Showing papers by "Nobuhiro Yamada published in 2006"

TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes.

Abstract: Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3β and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.

Prevalence of Metabolic Syndrome in the General Japanese Population in 2000

Abstract: To determine the prevalence of metabolic syndrome in the Japanese general population, we analyzed data from a nationwide survey conducted in 2000. According to the Japanese new diagnostic criteria for metabolic syndrome in 2005, we analyzed 3,264 people aged from 20 to 79 (men, 1,917; women, 1,347) from the total participants. The incidence of metabolic syndrome was 7.8%. Men had a higher incidence (12.1%) than women (1.7%). Most of the women satisfying the criteria were 50 years old or over, while the incidence in men started to rise from their 30s. When we applied the criteria of Adult Treatment Panel III, the incidence was about 3-fold higher. In this population visceral obesity was associated with metabolic abnormalities, such as higher LDL-cholesterol, triglyceride, glucose, and blood pressure and lower HDL-cholesterol. Thus we determined the incidence of metabolic syndrome and each metabolic abnormality in the Japanese general population in 2000 and found an association of visceral obesity with metabolic abnormalities. Intervention to reduce the incidence of metabolic syndrome in Japan is necessary to reduce the risk of cardiovascular disease.

Distinct effects of pravastatin, atorvastatin, and simvastatin on insulin secretion from a beta-cell line, MIN6 cells.

Abstract: In addition to the prevention of cardiovascular diseases by lowering plasma LDL cholesterol, recent studies suggest that statins could have some impact on insulin action. To estimate the direct effects of statins on insulin secretion from pancreatic beta-cells, MIN6 cells were treated with pravastatin, simvastatin, or atorvastatin. Basal insulin secretion at low glucose concentration was unexpectedly increased at very high doses of simvastatin or atorvastatin after 24- and 48-hour incubation. Insulin secretion at high glucose was not significantly changed, and thus, net glucose-stimulated insulin secretion was apparently decreased by these lipophilic statins. The changes in insulin secretion were highly associated with increased endogenous SREBP activities in response to HMG-CoA inhibition as estimated by SRE-luciferase assays, and finally after 48-hour incubation, accompanied by impaired cell viability as estimated by MTT assays. In contrast, these changes were much less prominent by the addition of pravastatin. Meanwhile, glucose-stimulated insulin secretion of islets isolated from C57BL/6 mice was not significantly changed by any of the statins. Overall, taken up by beta-cells, statins can affect insulin secretion through either HMG-CoA inhibition or cytotoxicity, as observed by the addition of extraordinary high doses of lipophilic statins, but not hydrophilic statins, to the medium.

The New Worldwide Definition of Metabolic Syndrome Is Not a Better Diagnostic Predictor of Cardiovascular Disease in Japanese Diabetic Patients Than the Existing Definitions Additional analysis from the Japan Diabetes Complications Study

Abstract: We previously reported (1) the limited clinical significance for Japanese diabetic patients of the widely used World Health Organization (WHO) (2) and National Cholesterol Education Program (NCEP) (3) definitions of metabolic syndrome and suggested that an international definition of metabolic syndrome that was applicable regardless of ethnicity was necessary (1). Recently, the International Diabetes Federation published a long-awaited new worldwide definition of metabolic syndrome (4) that is intended to be applicable to various ethnic groups. The new definition is similar to the NCEP definition (3) but has several important differences. Notably, most components of the new definition now include subjects who are receiving specific treatments for the abnormalities that comprise metabolic syndrome. Also, central obesity (defined by waist circumference with ethnic modification in its thresholds) has become a mandatory component in the new definition. In this report, we evaluated the predictive power of the new international definition for cardiovascular disease (CVD), as compared with that of previous definitions, in Japanese diabetic patients. The Japan Diabetes Complications Study (JDCS) has been described in detail elsewhere (1, 5). The same dataset was used for evaluation so that the new definition of metabolic syndrome could be directly compared with the WHO and NCEP definitions (1–4). A total of 1,424 Japanese patients (771 men and 653 women, age 58.4 ± 7.4 years [means ± SD]) with previously diagnosed type 2 diabetes but without known CVD were …

