※一部利用できない機能があります
| 1.
論文 |
論文
|
Misu, Hirofumi ; Takamura, Toshinari ; Takayama, Hiroaki ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Kurita, Seiichiro ; Ishikura, Kazuhide ; Ando, Hitoshi ; Takeshita, Yumie ; Ota, Tsuguhito ; Sakurai, Masaru ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Yamashita, Taro ; Honda, Masao ; Miyamoto, Kenichi ; Kubota, Tetsuya ; Kubota, Naoto ; Kadowaki, Takashi ; Kim, Han-Jong ; Lee, In-kyu ; Minokoshi, Yasuhiko ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Yamada, Yoshihiro ; Takakura, Nobuyuki ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral ti
…
ssues 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.
続きを見る
|
||||
| 2.
論文 |
論文
|
Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi
概要:
Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cau
…
se fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
続きを見る
|
||||
| 3.
論文 |
論文
|
Kurita, Seiichiro ; Ando, Hitoshi ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
金沢大学医薬保健研究域医学系
|
||||
| 4.
論文 |
論文
|
Uno, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Ando, Hitoshi ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Nabemoto, Satoko ; Akahori, Hiroshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
金沢大学医薬保健研究域医学系<br />Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and
…
is one of the most common liver diseases in the developed world. The histological findings of NASH are characterized by hepatic steatosis, inflammation, and fibrosis. However, an optimal treatment for NASH has not been established. Tranilast, N-(3′,4′-dimedioxycinnamoyl)- anthranilic acid, is an antifibrogenic agent that inhibits the action of transforming growth factor beta (TGF-β). This drug is used clinically for fibrogenesis-associated skin disorders including hypertrophic scars and scleroderma. TGF-β plays a central role in the development of hepatic fibrosis, and tranilast may thus ameliorate the pathogenesis of NASH. We investigated the effects of tranilast using an established dietary animal model of NASH, obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats fed a methionine-deficient and choline-deficient diet. Treatment with 2% tranilast (420 mg/kg/day) for 8 weeks prevented the development of hepatic fibrosis and the activation of stellate cells, and down-regulated the expression of genes for TGF-β and TGF-β-target molecules, including α1 procollagen and plasminogen activator-1. In addition, tranilast attenuated hepatic inflammation and Kupffer cell recruitment, and down-regulated the expression of tumor necrosis factor alpha. Unexpectedly, tranilast ameliorated hepatic steatosis and up-regulated the expression of genes involved in beta-oxidation, such as peroxisome proliferator-activated receptor α and carnitine O-palmitoyltransferase-1. Most of these effects were observed in LETO rats and OLETF rats, which suggest that the action of tranilast is mediated through the insulin resistance-independent pathway. Conclusion: Our findings suggest that targeting TGF-β with tranilast represents a new mode of therapy for NASH. Copyright © 2008 by the American Association for the Study of Liver Diseases.
続きを見る
|
||||
| 5.
論文 |
論文
|
Akahori, Hiroshi ; Takeshita, Yumie ; Saito, Reina ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
金沢大学医薬保健研究域医学系<br />Although the etiology of Graves' disease is still not clear, it is generally suggested that environm
…
ental factors such as infections contribute to the development of Graves' disease. We report here three cases of Graves' disease which presented simultaneously with infectious mononucleosis due to primary EBV infection. Acute EBV infection might play an important role in the onset of Graves' disease. These three women complained of a sore throat or neck pain, resembling subacute thyroiditis. In the case of thyrotoxicosis accompanied by sore throat or neck pain, Graves' disease must be distinguished from subacute thyroiditis. © 2010 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 6.
論文 |
論文
|
Ando, Hitoshi ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Shima, Kosuke R. ; Nakamura, Seiji ; Kumazaki, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Togawa, Naoyuki ; Fukushima, Tatsunobu ; Fujimura, Akio ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatt
…
y liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 7.
