Reduction of Insulin Resistance in Obese and/or Diabetic Animals by 5-[4-(1-Methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone), a New Antidiabetic Agent

Fujita, Toshio; Sugiyama, Yasuo; Taketomi, Shigehisa; Sohda, Takashi; Kawamatsu, Yutaka; Iwatsuka, Hisashi; Suzuoki, Ziro

doi:10.2337/diab.32.9.804

Cited by 201 publications

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“…The reduction in plasma insulin was highly significant (p<0.001 by t test) and of a magnitude similar to that previously reported in ciglitazone-treated obese rats by Fujita et al 7 Although we did not measure plasma concentrations of glucose, previous investigators have found that in fatty Zucker rats, the reductions in plasma insulin induced by ciglitazone are not accompanied by increases in circulating concentrations of glucose. 7 Oral administration of ciglitazone to obese Zucker rats caused a modest but statistically significant (p<0.05 by t test) reduction in blood pressure ( Figure IB). The blood pressures of the ciglitazone-treated fatty Zucker rats were similar to those of normotensive Lewis rats and lean Zucker rats.…”

Section: Effects Of Ciglitazone On Plasma Insulin and Blood Pressure supporting

confidence: 62%

“…These drugs increase insulin sensitivity in insulin-resistant states and reverse the associated hyperinsulinemia, hyperlipidemia, hypercholesterolemia, and hyperglycemia. 7 Given the possibility that insulin resistance and hyperinsulinemia contribute to hypertension, we hypothesized that administration of a thiazolidinedione might decrease blood pressure. To test this hypothesis, we determined whether the prototype thiazolidinedione, ciglitazone, could decrease blood pressure in the fatty Zucker rat, a rodent model of insulin resistance and mild hypertension.…”

Section: N Umerous Epidemiological and Clinical Studiesmentioning

confidence: 99%

“…Previous studies have shown that these rats are characterized by mild hypertension, insulin resistance, and hyperinsulinemia. 7 ' 8 The experimental group was fed a standard rat diet containing 0.05% (wt/wt) ciglitazone; the control group was given the same diet without ciglitazone. The rats were individually housed in metabolic cages, and daily food intake was measured for each rat.…”

Section: Whole Animal Studiesmentioning

confidence: 99%

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Effects of ciglitazone on blood pressure and intracellular calcium metabolism.

et al. 1993

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Ciglitazone is the prototype of the thiazolidinedione class of compounds currently being developed for the treatment of insulin resistance and non-insulin-dependent diabetes. The effects of thiazolidinediones on blood pressure and cell calcium metabolism are not well defined. In the obese Zucker rat, a widely studied model of insulin resistance associated with mild hypertension, we investigated the effects of ciglitazone on plasma insulin levels and mean arterial pressure. We also evaluated the effects of ciglitazone on the changes in cytosolic calcium induced by platelet-derived growth factor in A172 human glioblastoma cells and rat A10 vascular smooth muscle cells. Oral administration of ciglitazone, approximately 45 rag/kg per day for 4 weeks, induced significant reductions in plasma insulin levels (/>< 0.001) and blood pressure (p<0.05). Ciglitazone was also found to significantly attenuate the capacity of platelet-derived growth factor BB homodimer to induce sustained increases in intracellular free calcium. These findings suggest that thiazolidinediones may offer a novel pharmacological approach to the treatment of hypertension, and raise the possibility that these compounds may affect blood pressure not only by affecting insulin metabolism but also by modifying the cell calcium response to pressor agents, growth factors, or both. Blood pressure tends to correlate positively with hyperinsulinemia, and lean, nondiabetic hypertensive individuals appear to be characterized by hyperinsulinemia and insulin resistance. These observations suggest that hypertension is an insulin-resistant state, and it has been proposed that insulin resistance, per se, is a pathogenetic determinant of increased blood pressure. Furthermore, hyperinsulinemia stimulates proliferation of vascular smooth muscle, modifies ion transport in a variety of tissues, enhances sympathetic nervous activity, and promotes renal retention of sodium. 3 -6 These are all potential mechanisms whereby disordered insulin metabolism might increase blood pressure.The thiazolidinediones are a class of compounds being developed for the treatment of non-insulin-dependent diabetes mellitus. These drugs increase insulin sensitivity in insulin-resistant states and reverse the associated hyperinsulinemia, hyperlipidemia, hypercholesterolemia, and hyperglycemia.

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Section: Effects Of Ciglitazone On Plasma Insulin and Blood Pressure supporting

confidence: 62%

Section: N Umerous Epidemiological and Clinical Studiesmentioning

confidence: 99%

Section: Whole Animal Studiesmentioning

confidence: 99%

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Effects of ciglitazone on blood pressure and intracellular calcium metabolism.

et al. 1993

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“…Before even being identified formally as PPARg ligands, TZDs were shown to stimulate adipogenesis and to improve insulin sensitivity [203,204]. It is only more recently that TZDs were described as selective ligands for the receptor, bridging the gap between PPARg and insulin sensitivity ( Figure 5) [205,206].…”

Section: Pparg As a Therapeutic Target In Fat Related Diseasesmentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…The KKAy mice (the yellow offspring obtained from a cross of black KK females with obese yellow Ay males) are obese, hyperglycemic, hyperinsulinemic, insulin resistant severely hypertriglyceridemic and mildly hypercholesterolemic (Fujita et al, 1983;Iwatsuka, et al, 1970), and serve as an excellent animal model for studying diabetes. In this study, KKAy mice were used to investigate the effects of PC on antidiabetic potential in vivo.…”

Section: Introductionmentioning

confidence: 99%