Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains.
11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-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 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.
Alberts
Pēteris
P
Pharmacology 2, Department of Biology, Biovitrum SE12, SE-112 76 Stockholm, Sweden. peteris.alberts@biovitrum.com
Nilsson
Cecilia
C
Selen
Göran
G
Engblom
Lars O M
LO
Edling
Naimie H M
NH
Norling
Solveig
S
Klingström
Gunnel
G
Larsson
Catarina
C
Forsgren
Margareta
M
Ashkzari
Mandana
M
Nilsson
Catrine E
CE
Fiedler
Maj
M
Bergqvist
Elisabet
E
Ohman
Birgitta
B
Björkstrand
Eva
E
Abrahmsen
Lars B
LB
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009765:Obesity / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D010879:Piperazines; D012333:RNA, Messenger; D013449:Sulfonamides; D013844:Thiazoles; C474501:3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides