The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice

Shimaya, Akiyoshi; Kurosaki, Eiji; Nakano, Ryuichi; Hirayama, Reiko; Shibasaki, Masayuki; Shikama, Hisataka

doi:10.1016/s0026-0495(00)90440-2

Cited by 35 publications

(20 citation statements)

References 29 publications

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“…Similar results were observed with YM440 in diabetic db / db mice (18). Several groups reported that chronic treatment with pioglitazone or rosiglitazone decreased plasma glucose to normal levels, but caused significant body weight gain (5,11).…”

Section: Discussionsupporting

confidence: 83%

“…YM440 had little effect on both adipocyte differentiation and PPARγ transactivation in vitro. In diabetic db / db mice, this agent significantly decreased blood glucose to a level comparable to TZD-treated mice without causing body weight to change (18). Chronic treatment of ZF rats with YM440 ameliorated abnormalities in hepatic glycogen metabolism and hepatic gluconeogenesis (19,20); however, it is not clear whether YM440 has a significant effect on hepatic or peripheral insulin sensitivity throughout the body.…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2006

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Abstract. The novel hypoglycemic agent YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor (PPAR) γ. YM440 has unique pharmacological profiles both in vitro and in vivo, but, it is not clear whether the compound has a significant effect on hepatic or peripheral insulin response throughout the body. The aim of this study is to examine the effects of YM440 on hepatic and peripheral insulin resistance in Zucker fatty (ZF) rats using the euglycemic-hyperinsulinaemic clamp technique. Treatment of ZF rats with YM440 (300 mg / kg per day) for 2 weeks significantly decreased plasma concentrations of glucose and insulin without inducing obesity. YM440 caused a 2-fold increase in the glucose infusion rate during euglycemic clamping compared with the vehicle control. YM440 also decreased the percent change in hepatic glucose production rate caused by intravenous insulin infusion in ZF rats. YM440 had no significant effect on the glucose disposal rate. These results indicate that YM440 ameliorates hepatic, but not peripheral insulin resistance in ZF rats. These findings strongly suggest that the main target organ of YM440 is the liver, unlike other PPARγ agonist.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 97%

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

et al. 2006

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“…It is not known whether these observations are relevant for TZD treatment of humans, and hence it is not known whether the beneficial effect of PPARg treatment depends on these mechanisms, and whether this adipocyte recruitment effect can be sustained in the long term. A recent report with a novel PPARg compound with insulin-sensitizing activity with lower stimulation of adipogenesis, probably because of a new interaction mode with a 2 : 1 agonist : receptor binding relation, 107 and reports of non-TZD compounds showing hypoglycaemic effects without effects on body fat weight 108 remain to be clinically corroborated.…”

Section: Ppargamma Agonistsfadipogenic Treatment Of Type II Diabetes mentioning

confidence: 99%

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

Larsen¹,

Toubro²,

Astrup³

2003

Int J Obes

256

170

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The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARg in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARg seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARg-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these 'adipogenic compounds' is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes.

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“…The new TZDs RWJ241947 (MCC-555), NC-2100, and PAT5A, and also the antidiabetic oxadiazolidinedione YM440 (molecular structures in Fig. 1), carry antihyperglycaemic and insulin sensitizing potentials at least equal to those of established TZDs [38,39,80,81,82], although they have markedly lower efficacies for PPARγ affinity, PPARγ transactivation, and adipocyte differentiation in vitro [38,39,80,81]. In addition, no increases in fat and body weight which characterize most TZDs [57,58,59] are found in response to treatment with NC-2100 or YM440 [38,81], which suggests little adipogenic action in vitro and in vivo.…”

Section: Adipose Tissuementioning

confidence: 99%

“…1), carry antihyperglycaemic and insulin sensitizing potentials at least equal to those of established TZDs [38,39,80,81,82], although they have markedly lower efficacies for PPARγ affinity, PPARγ transactivation, and adipocyte differentiation in vitro [38,39,80,81]. In addition, no increases in fat and body weight which characterize most TZDs [57,58,59] are found in response to treatment with NC-2100 or YM440 [38,81], which suggests little adipogenic action in vitro and in vivo. Dissociation of adipogenic and metabolic TZD action has also been reported for isolated adipocytes transfected with a PPARγ dominant-negative mutant, in which TZDs and other agonists maintained their ability to stimulate glucose transport, albeit their adipogenic potential was severely impaired [83].…”

Section: Adipose Tissuementioning

confidence: 99%

Thiazolidinediones: metabolic actions in vitro

Fürnsinn¹,

Waldhäusl

2002

Diabetologia

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To unravel the molecular mechanisms and the causal chain of how thiazolidinediones (TZDs) affect glucose homeostasis, it is helpful to analyse their direct influence on isolated specimens of fat, muscle, and liver in vitro. Studies on isolated adipocytes have shown that the nuclear peroxisome proliferator-activated receptor-γ (PPARγ) is an important molecular target for TZDs, through which they trigger adipocyte differentiation and adipose tissue remodelling. It is not clear, however, if the activation of PPARγ in adipose tissue is the cause of all the metabolic actions of TZDs. Based on in vitro studies, two hypotheses have been developed. The first emphasizes PPARγ-mediated actions on adipose tissue, suggesting that insulin sensitization of skeletal muscle and liver is triggered indirectly by changes in circulating concentrations of adipocyte-derived non-esterified fatty acids and peptide hormones. The second states that TZDs improve glucose homeostasis independently from adipose tissue actions by the direct interaction with muscle and liver. This hypothesis is supported by direct TZD actions on fuel metabolism of skeletal muscle and liver in vitro, which seem to be independent from PPARγ signalling. Major progress has been made in understanding the mechanisms involved in the effects of TZDs on adipose tissue but the causal chain responsible for their antihyperglycaemic action is still not clear. The involvement of other molecular targets in addition to PPARγ, of adipocyte-derived messengers, and of direct interaction with skeletal muscle and liver have yet to be clarified. [Diabetologia (2002[Diabetologia ( ) 45:1211[Diabetologia ( -1223

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The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice

Cited by 35 publications

References 29 publications

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

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

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

Thiazolidinediones: metabolic actions in vitro

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