Endocrine Pharmacology
S26948, a new specific peroxisome proliferator activated receptor gamma modulator improved in vivo hepatic insulin sensitivity in 48 h lipid infused rats

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Abstract

We examined whether S26948, a new specific peroxisome proliferator activated receptor γ modulator prevented insulin-resistance induced by a 48 h intralipid-infusion in normal rat (IL rats). The effect of S26948 (30 mg/kg) was compared to rosiglitazone (10 mg/kg). Rats were catheterized in the right jugular vein 4 days before the beginning of the 48 h lipid or saline infusions. Animals were intraperitoneally injected once daily with vehicle, S26948 or rosiglitazone. At the end of the infusion the rats underwent either a glucose tolerance test or a euglycemic–hyperinsulinemic clamp. Finally isolation and incubation of hepatocytes in another series of rats were performed. Intralipid infusion leads to a 4-fold increase in plasma free fatty acid concentration compared to controls (C). Both S26948 and rosiglitazone decreased plasma free fatty acid concentration in IL rats compared to vehicle treated IL rats. Glucose-induced insulin secretion was significantly increased in IL compared to C and was associated with insulin resistance. Both S26948 and rosiglitazone treatments normalized glucose-induced insulin secretion and improved insulin action in IL rats. However, S26948 specifically improved hepatic insulin sensitivity whereas rosiglitazone improved both hepatic insulin sensitivity and insulin-stimulated glucose utilization. Finally, studies on isolated hepatocytes showed differential effect of both compounds on gene expression of key enzymes of glucose metabolism. Our data show that non thiazolidinedione S26948 may represent an alternative way for the management of dysregulated hepatic insulin sensitivity.

Introduction

Thiazolidinediones represent a class of oral hypoglycemic agents that have been shown to improve insulin sensitizing and reverse some of the metabolic processes responsible for the development of insulin resistance and, finally, type 2 diabetes in predisposed subjects (Bhatia and Viswanathan, 2006, Mudaliar and Henry, 2001). The insulin sensitizing effects of Thiazolidinediones are mediated through the peroxisome proliferator-activated receptor γ (PPARγ), (Bhatia and Viswanathan, 2006) which is highly abundant in adipose tissue and to a lesser extent in skeletal muscle and liver (Auwerx, 1999, Mudaliar and Henry, 2001). Thiazolidinediones lower hyperglycemia by increasing peripheral glucose utilization and decreasing hepatic glucose production in both human and in experimental models of insulin resistance (Bhatia and Viswanathan, 2006, Olefsky, 2000). They also lower plasma lipid concentration such as triglycerides (Yu et al., 2002) or free fatty acids (Racette et al., 2002). However, Thiazolidinediones treatment could have side effects (Chao et al., 2000, Scheen, 2001, Tolman and Chandramouli, 2003, Watkins et al., 2002). Indeed, the first of the drugs, troglitazone, has been proved to be hepatotoxic (Tolman, 2000) and two cases of hepatotoxicity of rosiglitazone have been also reported (Tolman, 2000). However, it appears that the incidence of hepatotoxicity of rosiglitazone is much lower than that of troglitazone (Tolman and Chandramouli, 2003). Finally, weight gain and fluid retention occur with Thiazolidinediones therapy, especially when they are administered in higher doses and in combination with insulin (Vasudevan and Balasubramanyam, 2004). In the past few years, there has been a considerable effort in identifying PPAR ligands capable of exerting their effects with less weight gain (Shi et al., 2007, Tonstad et al., 2007).

A novel non-Thiazolidinediones-drug, S26948 has been recently developed. It displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPARγ coactivator-1 alpha (Carmona et al., 2007). It has been showed that S26948 displayed pharmacological features of a high selective ligand for PPARγ with low potency in promoting adipocyte differentiation in 3T3-F442A cell line (Carmona et al., 2007). Finally, in vivo experiments evidenced that S26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver of obese (ob/ob) male C57BL/6 mice (Carmona et al., 2007).

The present work was first aimed at studying the comparative effects of S26948 and rosiglitazone on both insulin secretion and action in normal rats receiving a 48 h intravenous intralipid/heparin infusion, thus leading to insulin resistance. The second part was aimed at investigating the effect of S26948 in comparison with rosiglitazone in isolated hepatocytes on: 1) the interrelationships between fatty acid oxidation and glucose production and 2) the expression of genes encoding specific proteins involved in the glucose metabolic pathway in cultured hepatocytes. These experiments were carried out in hepatocytes isolated from 24 h fasted adult rats which exhibit an active fatty acid oxidation as well as an increased gluconeogenic rate.

Section snippets

Materials

The Servier compound S26948, a racemate of dimethyl-2-{4-[2-(6-benzoyl-2-oxo-1,3-benzothiazol-(2H)yl)ethoxy]benzyl}malonate (Blanc-Delmas et al., 2006) was synthesized at the Pharmaceutical Chemistry Institute, EA 1043, Faculty of Pharmacy of Lille (Prof. D. Lesieur). The reference compound (rosiglitazone) was obtained from the same source. Both compounds were solved in 10 mM DMSO.

Animal models

Animal studies were conducted according to French guidelines for the care and use of experimental animals. Male

Plasma parameters during infusions

Table 1 shows plasma free fatty acids concentrations measured before and during infusions at time 24 h and 48 h. In response to intralipid/heparin infusion, free fatty acids levels increased approximately fourfold above basal during the first 24 h (from 388 ± 32 µM to 1801 ± 258 µM, P < 0.01) and were maintained in this high range for the entire study in intralipid rats (48 h: 1658 ± 225 µM, P < 0.05 vs. basal and C rats). In contrast both S26948 and rosiglitazone treatments significantly reduced plasma

Discussion

The main result of our study was that S26948, a novel non Thiazolidinediones PPARγ agonist was effective to improved insulin sensitivity in free fatty acid-induced insulin resistance rat with a specific effect in liver.

In vivo effect of S26948 was studied in a rat model based upon a 48 h intralipid/heparin infusion leading insulin-resistance and increased glucose-induced insulin secretion (Clement et al., 2002). Improvement of insulin sensitivity by both S26948 and rosiglitazone could be partly

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