論文 |
論文
|
Takamura, Toshinari ; Shimizu, Akiko ; Komura, Takuya ; Ando, Hitoshi ; Zen, Yoh ; Minato, Hiroshi ; Matsushita, Eiki ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学<br />A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, wa
…
s diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BNU) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene. © 2007 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 8.
論文 |
論文
|
Koike, Nobuhiko ; Takamura, Toshinari ; Kaneko, Shuichi
概要:
大学院医学系研究科環境社会医学<br />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.
続きを見る
|
||||
| 9.
論文 |
論文
|
Ota, Tsuguhito ; Takamura, Toshinari ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系
|
||||
| 10.
論文 |
論文
|
Takamura, Toshinari ; Shimizu, Akiko ; Ando, Hitoshi ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学
|
||||
| 11.
論文 |
論文
|
Sakurai, Masaru ; Takamura, Toshinari ; Ota, Tsuguhito ; Ando, Hitoshi ; Akahori, Hiroshi ; Kaji, Kyosuke ; Sasaki, Motoko ; Nakanuma, Yasuni ; Miura, Katsuyuki ; Kaneko, Shuichi
概要:
金子, 周一<br />金沢大学大学院医学系研究科環境社会医学<br />Background: To address the hypothesis that liver steatosis causes systemic insulin
…
resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results: In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = -0.98, P = 0.076). Conclusions: Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD. © Springer-Verlag Tokyo 2007.
続きを見る
|
||||
| 12.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Hamaguchi, Erika ; Shimizu, Akiko ; Ota, Tsuguhito ; Sakurai, Masaru ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学<br />Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver
…
fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor α (TNF-α), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-α stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-κB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-α-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-κB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-α-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-α up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production. © 2006
続きを見る
|
||||
| 13.
論文 |
論文
|
Ando, Hitoshi ; Oshima, Yasuo ; Yanagihara, Hayato ; Hayashi, Yohei ; Takamura, Toshinari ; Kaneko, Shuichi ; Fujimura, Akio
概要:
金沢大学大学院医学系研究科環境社会医学<br />Although a number of genes expressed in most tissues, including the liver, exhibit circadian re
…
gulation, gene expression profiles are usually examined only at one scheduled time each day. In this study, we investigated the effects of obese diabetes on the hepatic mRNA levels of various genes at 6-h intervals over a single 24-h period. Microarray analysis revealed that many genes are expressed rhythmically, not only in control KK mice but also in obese diabetic KK-Ay mice. Real-time quantitative PCR verified that 19 of 23 putative circadianly expressed genes showed significant 24-h rhythmicity in both strains. However, obese diabetes attenuated these expression rhythms in 10 of 19 genes. More importantly, the effects of obese diabetes were observed throughout the day in only two genes. These results suggest that observation time influences the results of gene expression analyses of genes expressed circadianly. © 2006 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 14.
論文 |
論文
|
Hayakawa, Tetsuo ; Takamura, Toshinari ; Abe, Toshio ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学<br />A C825T polymorphism of the gene encoding the G-protein β3 subunit (GNB3) is associated with in
…
creased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies. © 2007.
続きを見る
|
||||
| 15.
論文 |
論文
|
Sakurai, Masaru ; Takamura, Toshinari ; Miura, Katsuyuki ; Kaneko, Shuichi ; Nakagawa, Hideaki
概要:
金沢大学医薬保健研究域医学系
|
||||
| 16.
論文 |
論文
|
Kurita, Seiichiro ; Takamura, Toshinari ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Uno, Masafumi ; Nabemoto, Satoko ; Ishikura, Kazuhide ; Misu, Hirofumi ; Ando, Hitoshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科<br />金沢大学医薬保健研究域医学系<br />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.
続きを見る
|
||||
| 17.
