HIS-388, a Novel Orally Active and Long-Acting 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Ameliorates Insulin Sensitivity and Glucose Intolerance in Diet-Induced Obesity and Nongenetic Type 2 Diabetic Murine Models
| Autor: | Yumiko Sekiya, Satoshi Sakami, Hiroki Kumagai, Takehiro Takahashi, Koji Kawai, Aiko Nitta, Seiji Okazaki, Tomokatsu Iwamura, Mikiya Sato, Mai Yagi, Junko Nakaki, Mie Kainoh |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Administration Oral Adamantane Type 2 diabetes Diabetes Mellitus Experimental Mice Insulin resistance 11β-hydroxysteroid dehydrogenase type 1 Internal medicine Diabetes mellitus 11-beta-Hydroxysteroid Dehydrogenase Type 1 Glucose Intolerance medicine Hyperinsulinemia Animals Humans Hypoglycemic Agents Obesity Enzyme Inhibitors Pharmacology Pioglitazone biology business.industry Insulin Type 2 Diabetes Mellitus Azepines Isoxazoles Triazoles medicine.disease Mice Inbred C57BL Endocrinology Carbenoxolone Microsomes Liver biology.protein Molecular Medicine Female Thiazolidinediones Insulin Resistance business medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 351:181-189 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.114.216556 |
| Popis: | 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus. In this study, we investigated the pharmacological properties of HIS-388 (N-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11β-HSD1 inhibitor, using several mouse models. In cortisone pellet-implanted mice in which hypercortisolism and hyperinsulinemia occur, single administration of HIS-388 exhibited potent and prolonged suppression of plasma cortisol and lowered plasma insulin levels. These effects were more potent than those achieved using the same dose of other 11β-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11β-HSD1 enzyme activity in vivo. In diet-induced obese mice, HIS-388 significantly decreased fasting blood glucose, plasma insulin concentration, and homeostasis model assessment-insulin resistance score, and ameliorated insulin sensitivity. In addition, HIS-388 significantly reduced body weight and suppressed the elevation of blood glucose during the pyruvate tolerance test. In nongenetic type 2 diabetic mice with disease induced by a high-fat diet and low-dose streptozotocin, HIS-388 also significantly decreased postprandial blood glucose and plasma insulin levels and improved glucose intolerance. The effects of HIS-388 on glucose metabolism were indistinguishable from those of an insulin sensitizer, pioglitazone. Our results suggest that HIS-388 is a potent agent against type 2 diabetes. Moreover, amelioration of diabetic symptoms by HIS-388 was at least in part attributable to an antiobesity effect or improvement of hepatic insulin resistance. Therefore, potent and long-lasting inhibition of 11β-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesity-associated disease. |
| Databáze: | OpenAIRE |
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