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Updated: Sep 28, 2026
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in
P Alberts1, L Engblom, N Edling
1Pharmacology 2, Department of Biology, Research, Biovitrum, Stockholm, Sweden. peteris.alberts@biovitrum.com
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.
Insights
A novel inhibitor targeting 11beta-hydroxysteroid dehydrogenase type 1 effectively lowered blood glucose and insulin levels in a mouse model. This suggests a promising new therapeutic strategy for managing Type II diabetes.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Current Type II diabetes treatments have limitations, necessitating novel approaches to mitigate long-term complications.
- Glucocorticoids influence glucose metabolism; the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates local active glucocorticoid levels.
- Inhibition of hepatic 11β-HSD1 is hypothesized to reduce excessive glucose production in hyperglycemia and diabetes.
Purpose of the Study:
- To evaluate the efficacy of BVT.2733, a selective inhibitor of 11β-HSD1, in lowering blood glucose.
- To assess the impact of 11β-HSD1 inhibition on glucose and insulin homeostasis in a hyperglycemic mouse model.
Main Methods:
- Administration of BVT.2733 via subcutaneous osmotic mini-pumps to spontaneously hyperglycemic KKA(y) mice for seven days.
- Measurement of hepatic gene expression (PEPCK, glucose-6-phosphatase, 11β-HSD1), blood glucose, serum insulin, liver function markers, food intake, and body weight.
Main Results:
- BVT.2733 significantly reduced hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose, and serum insulin levels compared to controls.
- No significant alterations were observed in hepatic 11β-HSD1 mRNA, liver enzyme markers, food intake, or body weight.
- The treatment demonstrated isoform selectivity for 11β-HSD1 without affecting other measured parameters.
Conclusions:
- Selective inhibition of 11β-HSD1 with BVT.2733 effectively lowers blood glucose and insulin in a preclinical model of Type II diabetes.
- This approach represents a potential new therapeutic strategy for managing hyperglycemia in Type II diabetes.
- Further research into selective 11β-HSD1 inhibitors is warranted for diabetes treatment development.
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