Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice.
OBJECTIVE
Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model.


METHODS
BVT.2733 was given to spontaneously hyperglycaemic KKA(y) mice for 7 days using subcutaneous osmotic mini-pumps.


RESULTS
BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment.


CONCLUSIONS
These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes.
Alberts
P
P
Pharmacology 2, Department of Biology, Research, Biovitrum, Stockholm, Sweden. peteris.alberts@biovitrum.com
Engblom
L
L
Edling
N
N
Forsgren
M
M
Klingström
G
G
Larsson
C
C
Rönquist-Nii
Y
Y
Ohman
B
B
Abrahmsén
L
L
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006943:Hyperglycemia / Q000097:blood* / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D001786:Blood Glucose; D017931:DNA Primers; D004791:Enzyme Inhibitors; D006913:Hydroxysteroid Dehydrogenases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); 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; C468386:HSD11B1 protein, human