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Biomedical subjects

Hirohito Sone

Publications and source records attributed to Hirohito Sone.

At least 19 recordsLinked to original sources
PubMed2006

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

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 HbA(1C) 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 HbA(1C) level, the greater the subsequent improvement. Moreover, the most dramatic improvements in HbA(1C) 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.

Aged↗
PubMed2006

Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.

Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.

Animals↗
PubMed2006

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

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.

Adiponectin↗
PubMed2006

[Long-term intervention studies of diabetic macroangiopathy in Japan and western countries].

Diabetes is a strong and independent predictor of cardiovascular disease that seriously affects mortality and morbidity of patients. Risk of macroangiopathy starts to increase from very early stages of diabetes compared to microangiopathy, therefore aggressive and early treatment is necessary to reduce its risk. Results of previous intervention studies suggest that treatment of each single risk factor is somewhat effective but not enough to achieve sufficient protection from macroangiopathy events, therefore simultaneous interventions of many cardiovascular risk factors are required. At this moment, intervention studies on East Asian patients are very limited and extensive future investigations are expected.

Cardiovascular Diseases↗
PubMed2005

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

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 3beta 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.

Adenoviridae↗
PubMed2005

Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47.

Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c.BETA2.E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.

Animals↗
PubMed2005

Plasma chloride concentration as a new diagnostic indicator of insulin insufficiency.

The medical criteria for initiating insulin therapy, based on clinical profiles of type 2 diabetic patients, have not yet been clearly established. We explored various parameters with 48 type 2 diabetic patients who were taking oral hypoglycemic medication. Among parameters, body mass index (BMI), the fasting plasma glucose level (FPG), and plasma chloride concentration were identified by forward-stepwise discriminant analysis as parameters that can discriminate between patients who were and those who were not undergoing insulin therapy. In combination, these parameters correctly diagnosed 86.4% of the patients who were undergoing insulin therapy, and 84.6% of those who were not undergoing insulin therapy. Further, we observed significant correlations between plasma chloride concentrations and either plasma sodium or organic acid concentrations, suggesting that impaired insulin action may reduce plasma chloride concentrations through changes in plasma sodium and organic acid metabolism. Our results suggest that plasma chloride concentration is a possible new indicator of insulin insufficiency.

Aged↗
PubMed2005

Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor.

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids, triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind directly to a novel SREBP binding site in the promoter of the p21(WAF1/CIP1) gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform consistently causes induction of p21 at both the mRNA and protein levels. Colony formation assays and polyploidy of livers from transgenic mice suggest that activation of p21 by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1 null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target might implicate a new paradigm in the link between lipid synthesis and cell growth.

Animals↗
PubMed2005

Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells.

Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.

Animals↗
PubMed2005

Is the diagnosis of metabolic syndrome useful for predicting cardiovascular disease in asian diabetic patients? Analysis from the Japan Diabetes Complications Study.

OBJECTIVE: The metabolic syndrome (MetS) is believed to be associated with an increased risk of cardiovascular disease (CVD). Although its prevalence is extremely high among diabetic patients, its prevalence in those with no history of CVD has not been determined. Moreover, prospective studies published on the association between MetS and cardiovascular events in diabetic populations have used only the World Health Organization (WHO) definition of MetS and included only white European subjects. The aim of this study was to determine the prevalence of MetS, as defined by both the WHO and the National Cholesterol Education Program (NCEP), and its predictive value for CVD in Asian diabetic patients in a long-term, prospective setting. RESEARCH DESIGN AND METHODS: The baseline characteristics and incidence/hazard ratio of cardiovascular events (coronary heart disease and stroke) were determined in 1,424 Japanese type 2 diabetic patients with and without MetS, as defined by WHO (WHO-MetS) or the NCEP. RESULTS: A high prevalence (38-53%, depending on sex and definition) of MetS was found among diabetic patients, even those with no history of CVD. During the 8-year study period, only WHO-MetS was a predictor for CVD in female patients. In male patients, although both definitions of MetS were significant predictors for CVD, individual components of MetS, such as hyperlipidemia or hypertension, were equivalent or better predictors. CONCLUSIONS: We found that MetS is relatively common in diabetic patients with no history of CVD. We suggest that the commonly used definitions of MetS, at least in their present forms, have limited clinical usefulness for Asian diabetic patients and may need some ethnic group-specific modifications for global use.

Adult↗
PubMed2004

Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes.

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor which regulates genes involved in the synthesis of fatty acids and triglycerides. The overexpression of nuclear SREBP-1a in transgenic mice under the control of the PEPCK promoter (TgSREBP-1a) caused a massively enlarged fatty liver and disappearance of peripheral white adipose tissue. In the current study, we estimated the impact of this lipid transcription factor on plasma glucose/insulin metabolism in vivo. TgSREBP-1a exhibited mild peripheral insulin resistance as evidenced by hyperinsulinemia both at fasting and after intravenous glucose loading, and retarded glucose reduction after insulin injection due to decreased plasma leptin levels. Intriguingly, hyperinsulinemia in TgSREBP-1a mice was markedly exacerbated in a fed state and sustained after intravenous glucose loading, and paradoxically decreased after the portal injection of glucose. TgSREBP-1a mice consistently showed very small plasma glucose increases after portal glucose loading because of a large capacity for hepatic glucose uptake. These data suggested that hepatic insulin resistance emerges postprandially. In addition, pancreatic islets from TgSREBP-1a were enlarged. These data demonstrate that SREBP-1a activation in the liver has a strong impact on plasma insulin levels, implicating the potential role of SREBPs in hepatic insulin metabolism relating to insulin resistance.

Animals↗
PubMed2004

WGEF is a novel RhoGEF expressed in intestine, liver, heart, and kidney.

Rho family GTPases regulate multiple cellular processes through their downstream effectors, where their activities are stimulated by the guanine nucleotide exchange factors. Here, we report a new member of RhoGEF, WGEF, which has the classical structure of DH-PH domain and a C-terminal SH3 domain. WGEF was shown to activate RhoA, Cdc42, and Rac1 by pulldown assay, and forced expression of WGEF resulted in marked rearrangement of the actin cytoskeleton, which is typically seen by the activation of RhoA, Cdc42, and Rac1. WGEF was highly expressed in intestine and also in liver, heart and kidney, which may suggest the involvement of WGEF in the development and functions of these organs. The expression pattern may also suggest the possible importance of WGEF in the understanding of diseases based on metabolic disorder.

Actins↗