic indicators for various chronic diseases and frailty. We aimed to clarify the clinical significance of PhA, ECW/TBW and SMI for anemia in patients with diabetes. Materials and methods: The values of PhA, ECW/TBW and SMI were estimated by a portable BIA device and blood samples were collected in 371 Japanese patients with diabetes. The relationships of PhA, ECW/TBW and SMI with hemoglobin (Hgb) and hematocrit (Hct) were statistically evaluated. Results: In simple linear regression analysis, PhA and SMI were positively correlated with Hgb and Hct levels in total subjects, male subjects and female subjects. In contrast, ECW/TBW was negatively correlated with Hgb and Hct levels regardless of sex. Multivariate regression analysis showed that both PhA and ECW/TBW but not SMI independently contributed to Hgb and Hct levels after adjustment of clinical confounding factors in both males and females. Conclusions: PhA and ECW/TBW but not SMI were associated with levels of Hgb and Hct in patients with diabetes. Therefore, aberrant values of PhA and ECW/TBW suggest a risk of anemia in diabetic patients

Vildagliptin vs liraglutide as a second-line therapy switched from sitagliptin-based regimens in patients with type 2 diabetes: A randomized, parallel-group study

Introduction: A step-up strategy for dipeptidyl peptidase (DPP)-4 inhibitor-based regimens has not yet been established. In addition, similarities and differences between DPP-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists remain to be elucidated in humans. We investigated the pleiotropic effects of vildagliptin vs liraglutide in patients with type 2 diabetes on sitagliptin-based regimens in an open-label, randomized, clinical trial. Materials and Methods: A total of 122 patients with type 2 diabetes that was inadequately controlled by sitagliptin-based regimens were randomly assigned to either vildagliptin (50 mg, twice daily) or liraglutide treatment (0.9 mg, once daily) for 12 weeks. The primary outcomes were glycated hemoglobin and body mass index. Results: Both vildagliptin and liraglutide significantly lowered glycated hemoglobin within 12 weeks after switching from sitagliptin, but liraglutide produced a greater reduction (-0.67 ± 0.12% vs -0.36 ± 0.53%). Liraglutide lowered body mass index, whereas vildagliptin did not affect body mass index. Vildagliptin lowered fasting C-peptide immunoreactivity, but liraglutide did not. Vildagliptin increased serum levels of adiponectin, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, whereas liraglutide had no effect on these levels. Quality of life, assessed using the diabetes treatment satisfaction questionnaire, was not impaired in either group. The most common adverse events were gastrointestinal symptoms, which occurred with similar frequencies in both groups. Conclusions: Vildagliptin-mediated improvements in glycemic control did not correlate with indices for insulin secretion and insulin sensitivity. Switching from sitagliptin to liraglutide is useful in managing hyperglycemia and weight. Each agent exerts unique pleiotropic effects. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. 000004953). © 2014 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd

Heparin Cofactor II and NAFLD in T2DM

Aims: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs), and thrombin-induced activation of PARs promotes the development of non-alcoholic fatty liver disease (NAFLD). Since heparin cofactor II (HCII) specifically inactivates thrombin action, we hypothesized that plasma HCII activity correlates with the severity of NAFLD. Methods: A cross-sectional study was conducted. Plasma HCII activity and noninvasive clinical markers of hepatic fibrosis including fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS) and aspartate aminotransferase-to-platelet ratio index (APRI) were determined in 305 Japanese patients with type 2 diabetes mellitus (T2DM). The relationships between plasma HCII activity and the clinical markers were statistically evaluated. Results: Multiple regression analysis including confounding factors showed that plasma HCII activity independently contributed to decreases in FIB-4 index (p＜0.001), NFS (p＜0.001) and APRI (p=0.004). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that plasma HCII activity was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: p=0.002, NFS: p=0.026 and APRI: p=0.012). Conclusions: Plasma HCII activity was inversely associated with clinical hepatic fibrosis indices including FIB-4 index, NFS and APRI and with the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of hepatic fibrosis of NAFLD in patients with T2DM

Heparin cofactor II reduces albuminuria

Aims/Introduction: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. Materials and Methods: Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). Results: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). Conclusions: The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria

Adult T-cell leukemia/lymphoma with multiple intracranial masses and CMV and HHV-6 reactivation at initial presentation

症例は55歳，男性。1ヶ月前からの咽頭痛の精査目的で紹介された。意識障害と項部硬直，口腔内の多発性有痛性潰瘍，全身に米粒大の紅斑を認めた。白血球数7,910/μL (異常リンパ球2%)，LDH 203U/L，補正カルシウム11.2mg/dL,可溶性IL-2受容体11,800U/mL，サイトメガロウイルス抗原(C10，C11)43/49。末梢血や骨髄，皮膚にCD4，25陽性の異常リンパ球あり，末梢血でHTLV-1プロウイルスDNAのモノクローナルな組み込みを確認し，成人T細胞白血病リンパ腫(ATLL)と診断した。CTで，脳実質内にリング状造影効果を有する腫瘤が多発し，髄液検査で細胞数1,320/mm3 (フローサイトメトリー法でATLL細胞が79%)，蛋白244mg/dL，HHV-6 DNA陽性を認めた。ヘルペスウイルス属感染症に対する治療や髄注を併用してmodified LSG15療法を行うも，意識障害が急速に進行し，入院21日目で死亡した。ATLLでは，中枢神経浸潤のさらなる病態の解明と標準治療の確立が求められる。A 55-year-old man, suffering from a sore throat for a month was referred to our hospital. Physical examination revealed disturbance of consciousness, nuchal rigidity, painful multiple ulcers in the oral cavity and rice grain sized erythema on the whole body. Hematological examination showed the following: white blood cell 7,910/μL (abnormal lymphocytes 2%), LDH 203U/L, corrected calcium 11.2mg/dL, soluble IL-2 receptor 11,800U/mL, and cytomegalovirus antigenemia (C10,C11) 43/49. Abnormal lymphocytes (CD4+CD25+) were found in the peripheral blood, bone marrow and skin samples. Southern blotting of peripheral blood confirmed monoclonal integration of HTLV-1 provirus DNA, consequently, he was diagnosed with adult T-cell leukemia/lymphoma (ATLL). Contrast-enhanced computed tomography revealed multiple tumors with ringed contrast effect in the brain parenchyma. Examination of the cerebrospinal fluid showed that the cell number was 1,320/mm3 (ATLL cells were 79% in flow cytometry), and the protein level was 244mg/dL; further, the examination revealed a positive result for human herpesvirus 6 DNA. Although treatment for herpesvirus genus and modified LSG15 therapy combined with intrathecal chemotherapy were performed, the patient became comatose, and he died on day 21 of hospitalization. A deeper understanding of the pathogenesis of and the establishment of standard treatment for ATLL with CNS involvement are required

Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

Background: Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Methodology/Principal Findings: Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. Conclusions/Significance: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance. © 2012 Kita et al