Identification of a Novel Member of the Carboxylesterase Family That Hydrolyzes Triacylglycerol: A Potential Role in Adipocyte Lipolysis

Abstract: Molecular mechanisms underlying lipolysis, as defined by mobilization of fatty acids from adipose tissue, are not fully understood. A database search for enzymes with α/β hydrolase folds, the GXSXG motif for serine esterase and the His-Gly dipeptide motif, has provided a previously unannotated gene that is induced during 3T3-L1 adipocytic differentiation. Because of its remarkable structural resemblance to triacylglycerol hydrolase (TGH) with 70.4% identity, we have tentatively designated this enzyme as TGH-2 and the original TGH as TGH-1. TGH-2 is also similar to TGH-1 in terms of tissue distribution, subcellular localization, substrate specificity, and regulation. Both enzymes are predominantly expressed in liver, adipose tissue, and kidney. In adipocytes, they are localized in microsome and fatcake. Both enzymes hydrolyzed p-nitophenyl butyrate, triolein, and monoolein but not diolein, cholesteryl oleate, or phospholipids; hydrolysis of short-chain fatty acid ester was 30,000-fold more efficient than that of long-chain fatty acid triacylglycerol. Fasting increased the expression of both genes in white adipose tissue, whereas refeeding suppressed their expression. RNA silencing of TGH-2 reduced isoproterenol-stimulated glycerol release by 10% in 3T3-L1 adipocytes, while its overexpression increased the glycerol release by 20%. Thus, TGH-2 may make a contribution to adipocyte lipolysis during period of increased energy demand.

The New Worldwide Definition of Metabolic Syndrome Is Not a Better Diagnostic Predictor of Cardiovascular Disease in Japanese Diabetic Patients Than the Existing Definitions

Abstract: We previously reported (1) the limited clinical significance for Japanese diabetic patients of the widely used World Health Organization (WHO) (2) and National Cholesterol Education Program (NCEP) (3) definitions of metabolic syndrome and suggested that an international definition of metabolic syndrome that was applicable regardless of ethnicity was necessary (1). Recently, the International Diabetes Federation published a long-awaited new worldwide definition of metabolic syndrome (4) that is intended to be applicable to various ethnic groups. The new definition is similar to the NCEP definition (3) but has several important differences. Notably, most components of the new definition now include subjects who are receiving specific treatments for the abnormalities that comprise metabolic syndrome. Also, central obesity (defined by waist circumference with ethnic modification in its thresholds) has become a mandatory component in the new definition. In this report, we evaluated the predictive power of the new international definition for cardiovascular disease (CVD), as compared with that of previous definitions, in Japanese diabetic patients. The Japan Diabetes Complications Study (JDCS) has been described in detail elsewhere (1, 5). The same dataset was used for evaluation so that the new definition of metabolic syndrome could be directly compared with the WHO and NCEP definitions (1–4). A total of 1,424 Japanese patients (771 men and 653 women, age 58.4 ± 7.4 years [means ± SD]) with previously diagnosed type 2 diabetes but without known CVD were …

The effect of exercise training on adiponectin receptor expression in KKAy obese/diabetic mice

Abstract: Adiponectin is an adipocyte-derived factor that plays a pivotal role in lipid and glucose metabolism. Recently, two types of adiponectin receptors (AdipoR1 and AdipoR2) were identified. We investigated whether exercise training (ET) or dietary restriction (DR) affects the expression of adiponectin receptors in skeletal muscle and liver, thereby improving glucose and lipid metabolism in KKAy mice. KKAy mice were subjected to 8 weeks of exercise training or food restriction. Following the experimental protocol, an intravenous glucose tolerance test and an intraperitoneal insulin tolerance test were performed in addition to the measurement of blood lipid and adiponectin concentrations. The mRNA levels of adiponectin, adiponectin receptors and genes that are putatively regulated by the adiponectin receptors were also analyzed. Both the 8-week exercise training and food restriction protocol improved insulin resistance in KKAy mice but did not alter plasma adiponectin concentration nor its mRNA expression. In comparison with C57BL/6 mice, AdipoR1 expression level was significantly decreased in skeletal muscle and AdipoR2 expression level was significantly increased in the liver in KKAy mice. After the 8-week experimental protocol, the expression level of AdipoR1 mRNA was approximately 1.8-fold greater in the skeletal muscle and 1.3-fold greater in the liver, and the level of AdipoR2 mRNA was 30% less in the liver of the ET group as compared with the control group. Additionally, in the ET group, mRNA expression of acyl coenzyme A-oxidase and carnitine palmitoyl transferase 1 (CPT1) was greater in the liver but not in skeletal muscle. In contrast, no significant changes were observed in the expression of genes encoding the adiponectin receptors in addition to other genes except for CPT1 in the DR group. These findings suggest that chronic exercise training affects the expression level of adiponectin receptors thereby improving insulin resistance in KKAy mice.