論文 |
論文
|
Komura, Takuya ; Sakai, Yoshio ; Honda, Masao ; Takamura, Toshinari ; Matsushima, Kouji ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />OBJECTIVE - Although patients with diabetes suffer from increased infections and a higher incidence
…
of cancer due to impaired immune function, details on diabetes-induced decrease in immunity are lacking. We assessed how immune-mediating peripheral blood mononuclear cells (PBMCs) are affected in diabetes. RESEARCH DESIGN AND METHODS - From 33 patients with type 2 diabetes and 28 healthy volunteers, we obtained PBMCs and investigated their susceptibility to apoptosis and functional alteration. RESULTS - In a subpopulation of PBMCs, monocytes derived from patients with diabetes were more susceptible to apoptosis than monocytes from healthy volunteers. Monocytes from patients with diabetes had decreased phagocytotic activity and were less responsive to Toll-like receptor (TLR) ligands, although the expression of TLRs did not differ significantly between the two groups. Furthermore, monocytes from patients with diabetes had a distinctly different gene expression profile compared with monocytes from normal volunteers as assessed with DNA microarray analysis. Specifically, quantitative real-time detection PCR measurements showed an elevated expression of the markers of endoplasmic reticulum (ER) stress in diabetic monocytes, and electron microscopic examination of monocytes revealed morphologic alterations in the ER of cells derived from patients with diabetes. Consistently, the ER stress inducer tunicamycin increased apoptosis of otherwise healthy monocytes and attenuated the proinflammatory responses to TLR ligands. CONCLUSIONS - These data suggest that monocytes comprise a substantially impaired subpopulation of PBMCs in patients with diabetes and that ER stress is involved in these pathologic changes mechanistically. This implies that the affected monocytes should be investigated further to better understand diabetic immunity. © 2010 by the American Diabetes Association.
続きを見る
|
||||
| 18.
論文 |
論文
|
Hamaguchi, Erika ; Takamura, Toshinari ; Sakurai, Masaru ; Mizukoshi, Eishiro ; Zen, Yoh ; Takeshita, Yumie ; Kurita, Seiichiro ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sasaki, Motoko ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />OBJECTIVE - The goal of this study was to examine whether metabolic abnormalities are responsible fo
…
r the histological changes observed in Japanese patients with nonalcoholic fatty liver disease (NAFLD) who have undergone serial liver biopsies. RESEARCH DESIGN AND METHODS - In total, 39 patients had undergone consecutive liver biopsies. Changes in their clinical data were analyzed, and biopsy specimens were scored histologically for stage. RESULTS - The median follow-up time was 2.4 years (range 1.0-8.5). Liver fibrosis had improved in 12 patients (30.7%), progressed in 11 patients (28.2%), and remained unchanged in 16 patients (41%). In a Cox proportional hazard model, decrease in A1C and use of insulin were associated with improvement of liver fibrosis independent of age, sex, and BMI. However, ΔA1C was more strongly associated with the improvement of liver fibrosis than use of insulin after adjustment for each other (χ2; 7.97 vs. 4.58, respectively). CONCLUSIONS - Tight glycemic control may prevent histological progression in Japanese patients with NAFLD. © 2010 by the American Diabetes Association.
続きを見る
|
||||
| 19.
論文 |
論文
|
Sakurai, Masaru ; Takamura, Toshinari ; Miura, Katsuyuki ; Kaneko, Shuichi ; Nakagawa, Hideaki
概要:
金沢大学医薬保健研究域医学系<br />We attempted to determine sex differences in obesity-related metabolic abnormalities in a relatively
…
large middle-aged Japanese population. The study population consisted of 2935 men and 1622 women who were 35 to 59 years old. Metabolic abnormalities were determined using the Japanese criteria for metabolic syndrome, and we evaluated the number of metabolic abnormalities discriminated by waist circumference. In men, the mean number of metabolic abnormalities increased as the waist circumference increased. In women, although the mean number of metabolic abnormalities increased as the waist circumference increased, the mean number was less than 1 even in those with a waist circumference of at least 95 cm. According to the receiver operating characteristic curve, the cutoff levels yielding the maximal sensitivity plus specificity for predicting the prevalence of one or more obesity-related metabolic abnormalities were 80 cm in men and 73 cm in women. However, the positive predictive value was as low as 28.8% in men and 7.1% in women, which may not be suitable for a screening test, especially in women. Middle-aged Japanese women seem to be resistant to obesity-induced metabolic abnormalities, and waist circumference would not effectively predict the existence of metabolic syndrome. In setting the cutoff points in guidelines, a greater emphasis should be placed on the absolute risk of having abnormalities or diseases. © 2009 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 20.
