The Novel Hypoglycemic Agent YM440 Improves Hepatic Insulin Resistance in Obese Zucker Fatty Rats

Nakano, Ryuichi; Kurosaki, Eiji; Shimaya, Akiyoshi; Shibasaki, Masayuki

doi:10.1254/jphs.fp0060360

Cited by 5 publications

(4 citation statements)

References 28 publications

(38 reference statements)

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“…Plasma glucose and HbA 1c were increased in ZDF compared with ZL and ZF (Table 2). These characteristics are almost consistent with the previously reported data (Finegood et al 2001; Wang et al 2001; Oana et al 2005; Nakano et al 2006). These factors suggest that ZF exhibits only obesity and ZDF exhibits hyperglycaemia and diabetes at 16 weeks of age.…”

Section: Discussionsupporting

confidence: 93%

Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator‐activated receptor‐γ coactivator‐1α of fibres in the soleus muscle of Zucker diabetic fatty rats

Adachi

Kikuchi²,

Yasuda³

et al. 2007

Experimental Physiology

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We have reported that a change in muscle fibre type distribution is present in two strains of diabetic rats (Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats). In this study, we determined whether the change in soleus muscle fibre type distribution was caused by diabetes, using obese, diabetic (Zucker diabetic fatty, ZDF), obese, non-diabetic (Zucker fatty, ZF) and non-diabetic, non-obese rats (Zucker lean, ZL). Moreover, we investigated whether the gene expression levels of metabolic key molecules, namely the transcriptional factors of metabolic genes, exemplified by peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and the oxidative enzymes in mitochondria, exemplified by succinate dehydrogenase (SDH), were changed in type I and II muscle fibres in each type of rat, using the new technique of laser capture microdissection (LCM). Both plasma glucose and glucosylated haemoglobin levels were significantly higher in ZDF than in ZL and ZF rats. A lower percentage of type IIA fibres was observed in the muscles of ZDF rats than in those of ZL and ZF rats. The mRNA expression levels of SDH in type II fibres and of PGC-1α in type I fibres were significantly lower in ZDF than in ZL and ZF rats as assessed by LCM and real-time PCR analysis. We have shown, for the first time, that a lower percentage of type IIA fibres was observed in ZDF rats. We have also discovered that the expression levels of the oxidative metabolism-related genes, PGC-1α and SDH, decreased in type I and type II fibres, respectively, of ZDF rats.

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Section: Discussionsupporting

confidence: 93%

Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator‐activated receptor‐γ coactivator‐1α of fibres in the soleus muscle of Zucker diabetic fatty rats

Adachi

Kikuchi²,

Yasuda³

et al. 2007

Experimental Physiology

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“…The Zucker diabetic fatty (ZDF) rat strain has been characterized as an animal model of type-2 diabetes, and mimics the development and progression of type-2 diabetes in humans. As they age, ZDF rats spontaneously develop mesangial proliferation and proteinuria, which ultimately lead to renal failure [4,5,6]. The pathogenesis of diabetic nephropathy appears to be multifactorial.…”

Section: Introductionmentioning

confidence: 99%

PPAR-Alpha Agonist Fenofibrate Induces Renal CYP Enzymes and Reduces Blood Pressure and Glomerular Hypertrophy in Zucker Diabetic Fatty Rats

Zhao

2008

Am J Nephrol

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We have previously shown that fenofibrate, a peroxisome proliferator-activated receptor-α activator, increases renal cytochrome P450 (CYP)-derived eicosanoids and improves endothelial function in pre-diabetic obese rats. The present study was designed to explore the efficacy of fenofibrate on blood pressure and renal injury in the advanced stage of type-2 diabetes. 26-week-old male Zucker diabetic fatty rats (ZDF) were fed fenofibrate (100 mg/kg/day) for 6 weeks. Chronic treatment with fenofibrate normalized systolic blood pressure and reduced glomerular size by 19% in diabetic rats. Western blot and fluorescent immunostaining revealed that the over-expression of collagen type IV and α-smooth muscle actin was significantly attenuated in the kidney of fenofibrate-treated ZDF (F-ZDF) rats. In addition, fenofibrate administration dramatically decreased the cyclin D1 protein level in the kidney of diabetic rats. In contrast, renal CYP2C23 and CYP4A proteins were significantly increased in F-ZDF rats. These fenofibrate effects were observed in the absence of significant changes in glucose, insulin or lipid levels. Taken together, our results demonstrate that fenofibrate may lower blood pressure and attenuate glomerular hypertrophy and collagen accumulation through the downregulation of cyclin D1 and upregulation of CYP monooxygenases in the late stage of type-2 diabetes.