Antioxidants and an inhibitor of advanced glycation ameliorate death of retinal microvascular cells in diabetic retinopathy.

Abstract: Background Pericyte ghosts and acellular capillaries are well known as early histological changes resulting from diabetic retinopathy. These histological changes mean that the cell death of retinal microvessels has accelerated. It was reported that apoptosis of retinal microvascular cells (RMCs) was increased in diabetic patients. Therefore, we investigated apoptosis of RMCs in Goto-Kakizaki (GK) rats, a type 2 diabetic model, and involvement with antioxidants (a combination of vitamins C and E) or a novel inhibitor of advanced glycation, OPB-9195. Methods GK rats were treated with the antioxidants combination or OPB-9195 for 36 weeks. We obtained isolated preparations of the vascular network from their retinas by trypsin digestion. Apoptosis of retinal vascular cells was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Results We found that apoptosis of RMCs was increased in the diabetic GK rats. Furthermore, a combination of vitamins C and E and an advanced glycation end-products inhibitor mostly inhibited this increased apoptosis. Conclusions We concluded that apoptosis of RMCs was a good marker that indicates the progression of diabetic retinopathy in GK rats. Both oxidative stress and the accumulation of advanced glycation end-products appears to promote the apoptosis of retinal microvascular cells, and antioxidants or advanced glycation end-products inhibitors might ameliorate diabetic retinopathy. Copyright © 2005 John Wiley & Sons, Ltd.

Outcome of one-year of specialist care of patients with type 2 diabetes: a multi-center prospective survey (JDDM 2).

Abstract: OBJECTIVE: Specialist care is reportedly associated with favorable therapeutic results, although detailed outcomes of recent large-scale prospective surveys of specialist care have yet to be published. The goal of this study was to elucidate the effects of one year's specialist care on the management of type 2 diabetes. PATIENTS AND METHODS: A multi-centered, prospective observational study was undertaken. 754 type 2 diabetes patients, who made their first visit to one of eleven participating outpatient clinics specializing in diabetes care, were enrolled. Routine structured diabetes care according to established guideline, including diabetes self-management education, was provided to all patients at each clinic visit. Parameters relating to glycemic control, serum lipids, blood pressure, patient follow-up status and others were followed for twelve months. RESULTS: The HbA1C level had improved significantly from 8.4±2.2% at baseline to 6.8±1.2% after six months and was 7.0±1.3% after twelve months (mean±SD). The higher the baseline HbA1C level, the greater the subsequent improvement. Moreover, the most dramatic improvements in HbA1C levels were seen within the first three months. The proportion of patients satisfying all of the therapeutic goals was extremely low at baseline and remained at less than 10% after twelve months of specialist care. CONCLUSIONS: Diabetic patients under specialist care experienced substantial improvement, especially in glycemic control, as early as a few months after the first visit. However, 35 percent of patients dropped out during the 12-month study period and this is one area that needs to be improved.

Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis

Abstract: Supernatant protein factor (SPF) is a novel cholesterol biosynthesis-accelerating protein expressed in liver and small intestine. Here, we report on the physiological role of SPF by using Spf-deficient mice. Although plasma cholesterol levels were similar in chow-fed Spf−/− and wild-type (WT) mice, fasting significantly decreased plasma cholesterol levels in Spf−/− mice but not in WT mice. While fasting reduced hepatic cholesterol synthesis rate in WT mice, a more pronounced reduction was observed in Spf−/− mice. The expression of cholesterogenic enzymes was dramatically suppressed by fasting both in WT and Spf−/− mice. In contrast, hepatic SPF expression of WT mice was up-regulated by fasting in peroxisome proliferator-activated receptor α (PPAR-α)-dependent manner. These results indicate that in WT mice, the decrease of hepatic cholesterol synthesis under fasting conditions is at least in part compensated by SPF up-regulation. Fibrates, which function as a PPAR-α agonist and are widely used as hypotrigl...