論文 |
論文
|
Sakurai, Sho ; Miura, K. ; Takamura, Toshinari ; Ishizaki, Masao ; Morikawa, Y. ; Nakamura, K. ; Yoshita, Katsushi ; Kido, Teruhiko ; Naruse, Yuchi ; Kaneko, Shuichi ; Nakagawa, H.
概要:
金沢大学医薬保健研究域医学系<br />金沢医科大学健康増進予防医学（公衆衛生学）<br />Aims This study investigated the relationship between waist circumference
…
and the subsequent incidence of Type 2 diabetes and the association with insulin resistance and pancreatic B-cell function in relatively lean Japanese individuals. Methods The study participants were 3992 employees (2533 men and 1459 women, aged 35-55 years) of a metal-products factory in Japan. The incidence of diabetes was determined in annual medical examinations during an 8-year follow-up. We calculated age- and sex-adjusted hazard ratios (HRs) according to the sex-specific quintile of waist circumference at baseline. Differences in baseline insulin resistance [homeostatis model assessment (HOMA)-IR] and pancreatic B-cell function (HOMA-B) were compared between participants who developed diabetes and those who did not. Results During the follow-up, 218 participants developed diabetes. Age- and sex-adjusted HRs across the quintiles of waist circumference were 1.78, 1.00 (reference), 1.59, 3.11 and 3.30, respectively (P for trend, < 0.0001). The HR for the lowest quintile was significantly higher than that for the second quintile. Among participants with waist circumference of the lowest quintile, HOMA-B was lower in those who developed diabetes than in those who did not [33.1 (24.1-45.0) vs. 54.3 (37.9-74.6) median (interquartile range), P < 0.0001], but HOMA-IR did not differ between these groups. Conclusions There was a J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes in relatively lean Japanese individuals; lower pancreatic B-cell function may also increase the risk of diabetes in very lean Japanese people. © 2009 Diabetes UK.
続きを見る
|
||||
| 21.
論文 |
論文
|
Matsuzawa-Nagata, Naoto ; Takamura, Toshinari ; Ando, Hitoshi ; Nakamura, Seiji ; Kurita, Seiichiro ; Misu, Hirofumi ; Ota, Tsuguhito ; Yokoyama, Masayoshi ; Honda, Masao ; Miyamoto, Ken-ichi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial e
…
vents triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c-related fatty acid synthesis and peroxisome proliferator-activated receptor α-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor-α and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance. © 2008 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 22.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Inoue, Oto ; Okumura, Miki ; Kato, Kenichiro ; Sunagozaka, Hajime ; Arai, Kuniaki ; Misu, Hirofumi ; Nakamura, Minoru ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
A 73-year-old woman had previously been diagnosed with CREST syndrome, PBC and diabetes. Hepatic fibrosis was not eviden
…
t, in spite of the transudative ascites and active esophageal varices. ACA were positive, whereas AMA and anti-gp210 antibodies were negative. She showed low urinary excretion of C-peptide and was weakly positive for anti-GAD antibody. She was diagnosed with a form of PBC that progresses via portal hypertension rather than liver failure and with SPIDDM. Her HLA type did not contain risk allele for IDDM or PBC. SPIDDM should be considered when patients with PBC with portal hypertension-type progression develop diabetes. © 2012 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 23.
