Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which is expressed primarily in adipose tissues. To elucidate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (< 2,500 micron2) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000 micron2) by approximately 50%. In fact, the percentage of apoptotic nuclei was approximately 2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue than control. Concomitantly, troglitazone normalized the expression levels of TNF-alpha which were elevated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARgamma. The increased number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF-alpha and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance.
The KK obese mouse is moderately obese and has abnormally high levels of plasma insulin (hyperinsulinemia), glucose (hyperglycemia) and lipids (hyperlipidemia). In one strain (KK/San), we observed abnormally low plasma lipid levels (hypolipidemia). This mutant phenotype is inherited recessively as a mendelian trait. Here we report the mapping of the hypolipidemia (hypl) locus to the middle of chromosome 4 and positional cloning of the autosomal recessive mutation responsible for the hypolipidemia. The hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which we named Allm1. It is identical to angiopoietin-like protein 3, encoded by Angptl3, and has a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in C57BL/6J normal mice. Taken together, these data suggest that Angptl3 regulates lipid metabolism in animals.
CS-045 is a new oral antidiabetic agent that was effective in insulin-resistant diabetic animal models, including the KK mouse, the ob/ob mouse, and the Zucker fatty rat. CS-045 was not effective in the streptozocin-treated mouse, an insulin-deficient diabetic animal model. In fed KK mice, CS-045 lowered the plasma glucose levels in a dose-dependent manner after a single oral administration, and the hypoglycemic effect lasted for at least 18 h. In normal rats, however, plasma glucose levels were not changed after administration of CS-045. CS-045 when given chronically (2 wk) to diabetic KK and ob/ob mice as a 0.2% food admixture dramatically improved hyperglycemia, hyperinsulinemia, and hypertriglyceridemia to near-normal values and decreased plasma lactate, free fatty acid, and ketone body levels without reducing food intake or body weight. In the obese Zucker fatty rat, oral administration of CS-045 had a similar effect in lowering plasma glucose, insulin, triglyceride, free fatty acid, lactate, and ketone body levels. The CS-045-treated Zucker fatty rats showed increased glucose tolerance and decreased insulin secretion in response to oral glucose. After 9 days of treatment, insulin binding to adipocyte plasma membranes from both CS-045-treated Zucker fatty rats and KK mice was increased. Furthermore, 2-deoxyglucose uptake in CS-045-treated adipocytes was increased and the insulin dose-response curve was shifted to the left. These findings suggest that CS-045 increases not only insulin sensitivity but also insulin responsiveness. Based on its pharmacological profile, CS-045 is a new orally effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism in obese and non-insulin-dependent diabetes mellitus patients with insulin resistance.
H NMR and IR studies were carried out for 1,4-dioxane/H 2 O mixtures over the whole concentration range at temperatures of 1, 25, and 50 °C. 1 H NMR spectra were also acquired for 1,3-dioxane/H 2 O and 4-methyl-1,3-dioxane/H 2 O mixtures. All the chemical shift data were measured by referring to an external reference and corrected using in situ bulk susceptibilities as determined on a unified scale. The results are compared with those previously obtained for dimethyl sulfoxide/H 2 O and acetone/H 2 O mixtures in order to determine the influence of the polar group on the hydrogen bond formation of water at the polar and hydrophobic groups. It was found that an anomalous polarization of the water molecules, which had been observed in the dimethyl sulfoxide/H 2 O and acetone/H 2 O mixtures, did not occur in the three different aqueous dioxane mixtures. Thus, we have concluded that the hydrophobic moiety in an organic solute having a polar group does not play a role in anomalously high polarization of the water molecules. We have also concluded that the hydrogen-bonding basicity of the polar group is an important factor for the anomalous polarization of the water in the water-rich region and that the basicities of the ether oxygens in the three dioxanes are not strong enough to cause the anomalous polarization of water. It was found that the frequencies of IR C-H stretching vibration modes of 1,4-dioxane increase and the absorption intensities of the modes decrease with increasing water concentration. Since these spectroscopic features correspond well to the formation of the blue-shifting C-H‚‚‚OH 2 hydrogen bonds obtained from ab initio calculations for complexations in gas phases, we can categorize the solvation of the C-H groups in the dioxanes in aqueous solutions as blue-shifting C-H‚‚‚O hydrogen bonding. Thus, we propose for the first time that the hydration of CH groups in organic solutes having a polar group is due to the formation of blue-shifting C-H‚‚‚OH 2 hydrogen bonds. As a picture of the hydration of the C-H groups in 1,4-dioxane, we propose the formation of a bifunctional hydrogen-bonded hydration complex in which each water molecule plays a role as both a proton donor in the conventional O-H‚‚‚O hydrogen bonding with the ether oxygen and a proton acceptor in the blue-shifting C-H‚‚‚O hydrogen bonding simultaneously.
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