Inhibition of 11β‐hydroxysteroid dehydrogenase 1 by carbenoxolone affects glucose homeostasis and obesity in db/db mice

Abstract

1. One of the major causes of metabolic syndrome is elevated 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in the liver and adipose tissue. High 11β-HSD1 expression contributes significantly to the diabetic phenotype in db/db mice. The purpose of the present study was to test the effect of the pharmacological inhibition of 11β-HSD1 inhibition by carbenoxolone in db/db mice, a genetic model of diabetes. 2. Inhibition of 11β-HSD1 by carbenoxolone was evaluated in liver homogenates obtained from untreated mice. At 0.4, 0.8, 1.6 and 3.2 μmol/L, carbenoxolone reduced the conversion of cortisone to cortisol by 21%, 48%, 82% and 95%, respectively. 3. In another series of experiments in which female db/db mice were dosed orally with carbenoxolone (10, 25 and 50 mg/kg, twice daily) for 10 days, dose-dependent decreases were observed in 11β-HSD1 activity in the brain, adipose and liver. In the case of 10 mg/kg carbenoxolone, the effects were not significant. In addition, the bodyweight of female db/db mice was reduced by 10% and 13% following treatment with 10 and 50 mg/kg carbenoxolone, respectively. Carbenoxolone treatment dose-dependently improved fat mass, energy expenditure, the serum lipid profile, serum leptin and insulin and glucose tolerance. Furthermore, 50 mg/kg carbenoxolone reduced both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity in the liver by 75% and 52%, respectively. These decreases were associated with increased glucokinase protein expression and activity in the liver. 4. Carbenoxolone inhibition of 11β-HSD1 in the liver, adipose and brain significantly improves the symptoms of metabolic syndrome in db/db mice. These improvements can be attributed to increased energy expenditure, decreased activity of the gluconeogenic enzymes PEPCK and G6Pase in the liver and improved glucokinase function in the liver and pancreas.

Filtration is a time-efficient option to Histopaque, providing good-quality islets in mouse islet isolation

“…Therefore, we decided to filter preparations through a 100 lm cell strainer, as reported by Salvalaggio et al (2002). Other reports included an extra step of purification by handpicking after applying this protocol (Daniel et al 2011;Dhanesha et al 2012;Mosedale et al 2012;Pang et al 2010) and our results further confirm the improvement of islet purity after adding this extra step.…”

Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells

“…CBX is known as a global disruptor of gap junction assembly, used to study the nonspecific blockage of Cxs, and our results revealed an antileukemic effect which was synergistic with Ara-C. CBX blocks the assembly of Cxs in the gap junctions and regulates the transfer of mi-RNA and several metabolites such as Ca 2+ and glucose. Moreover, it has been described that CBX inhibits 11β-hydroxysteroid deshydrogenase [39], but this enzyme was not expressed in the leukemic cells. Cancer cell survival is linked to the cell metabolism pathways including glycolysis, OXPHOS as well as amino acids and fatty acids metabolism [48].…”

“…The antileukemic effects of CBX cannot be explained by off target effects on 11β-hydroxysteroid deshydrogenase ( Supplementary Fig. S8a) [39]. HSD11B1 mRNA was not detectable in 22 AML cell lines and 11β-hydroxysteroid deshydrogenase protein was not found or induced by CBX in six AML cell lines ( Supplementary Fig.…”

Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs

“…Therefore, we cannot exclude that after sustained administration CBX might interact with other yet undetermined targets, exerting direct or indirect effects on the emotional parameter investigated here. CBX is known to inhibit the 11β‐hydroxysteroid dehydrogenase therefore competing with the synthesis of endogenous corticosterone which is itself known to regulate the expression of astroglial Cxs . It was also shown that CBX binds, albeit with a low affinity, to mineralo‐ and gluco‐corticoid receptors .…”