論文 |
論文
|
Sakurai, Masaru ; Nakamura, Koshi ; Miura, Katsuyuki ; Takamura, Toshinari ; Yoshita, Katsushi ; Morikawa, Yuko ; Ishizaki, Masao ; Kido, Teruhiko ; Naruse, Yuchi ; Suwazono, Yasushi ; Kaneko, Shuichi ; Sasaki, Satoshi ; Nakagawa, Hideaki
概要:
This cohort study investigated the association between dietary glycemic index (GI), glycemic load (GL), and the incidenc
…
e of type 2 diabetes mellitus in middle-aged Japanese men, and the effect of insulin resistance and pancreatic B-cell function on the association. Participants were 1995 male employees of a metal products factory in Japan. Dietary GI and GL were assessed using a self-administered diet history questionnaire. The incidence of diabetes was detected in annual medical examinations over a 6-year period. The association between GI, GL, and the incidence of diabetes was evaluated using Cox proportional hazards models. During the study, 133 participants developed diabetes. Age- and body mass index-adjusted hazard ratios across the GI quintiles were 1.00 (reference), 1.62, 1.50, 1.68, and 1.80; and those of GL were 1.00 (reference), 1.07, 1.48, 0.95, and 0.98. The hazard ratio for the highest GI quintile was significantly greater than that for the lowest quintile. The influence of GI was more pronounced in the lowest insulin resistance subgroups. GI and pancreatic B-cell function were independently associated with the incidence of type 2 diabetes mellitus; participants with low B-cell function and the highest tertile of GI had the highest risk of diabetes. Dietary GI is associated with the incidence of diabetes in middle-aged Japanese men. GI and B-cell function were independently associated with incidence of diabetes. © 2012 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 24.
論文 |
論文
|
Misu, Hirofumi ; Ishikura, Kazuhide ; Kurita, Seiichiro ; Takeshita, Yumie ; Ota, Tsuguhito ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Background: We recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resist
…
ance 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 = -0.355, P = 0.034; r = -0.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (β = -0.343, P = 0.022; β = -0.357, 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. © 2012 Misu et al.
続きを見る
|
||||
| 25.
論文 |
論文
|
Nakade, Yusuke ; Takamura, Toshinari ; Sakurai, Masaru ; Misu, Hirofumi ; Nagata, Mitsuko ; Nanbu, Yuko ; Oe, Hiroyasu ; Takamura, Toshiji ; Sakai, Yoshio ; Kaneko, Shuichi ; Wada, Takashi
概要:
The aim of the present study was to examine whether there is a relationship between autonomic function and post-challeng
…
e hyperglycemia in patients with type 2 diabetes. Subjects included 122 Japanese patients newly diagnosed with type 2 diabetes. Autonomic nerve function was assessed using coefficients of variation of the R-R intervals on electrocardiograms (CVRR). Unlike anthropometry, insulin secretion and insulin resistance, age (r =)0.209, P < 0.021) and post-challenge plasma glucose at 120 min (PG120; r =)0.219, P < 0.015) were the only variables significantly correlated with CVRR. Age was not significantly correlated with PG120. In multiple regression analyses, CVRR Z-score, but not age, was significantly correlated with PG120. The present results suggest that autonomic function affects post-challenge blood glucose levels independently of age. © 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd.
続きを見る
|
||||
| 26.
論文 |
論文
|
Ando, Hitoshi ; Kurita, Seiichiro ; Shimizu, Akiko ; Kato, Ken-ichiro ; Ishikura, Kazuhide ; Taji, Koumei ; Uno, Masafumi ; Takeshita, Yumie ; Misu, Hirofumi ; Fujimura, Akio ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, espe
…
cially 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.
続きを見る
|
||||
| 27.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Minato, Hiroshi ; Misu, Hirofumi ; Ando, Hitoshi ; Yamashita, Tatsuya ; Ikeda, Hiroko ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />金沢大学医薬保健研究域医学系恒常性制御学<br />Multiple liver metastases were incidentally detected in the lobe of the li
…
ver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic transformation from papillary thyroid carcinoma during treatment. We report a rare case of multiple liver metastases from a papillary thyroid carcinoma, which we believe to be the result of anaplastic transformation during postoperative radioactive iodine-131 therapy. © 2008 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 28.
