Characterization of New Oral Antidiabetic Agent CS-045: Studies in KK and ob/ob Mice and Zucker Fatty Rats

Abstract

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.

Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

“…Furthermore, troglitazone metabolites, which circulate at high concentrations in chronically treated rats, may signi®cantly contribute to its long-term action in vivo (Ciaraldi et al, 1995;Khourshed et al, 1995). Beside stimulation of glucose uptake in vivo and in vitro Okuno et al, 1997), short-term exposure to troglitazone or other thiazolidine derivatives triggers a number of further insulin-like responses (Fujiwara et al, 1988;Zhang et al, 1994;Maegawa et al, 1995). However, with regard to isolated muscle glucose handling, insulin-induced glucose uptake is associated with an anabolic response characterized by distinct augmentation of glycogenesis, moderate stimulation of glycolysis and glycogen accumulation (Crettaz et al, 1980;FuÈ rnsinn et al, 1995; and this study).…”

“…Chronic oral administration markedly improves insulin sensitivity as well as glucose and lipid metabolism in various animal models of obesity and type 2 diabetes (Fujiwara et al, 1988;1995;Lee et al, 1994). A bene®cial action of chronic troglitazone treatment has also been demonstrated in man (Iwamoto et al, 1991;Nolan et al, 1994) making the compound an important new alternative for the treatment of insulin resistance and type 2 diabetes.…”

“…Thiazolidinediones are known to bind to and activate nuclear peroxisome proliferator-activated receptor g (PPARg), which regulates the expression of genes involved in adipocyte di erentiation (Forman et al, 1995;Lehmann et al, 1995;De Vos et al, 1996), but the extent to which PPARg-dependent modulation of gene expression contributes to the antidiabetic action of these compounds has not yet been established. In addition to their chronic insulin-sensitizing action, thiazolidinediones can a ect glucose metabolism more rapidly than might be expected via gene transcription (Fujiwara et al, 1988;Kreutter et al, 1990;Okuno et al, 1997).…”

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

“…The nuclear receptor for thiazolidinedione, peroxisome proliferator-activated receptor (PPAR) γ, is highly expressed in adipocytes suggesting that thiazolidinediones mainly exert their insulin-sensitising effect through the adipose tissue although controversial results have been published [1,2]. Thiazolidinediones improve insulin sensitivity both in man and in different animal models of insulin resistance [3,4]. The improvement in insulin resistance is, at least in rodent models, accompanied by a remodelling of the adipose tissue, where large adipocytes are replaced by an increased recruitment of small and more insulin-sensitive cells [5,6].…”

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

“…They lower plasma insulin concentrations and enhance insulin action in obese diabetic animals [11]. In Type II diabetic patients, thiazolidinediones reduce basal and postprandial blood glucose values as well as HbA 1 c and fructosamine values [10].…”