Exercise Training for Ameliorating Cardiovascular Risk Factors-focusing on Exercise Intensity and Amount

Abstract: Exercise training suppresses cardiovascular risk factors by improving lipid/glucose metabolism, insulin resistance and hypertension. There is an optimum amount and intensity of exercise that will suppress each risk factor, although limited information is currently available on this area. For instance, the level of high-density lipoprotein cholesterol seems to be dependent more on the amount than on the intensity of exercise training; the situation with exercise-induced suppression of triglyceride levels is less clear. It is notable that the ability of mild intensity or a low amount of exercise to suppress or prevent cardiovascular risk factors is largely unknown. This knowledge is essential for prescribing safe and effective exercise training to elderly people. At the same time, very few studies on the associations between cardiovascular risk factors in response to exercise can be found. For example, improvement in lipid metabolism or insulin resistance seems to be related to the weight loss seen during exercise training but weight-independent effects could also be observed. The optimal intensity and amount of exercise training for each cardiovascular risk factor and the relationships between the effects of exercise training on each risk factor need to be clarified in the near future in order to establish guidelines that can be applied to the majority of elderly people at risk of cardiovascular diseases.

Role of Macrophage Colony‐Stimulating Factor in the Initial Process of Atherosclerosis

Abstract: The early atherosclerotic lesion is characterized by the presence of macrophage-derived foam cells. Macrophage colony-stimulating factor (M-CSF) specifically stimulates the functions of the monocyte-macrophages. To elucidate the role of M-CSF in the atherogenic process in vitro and in vivo, we studied the effects of M-CSF on enzyme activities of acidic cholesteryl ester (CE) hydrolase, neutral CE hydrolase, and acyl-coenzyme A:cholesterol acyltransferase (ACAT), and 300 micrograms of M-CSF was intravenously injected into WHHL rabbits aged 2.5 months for 8.5 months. M-CSF (100 ng/ml) enhanced acidic and neutral CE hydrolase, and ACAT activities by 3.2-fold, 4-fold, and 2.3-fold, respectively, in the presence of acetyl LDL, and M-CSF increased ratios of both acidic and neutral CE hydrolase activities to ACAT activity. After M-CSF injection into WHHL rabbits, we found very retarded progression of atherosclerosis. The accumulation of cholesterol ester was remarkably decreased in the aortae of M-CSF-treated animals (0.60 +/- 0.32 mg/g tissue), as compared to those of controls (4.21 +/- 0.65 mg/g tissue). The results suggest that M-CSF prevents the progression of atherosclerosis in WHHL rabbits by increasing net hydrolysis of cholesteryl ester in macrophages.

Cut Points of Waist Circumference: Response to Oda

Abstract: We are grateful for Dr. Oda’s comments (1) on our recent reports (2,3) regarding the utility of waist circumference cutoff values in clinical risk assessments for cardiovascular disease. We agree with his point that the current Japanese criteria for abdominal obesity (85 cm for men and 90 cm for women in waist circumference) (4) are problematical, notwithstanding their adoption by the International Diabetes Federation (IDF) (5) and the …

Animal Models for Hyperinsulinemia and Insulin Resistance

Abstract: The direct effect of endogenous insulin on the atherosclerotic process has not been well understood. To clarify this question, we performed pancreas transplantation in Wistar Shionogi (WS) rats. Hyperinsulinemia was not related to coronary risk factors such as dyslipidemia and hypertension in transplanted rats. After 9 months of transplantation, the cholesterol ester contents of the aortas of transplanted WS rats were significantly higher than in the control rats. The effects of insulin resistance on coronary risk factors were examined in mice deficient in insulin substrate-1-deficient (IRS-1) mice, a non-obese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1-deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1-deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis was involved in the increased plasma triglyceride levels under insulin-resistant conditions.