論文 |
論文
|
Kita, Yuki ; Takamura, Toshinari ; Misu, Hirofumi ; Ota, Tsuguhito ; Kurita, Seiichiro ; Takeshita, Yumie ; Uno, Masafumi ; Matsuzawa-Nagata, Naoto ; Kato, Ken-ichiro ; Ando, Hitoshi ; Fujimura, Akio ; Hayashi, Koji ; Kimura, Toru ; Ni, Yinhua ; Otoda, Toshiki ; Miyamoto, Ken-ichi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
Background: Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for ind
…
ividuals 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.
続きを見る
|
||||
| 29.
論文 |
論文
|
Kato, Ken-ichiro ; Takamura, Toshinari ; Takeshita, Yumie ; Ryu, Yasuji ; Misu, Hirofumi ; Ota, Tsuguhito ; Tokuyama, Kumpei ; Nagasaka, Shoichiro ; Matsuhisa, Munehide ; Matsui, Osamu ; Kaneko, Shuichi
概要:
Objective: The aim of this study was to examine the association between ectopic fat and organ-specific insulin resistanc
…
e (IR) in insulin-target organs in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Organ-specific IR in the liver (hepatic glucose production (HGP)6fasting plasma insulin (FPI) and suppression of HGP by insulin [%HGP]), skeletal muscle (insulin-stimulated glucose disposal [Rd]), and adipose tissue (suppression of FFA by insulin [%FFA]) was measured in 69 patients with NAFLD using a euglycemic hyperinsulinemic clamp with tracer infusion ([6,6-2H 2]glucose). Liver fat, intramyocellular lipid (IMCL), and body composition were measured by liver biopsy, proton magnetic resonance spectroscopy, and bioelectrical impedance analysis, respectively. Results: HGPxFPI was significantly correlated with Rd (r = -0.57, P<0.001), %HGP with %FFA (r = 0.38, P<0.01), and Rd with %FFA (r = 0.27, P<0.05). Liver steatosis score was negatively associated with Rd (r = -0.47, P<0.001) as well as with HGPxFPI ( r = 0.43, P<0.001). Similarly, intrahepatic lipid was negatively associated with Rd (r = -0.32, P<0.05). IMCL was not associated with Rd (r = -0.16, P = 0.26). Fat mass and its percentage were associated with HGPxFPI (r = 0.50, P<0.001; r = 0.48, P<0.001, respectively) and Rd (r = -0.59, P<0.001; r = -0.52, P<0.001, respectively), but not with %FFA (r = -0.21, P = 0.10; r = -0.001, P = 0.99, respectively). Conclusion: Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific IR. Instead, liver fat was associated not only with hepatic IR but also with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle. © 2014 Kato et al.
続きを見る
|
||||
| 30.
論文 |
論文
|
Lan, Fei ; Misu, Hirofumi ; Chikamoto, Keita ; Takayama, Hiroaki ; Kikuchi, Akihiro ; Mohri, Kensuke ; Takata, Noboru ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Takeshita, Yumie ; Noda, Hiroyo ; Matsumoto, Yukako ; Ota, Tsuguhito ; Nagano, Toru ; Nakagen, Masatoshi ; Miyamoto, Ken-ichi ; Takatsuki, Kanako ; Seo, Toru ; Iwayama, Kaito ; Tokuyama, Kunpei ; Matsugo, Seiichi ; Tang, Hong ; Saito, Yoshiro ; Yamagoe, Satoshi ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but
…
the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. © 2014 by the American Diabetes Association.
続きを見る
|
||||
| 31.
論文 |
論文
|
Kato, Ken-ichiro ; Takeshita, Yumie ; Misu, Hirofumi ; Zen, Yoh ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Aims/Introduction: To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease.
…
Materials and Methods: Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. Results: The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P < 0.001; grade r = -0.54, P < 0.001; stage r = -0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P < 0.05) and grade (coefficient = -0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = -0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). Conclusions: Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.
続きを見る
|
||||
| 32.
論文 |
論文
|
Kuroda, Kaori ; Takeshita, Yumie ; Kaneko, Shuichi ; Takamura, Toshinari
|
||||
| 33.
