Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

Diabetologia. 2002 Nov;45(11):1528-32. doi: 10.1007/s00125-002-0959-6. Epub 2002 Sep 18.

Abstract

Aims/hypothesis: 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.

Conclusion/interpretation: 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.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Animals
  • Base Sequence
  • Blood Glucose / metabolism*
  • DNA Primers
  • Enzyme Inhibitors / pharmacology*
  • Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • Hydroxysteroid Dehydrogenases / genetics
  • Hyperglycemia / blood*
  • Hyperglycemia / enzymology
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Mice
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Piperazines / pharmacology*
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • Sulfonamides / pharmacology*
  • Thiazoles / pharmacology*

Substances

  • 3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide
  • Blood Glucose
  • DNA Primers
  • Enzyme Inhibitors
  • Piperazines
  • RNA, Messenger
  • Sulfonamides
  • Thiazoles
  • Hydroxysteroid Dehydrogenases
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • HSD11B1 protein, human
  • Phosphoenolpyruvate Carboxykinase (GTP)