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“…1). 8,9) Endogenous ligands for PPARg have been reported to be fatty acids and eicosanoids, such as 15-deoxy-D 12,14 -prostaglandin J 2 .2,10) Thus, a number of carboxylic acid derivatives have been designed and synthesized to enhance drug-protein interaction and to modify PPAR subtype selectivity ( Fig. 1) 2, [11][12][13] ; however, no nonthiazolidinedione derivatives have been developed successfully as new anti-diabetic drugs; therefore, further efforts are necessary to identify a structurally new PPARg agonist.…”

mentioning

confidence: 99%

“…1). 8,9) Endogenous ligands for PPARg have been reported to be fatty acids and eicosanoids, such as 15-deoxy-D 12,14 -prostaglandin J 2 .…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

Azukizawa

Kasai

Takahashi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Peroxisome proliferators-activated receptors (PPARs) are a subfamily of nuclear hormone receptors, which are ligandactivated transcription factors. There are three subtypes of PPAR: PPARa expressed in the liver and related to fatty acid metabolism, PPARg expressed in adipocytes and playing a role in its differentiation, and PPARd expressed in most cell types and involved in dyslipidemia, cancer and the central nervous system; therefore, PPARs have been focused on as a potential target for metabolic diseases such as diabetes, dyslipidemia and atherosclerosis.1-3) Fibrates such as clofibrate, bezafibrate and fenofibrate, which have been long and widely used as anti-hyperlipidemic drugs, are known to exert their effect via activation of PPARa. Thiazolidinedione derivatives (glitazones), such as pioglitazone and rosiglitazone, known as anti-diabetic drugs, activate PPARg and enhance insulin sensitivity. 4,5) Thiazolidinedione derivatives cause edema, increase the risk of weight gain and congestive heart failure, and rarely show hepatotoxicity.6,7) There have been a great number of attempts to find a novel PPARg agonist that is structurally different from thiazolidinedione derivatives and has higher efficacy and safety. Thiazolidinedione moiety was replaced by oxadiazolidinedione and isoxazolidinedione in YM-440 and JTT-501, respectively (Fig. 1). 8,9) Endogenous ligands for PPARg have been reported to be fatty acids and eicosanoids, such as 15-deoxy-D 12,14 -prostaglandin J 2 .2,10) Thus, a number of carboxylic acid derivatives have been designed and synthesized to enhance drug-protein interaction and to modify PPAR subtype selectivity ( Fig. 1) 2, [11][12][13] ; however, no nonthiazolidinedione derivatives have been developed successfully as new anti-diabetic drugs; therefore, further efforts are necessary to identify a structurally new PPARg agonist.As shown in Fig. 1, some recent PPARg agonists are benzene derivatives with carboxylic acid moiety and two lipophilic moieties, which are postulated to have lipophilic interaction with two regions of a PPARg protein.14) However, in these compounds, a carboxylic acid moiety, lipophilic moiety and benzyl moiety with a lipophilic chain are attached to a central atom (C or N) via a single bond, thus, each moiety can bend and/or rotate freely (Fig. 1). We hypothesized that in these carboxylic acid-type derivatives, the limitation of movement of the three moieties and fixation of their direction may enhance their PPARg agonist activity and reduce their side effects. In the present study, a tyrosine derivative was cyclized to a 1,2,3,4-tetrahydroisoquinoline derivative and then various side chains were introduced into the 2nd and 7th positions of the 1,2,3,4-tetrahydroisoquinoline ring (Fig. 2). Biological activities were evaluated in a series of 1,2,3,4-tetrahydroisoquinoline derivatives and their structure-activity relationships are discussed.Chemistry The general approach to the synthesis of (S)-2-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives 19 ...

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The Novel Hypoglycemic Agent YM440 Improves Hepatic Insulin Resistance in Obese Zucker Fatty Rats

Cited by 5 publications

References 28 publications

Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator‐activated receptor‐γ coactivator‐1α of fibres in the soleus muscle of Zucker diabetic fatty rats

Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator‐activated receptor‐γ coactivator‐1α of fibres in the soleus muscle of Zucker diabetic fatty rats

PPAR-Alpha Agonist Fenofibrate Induces Renal CYP Enzymes and Reduces Blood Pressure and Glomerular Hypertrophy in Zucker Diabetic Fatty Rats

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

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