論文 |
論文
|
Isobe, Yuki ; Sakurai, Masaru ; Kita, Yuki ; Takeshita, Yumie ; Misu, Hirofumi ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Aims/Introduction: To investigate the clinical and anthropometrical parameters that are associated with non-exercise act
…
ivity thermogenesis that is composed of basal energy expenditure (BEE) and diet-induced thermogenesis (DIT) in patients with diabetes. Materials and Methods: Body composition was assessed using bioelectrical impedance, and BEE and DIT were measured using indirect calorimetry in 40 Japanese patients with diabetes. Results: BEE correlated positively with bodyweight, body mass index, fat mass, and fat-free mass, and correlated negatively with age in both men and women. In multivariate logistic regression analysis, BEE correlated positively with both fat mass and fat-free mass independently of sex and age. In addition, DIT correlated positively with bodyweight, body mass index, fat mass and fat-free mass, and correlated negatively with age in women, but not men. Fat-free mass contributed to DIT at least partly, and an aging-related decrease in DIT was observed. The best anthropometric parameter that reflected fat mass and fat-free mass was hip circumference (HC) and calf circumference (CC), respectively, in both men and women. Indeed, both HC (men β = 0.600, P < 0.001; women β = 0.752, P < 0.001) and CC (men β = 0.810, P = 0.012; women β = 0.821, P = 0.002) were correlated with BEE independently of age and sex. In addition, CC (β = 0.653, P = 0.009), but not HC was correlated with DIT significantly only in females, independently of age. Conclusions: HC reflects fat mass and was positively associated with BEE, but not with DIT. In contrast, CC reflects fat-free mass, and was positively associated with BEE in both men and women, and with DIT in women. © 2015 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.
続きを見る
|
||||
| 34.
論文 |
論文
|
Takazakura, Akiko ; Sakurai, Masaru ; Bando, Yukihiro ; Misu, Hirofumi ; Takeshita, Yumie ; Kita, Yuki ; Shimizu, Akiko ; Hayakawa, Tetsuo ; Kato, Ken-ichiro ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
Introduction: Several studies have shown that statins suppress the progression of diabetic nephropathy. However, few rep
…
orts have directly compared the renoprotective effects between potent and conventional statins. Materials and Methods: Patients with diabetic nephropathy, selected as those with a serum creatinine level of 0.9-1.5 mg/dL and simultaneously having either microalbuminuria or positive proteinuria, were randomly assigned to one of three groups: a conventional diet therapy group, a group given 10 mg of pravastatin and a group given 10 mg of atorvastatin. Renal function was evaluated before and after a 12-month period of therapy. Results: The atorvastatin group had a significant decrease in low-density lipoprotein cholesterol at 3 months and thereafter compared with the other groups. The urinary albumin-to-creatinine ratio significantly decreased in the atorvastatin group; the degree of this decrease was significantly greater than that in the diet therapy group. The kidney function estimated with cystatin C (CysC) and the estimated glomerular filtration rate calculated from CysC were significantly preserved in the atorvastatin group compared with the pravastatin group. In a multivariate regression analysis, the use of atorvastatin was the only explanatory variable for the changes in CysC; this was independent of changes in low-density lipoprotein cholesterol. Conclusions: Atorvastatin is more effective than pravastatin for the prevention of increase in CysC, and this renoprotective effect was considered to a result of the pleiotropic effect of atorvastatin independent of its lipid-lowering effect. This study was registered with UMIN (no. UMIN 000001774). © 2014 The Authors.
続きを見る
|
||||
| 35.
論文 |
論文
|
Ando, Hitoshi ; Takamura, Toshinari ; Nagai, Yukihiro ; Kaneko, Shuichi
概要:
金沢大学医学部附属病院内科<br />The relationship between the effect of aldose reductase inhibitors (ARIs) on the activation of the po
…
lyol 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.
