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teris AlbertsBiovitrum SE12, SE-112 76, Stockholm, Sweden
Address all correspondence and requests for reprints to: Dr. P. Alberts, Pharmacology 2, Department of Biology, Biovitrum SE12, SE-112 76 Stockholm, Sweden. E-mail: peteris.alberts{at}biovitrum.com.
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11ß-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11ß-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg·d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50–88% of control) and insulin (52–65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65–75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62–74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21–61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81–86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11ß-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.
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S. Arampatzis, B. Kadereit, D. Schuster, Z. Balazs, R. A S Schweizer, F. J Frey, T. Langer, and A. Odermatt Comparative enzymology of 11{beta}-hydroxysteroid dehydrogenase type 1 from six species J. Mol. Endocrinol., August 1, 2005; 35(1): 89 - 101. [Abstract] [Full Text] [PDF]
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I. J Bujalska, N. Draper, Z. Michailidou, J. W Tomlinson, P. C White, K. E Chapman, E. A Walker, and P. M Stewart Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11{beta}-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol., June 1, 2005; 34(3): 675 - 684. [Abstract] [Full Text] [PDF]
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K. N. Hewitt, E. A. Walker, and P. M. Stewart Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity Endocrinology, June 1, 2005; 146(6): 2539 - 2543. [Abstract] [Full Text] [PDF]
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R. Andrew, J. Westerbacka, J. Wahren, H. Yki-Jarvinen, and B. R. Walker The Contribution of Visceral Adipose Tissue to Splanchnic Cortisol Production in Healthy Humans Diabetes, May 1, 2005; 54(5): 1364 - 1370. [Abstract] [Full Text] [PDF]
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G. Apostolova, R. A. S. Schweizer, Z. Balazs, R. M. Kostadinova, and A. Odermatt Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E957 - E964. [Abstract] [Full Text] [PDF]
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E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, and J. S. Flier Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity Diabetes, April 1, 2005; 54(4): 1023 - 1031. [Abstract] [Full Text] [PDF]
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T. C. Sandeep, R. Andrew, N. Z.M. Homer, R. C. Andrews, K. Smith, and B. R. Walker Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone Diabetes, March 1, 2005; 54(3): 872 - 879. [Abstract] [Full Text] [PDF]
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D. J. Hosfield, Y. Wu, R. J. Skene, M. Hilgers, A. Jennings, G. P. Snell, and K. Aertgeerts Conformational Flexibility in Crystal Structures of Human 11{beta}-Hydroxysteroid Dehydrogenase Type I Provide Insights into Glucocorticoid Interconversion and Enzyme Regulation J. Biol. Chem., February 11, 2005; 280(6): 4639 - 4648. [Abstract] [Full Text] [PDF]
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A. J. Drake, D. E. W. Livingstone, R. Andrew, J. R. Seckl, N. M. Morton, and B. R. Walker Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats Endocrinology, February 1, 2005; 146(2): 913 - 919. [Abstract] [Full Text] [PDF]
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S. Boullu-Ciocca, A. Dutour, V. Guillaume, V. Achard, C. Oliver, and M. Grino Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood: Its Relationship With the Metabolic Syndrome Diabetes, January 1, 2005; 54(1): 197 - 203. [Abstract] [Full Text] [PDF]
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 J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]
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K. Kannisto, K. H. Pietilainen, E. Ehrenborg, A. Rissanen, J. Kaprio, A. Hamsten, and H. Yki-Jarvinen Overexpression of 11{beta}-Hydroxysteroid Dehydrogenase-1 in Adipose Tissue Is Associated with Acquired Obesity and Features of Insulin Resistance: Studies in Young Adult Monozygotic Twins J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4414 - 4421. [Abstract] [Full Text] [PDF]
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G. Valsamakis, A. Anwar, J. W. Tomlinson, C. H. L. Shackleton, P. G. McTernan, R. Chetty, P. J. Wood, A. K. Banerjee, G. Holder, A. H. Barnett, et al. 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity in Lean and Obese Males with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4755 - 4761. [Abstract] [Full Text] [PDF]
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C. Frick, A. G. Atanasov, P. Arnold, J. Ozols, and A. Odermatt Appropriate Function of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in the Endoplasmic Reticulum Lumen Is Dependent on Its N-terminal Region Sharing Similar Topological Determinants with 50-kDa Esterase J. Biol. Chem., July 23, 2004; 279(30): 31131 - 31138. [Abstract] [Full Text] [PDF]
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G. Banhegyi, A. Benedetti, R. Fulceri, and S. Senesi Cooperativity between 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-phosphate Dehydrogenase in the Lumen of the Endoplasmic Reticulum J. Biol. Chem., June 25, 2004; 279(26): 27017 - 27021. [Abstract] [Full Text] [PDF]
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R. A. S. Schweizer, M. Zurcher, Z. Balazs, B. Dick, and A. Odermatt Rapid Hepatic Metabolism of 7-Ketocholesterol by 11{beta}-Hydroxysteroid Dehydrogenase Type 1: SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME J. Biol. Chem., April 30, 2004; 279(18): 18415 - 18424. [Abstract] [Full Text] [PDF]
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 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
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