Improvement of Glucose Tolerance in NIDDM by Clofibrate Randomized Double-Blind Study

Kobayashi, Masashi; Shigeta, Yukio; Hirata, Yoshihiro; Omori, Yasue; Sakamoto, Nobuo; Nambu, Seiki; Baba, Shigeaki

doi:10.2337/diacare.11.6.495

Cited by 78 publications

(51 citation statements)

References 13 publications

(18 reference statements)

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“…Based on these results, we conclude that in vivo activation of PPAR␣ preferentially modulates triglyceride metabolism without substantially affecting insulin sensitivity. This is consistent with clinical findings where therapeutic doses of fibrates reliably lower elevated triglycerides but produce variable, and/or subtle, effects on glucose metabolism (38,48,49).…”

Section: Resultssupporting

confidence: 87%

Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects

Berger¹,

Leibowitz²,

Doebber³

et al. 1999

Journal of Biological Chemistry

408

267

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The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPAR␣, PPAR␦, and PPAR␥. PPAR␥ has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPAR␥ and PPAR␦ that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPAR␥ and PPAR␦ directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPAR␥ agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPAR␥ agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and triglyceride concentrations. In contrast, selective in vivo activation of PPAR␦ did not significantly affect these parameters. In vivo PPAR␣ activation with WY-14653 resulted in reductions in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1) synthetic non-thiazolidinediones can serve as ligands of PPAR␥ and PPAR␦; 2) ligand-dependent activation of PPAR␦ involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding protein; 3) PPAR␥ activation (but not PPAR␦ or PPAR␣ activation) is sufficient to potentiate preadipocyte differentiation; 4) non-thiazolidinedione PPAR␥ agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPAR␣ activation is sufficient to affect triglyceride metabolism, PPAR␦ activation does not appear to modulate glucose or triglyceride levels.

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Section: Resultssupporting

confidence: 87%

Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects

Berger¹,

Leibowitz²,

Doebber³

et al. 1999

Journal of Biological Chemistry

408

267

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“…Clo®brate or acipimox, which decreases plasma NEFA concentration, improves glucose tolerance or insulin sensitivity in NIDDM patients. 27,28 Therefore, there is a possibility that the reduction in NEFA by YM268 is the driving force for the metabolic changes observed in this study. Further work will be necessary to examine this possibility.…”

Section: Discussionmentioning

confidence: 84%

Role of plasma insulin concentration in regulating glucose and lipid metabolism in lean and obese Zucker rats

Noshiro¹,

Hirayama²,

Shimaya³

et al. 1997

Int J Obes

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OBJECTIVE: To determine the role of plasma insulin concentration in regulating glucose and lipid metabolism in insulin-resistant obese Zucker rats and to compare obese rats with lean controls with respect to changes in insulin sensitivity. DESIGN: Animal study of lean and obese rats with or without insulin sensitizer, YM268. ANIMALS: Nine week old male lean (Fa/±) and obese (fa/fa) Zucker rats. MEASUREMENTS: Plasma glucose, insulin, triglyceride (TG), non-esteri®ed fatty acid (NEFA), cholesterol at baseline and after 14 d, the dose of YM268 for exhibiting a 30% decrease in each parameter (ED 30 ). RESULTS: Insulin, TG, and NEFA concentrations were approximately 2±6 times higher in obese rats. YM268 had no effect on glucose but decreased insulin in lean and obese rats with ED 30 of 3.0 and 2.9 mg/kg. YM268 also reduced TG and NEFA in lean and obese rats [ED 30 (mg/kg): lean; 4.1 (TG), 5.0 (NEFA), obese; 2.1, 3.0]. A signi®cant correlation of either TG or NEFA level to insulin was established in lean and obese rats. CONCLUSION: Plasma TG and NEFA, but not cholesterol concentration, are dependent on plasma insulin in lean and obese Zucker rats, and insulin sensitivity with respect to TG and NEFA metabolism in obese rats may not be different from that in lean rats.

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“…The agonistic activity of KRP-101 in dog PPAR␣ transcriptional assay was Ͼ1,250-fold more potent than that of fenofibric acid, which is a major active metabolite of fenofibrate as a clinically relevant agonist. Whether fibrates are effective for glycemic control for type 2 diabetic patients has been controversial (16,20,23). In addition, there is no clear evidence supporting the clinical efficacy of fibrates for obesity and fatty liver (20,39).…”

Section: Discussionmentioning

confidence: 99%

“…Concomitantly, it has been shown that PPAR␣ agonists prevent increases in adiposity and body weight in rodent disease models without reducing food intake (15). Fibrates often improve glucose intolerance in type 2 diabetic patients (16,23). However, the recent Fenofibrate Intervention and Event Lowering in Diabetes study in a larger number of subjects did not consistently show a pronounced effect on glucose levels in type 2 diabetic patients (20).…”

mentioning

confidence: 99%

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

Tsunoda¹,

Kobayashi²,

Ide³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Tsunoda M, Kobayashi N, Ide T, Utsumi M, Nagasawa M, Murakami K. A novel PPAR␣ agonist ameliorates insulin resistance in dogs fed a high-fat diet. Am J Physiol Endocrinol Metab 294: E833-E840, 2008. First published January 22, 2008 doi:10.1152/ajpendo.00627.2007.-Agonism of peroxisome proliferator-activated receptor (PPAR) ␣, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPAR␣ agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPAR␣ agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 KRP-101 (n ϭ 5) or vehicle (n ϭ 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPAR␣ agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.

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Improvement of Glucose Tolerance in NIDDM by Clofibrate Randomized Double-Blind Study

Cited by 78 publications

References 13 publications

Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects

Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects

Role of plasma insulin concentration in regulating glucose and lipid metabolism in lean and obese Zucker rats

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

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