続きを見る
|
||||
| 36.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Kita, Yuki ; Ando, Hitoshi ; Ueda, Teruyuki ; Kato, Kenichiro ; Misu, Hirofumi ; Sunagozaka, Hajime ; Sakai, Yoshio ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
概要:
Branched-chain amino acids (BCAAs) improve disorders of albumin metabolism, quality of life, subjective symptoms, and pr
…
ognosis in patients with chronic hepatitis. However, it remains unclear whether they improve insulin resistance. We examined the effects of BCAAs on glucose tolerance and insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Individuals with a definitive diagnosis of chronic hepatitis C and insulin resistance were eligible for participation. Eligible participants were randomly assigned to the BCAA group or a control group. Participants were then crossed over to the other treatment for a further 12 weeks. Baseline clinical features, laboratory markers, fatty acid levels, and insulin sensitivity, assessed with oral glucose tolerance tests and a hyperinsulinemic euglycemic clamp, were also examined before and 12 and 24 weeks after the beginning of the study. Of the 27 patients who completed the study, 14 began in the BCAA group and 13 began as controls. There were no significant differences in glucose metabolism parameters or lipid profiles between the groups. HbA1c values were improved in 10 patients and worsened or remained unchanged in 17 patients. The only predictive variable for change in HbA1c was the baseline Matsuda index: the lower the index, the greater the improvement in HbA1c values. BCAA therapy did not have adverse effects on glucose tolerance or insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Moreover, it had a therapeutic effect on HbA1c values in patients with marked peripheral (primarily muscle) insulin resistance. © 2012 Elsevier Inc.
続きを見る
|
||||
| 37.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Kita, Yuki ; Takazakura, Akiko ; Kato, Ken-ichiro ; Isobe, Yuki ; Kaneko, Shuichi
概要:
Purpose We determined the feasibility of substituting sitagliptin or mitiglinide for bolus insulin injection therapy in
…
patients with type 2 diabetes. Methods 60 patients with type 2 diabetes were enrolled and randomized to switch from mealtime dosing of a rapid-acting insulin analog to either sitagliptin or mitiglinide for 16 weeks. Results Body weight, body mass index, and waist circumference decreased significantly in both groups at the end of the study. Mitiglinide significantly increased fasting plasma glucose (FPG) levels at the end of the study from 146.5±36.3 to 168.0±38.8 mg/dL, whereas sitagliptin did not affect FPG. Glycated hemoglobin (HbA1c) and 1,5-anhydroglucitol increased significantly in both groups. The C peptide immunoreactivity (CPR) responses after arginine were diminished in both groups. γ-GTP and triglycerides increased, and high-density lipoprotein cholesterol and adiponectin decreased, in the sitagliptin group, but not in the mitiglinide group. Mean Diabetes Treatment Satisfaction Questionnaire scores improved significantly in both groups. Patients whose mean total daily doses of rapid-acting insulin analog were 16.6 and 17.8 units were switched to sitagliptin and mitiglinide, respectively, without a change in the HbA1c level. Total insulin doses/body weight predicted changes in HbA1c only in the sitagliptin group, but not in the mitiglinide group. Use of >0.27 IU/kg of a rapid-acting insulin analog predicted an increase in HbA1c after switching to sitagliptin. The CPR index (CPI) was also a predictor for a change in HbA1c in the sitagliptin group, but not in the mitiglinide group; patients with a CPI<1.4 developed a worse HbA1c after switching to sitagliptin. Conclusions Sitagliptin may predominantly act on FPG, whereas mitiglinide may act on postprandial plasma glucose to achieve glycemic control after switching from a bolus insulin regimen. Additional therapy to sitagliptin or mitiglinide is clearly required to obtain equivalent glycemic control in patients using a higher dose of insulin.
続きを見る
|
||||
| 38.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Kita, Yuki ; Otoda, Toshiki ; Kato, Ken-ichiro ; Wakakuri, Hitomi ; Yamada, Masayuki ; Misu, Hirofumi ; Matsushima, Yukiko ; Kaneko, Shuichi
概要:
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.
続きを見る
|
