JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11ß-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11ß-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11ß-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11ß-HSD1 in the adipose tissue, liver, and kidney.

An 11-Beta Hydroxysteroid Dehydrogenase Type 1 Inhibitor, JTT-654 Ameliorates Insulin Resistance and Non-obese Type 2 Diabetes.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is the only enzyme that converts inactive glucocorticoids to active forms and plays an important role in the regulation of glucocorticoid action in target tissues. JTT-654 is a selective 11ß-HSD1 inhibitor and we investigated its pharmacological properties in cortisone-treated rats and non-obese type 2 diabetic Goto-Kakizaki (GK) rats because Asians, including Japanese, are more likely to have non-obese type 2 diabetics. Systemic cortisone treatment increased fasting plasma glucose and insulin levels and impaired insulin action on glucose disposal rate and hepatic glucose production assessed by hyperinsulinemic-euglycemic clamp, but all these effects were attenuated by JTT-654 administration. Cortisone treatment also reduced basal and insulin-stimulated glucose oxidation in adipose tissue, increased plasma glucose levels after administration of the pyruvate, the substrate of gluconeogenesis, and increased liver glycogen content. Administration of JTT-654 also inhibited all of these effects. Cortisone treatment decreased basal and insulin-stimulated 2-deoxy-D-[1-3H]-glucose uptake in 3T3-L1 adipocytes and increased the release of free fatty acids and glycerol, a gluconeogenic substrate, from 3T3-L1 adipocytes, and JTT-654 significantly attenuated these effects. In GK rats, JTT-654 treatment significantly reduced fasting plasma glucose and insulin levels, enhanced insulin-stimulated glucose oxidation in adipose tissue, and suppressed hepatic gluconeogenesis as assessed by pyruvate administration. These results demonstrated that glucocorticoid was involved in the pathology of diabetes in GK rats, as in cortisone-treated rats, and that JTT-654 ameliorated the diabetic conditions. Our results suggest that JTT-654 ameliorates insulin resistance and non-obese type 2 diabetes by inhibiting adipose tissue and liver 11ß-HSD1.

Effects of unilateral nephrectomy on renal function in male Spontaneously Diabetic Torii fatty rats: a novel obese type 2 diabetic model.

The Spontaneously Diabetic Torii (SDT) fatty rat is a new model for obese type 2 diabetes. The aim of the present study was to investigate the effect of 1/2 nephrectomy (Nx) on renal function and morphology and on blood pressure in SDT fatty rats. Male SDT fatty rats underwent 1/2 Nx or a sham operation (Sham). Subsequently, animals were studied with respect to renal function and histological alterations. Induction of 1/2 Nx in SDT fatty rats led to functional and morphological damage to the remnant kidney and to hypertension, which are considered main characteristics of chronic kidney disease, at a younger age compared with the sham group. In conclusion, the SDT fatty rat is useful in investigations to elucidate the pathogenesis of human diabetic nephropathy and in new drug discovery.

Physiological changes induced by salt intake in female Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rat, a novel obese type 2 diabetic model.

Salt plays an important role in the control of blood pressure in obesity and diabetes mellitus. In this study, we investigated physiological changes such as blood pressure and renal function in salt-loaded female Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rats. SDT fatty rats were given 1% NaCl in drinking water for 14 weeks, from 4 to 18 weeks of age. Significant salt-sensitive hypertension was observed in the salt-loaded SDT fatty rats. Moreover, the salt-loaded rats showed a decrease of creatinine clearance and deterioration on pathological renal findings, including glomerulosclerosis and tubular and interstitial lesions. Female SDT fatty rat is a useful model for investigating the mechanisms of high salt sensitivity in obesity and diabetes mellitus.

Metabolic Disorders and Diabetic Complications in Spontaneously Diabetic Torii Lepr (fa) Rat: A New Obese Type 2 Diabetic Model.

Spontaneously Diabetic Torii Lepr (fa) (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, in SDT fatty rats were seen at younger ages compared to those in the SDT rats. In this paper, we overview pathophysiological features in SDT fatty rats and also describe new insights regarding the hematology, blood pressure, renal complications, and sexual dysfunction. The SDT fatty rats showed an increase of leukocytes, especially the monocyte count, prominent hypertension associated with salt drinking, end-stage renal disease with aging, and hypogonadism. Unlike other diabetic models, the characteristic of SDT fatty rat is to present an incidence of diabetes in females, hypertension, and retinopathy. SDT fatty rat is a useful model for analysis of various metabolic disorders and the evaluation of drugs related to metabolic disease.

Blood pressure characteristics of female spontaneously diabetic Torii-Lepr(fa) rats.

Blood pressure in female SDT-fa/fa rats was periodically investigated at ages 8, 16, and 24 weeks. Furthermore, an insulin therapy was performed for 5 weeks in the female rats at age 11 weeks, and the change of blood pressure was examined. In addition to obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia, hyperleptinemia and increased urinary angiotensinogen level were observed during the experimental period. Blood pressure was elevated at ages 8 and 16 weeks, but that at 24 weeks was comparable to that in Sprague-Dawley (SD) rats. Heart rate was decreased from age 8 to 24 weeks. Insulin therapy induced good glycemic control and improvement of hyperlipidemia, but the blood pressure was not reduced. Blood pressure in female SDT-fa/fa rats was elevated temporarily. The blood pressure was not decreased by insulin treatment. SDT-fa/fa rat is a useful model to investigate the relation between diabetes mellitus and hypertension.

Evaluation of blood pressure in Spontaneously Diabetic Torii-Lepr(fa) rats.

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals.

This study evaluated JTT-705, S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate, as a cholesteryl ester transfer protein (CETP) inhibitor in several animal species. In vitro, JTT-705 inhibited plasma CETP activities of humans, rabbits, hamsters, cynomolgus monkeys and marmosets with IC(50) values of 5.5, 1.0, 11.7, 2.4 and 6.3 microM, respectively. The thiol form (JTP-25203) also inhibited those activities with IC(50) values of 2.8, 0.44, 0.52, 1.3 and 1.1 microM, respectively. Following oral administration to normolipidemic animals (rabbits, hamsters and marmosets), JTT-705 reduced plasma CETP activity, increased high density lipoprotein cholesterol (HDL-cholesterol), and decreased the ratio of non-HDL-cholesterol to HDL-cholesterol (atherogenic index) in all species. In marmosets, JTT-705 increased slow alpha-migrating lipoprotein (apolipoprotein E-rich HDL) in agarose gel electrophoresis, indicating that HDL metabolism in JTT-705-treated marmosets is similar to that in CETP-deficient humans. These results indicate that JTT-705 can be expected to inhibit plasma CETP activity and improve plasma lipoprotein profiles in a wide range of animal species, including humans.