Endocrine Abstracts

High systemic cortisol levels contribute to insulin resistance and may exacerbate the development of diabetes by impairing the insulin secretory response of the pancreatic beta-cells (β-cells). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key modulator of glucocorticoid effect within target tissues and high adipose or liver levels of this enzyme may contribute to obesity and/or metabolic disease. We investigated cellular localization of 11β-HSD1 in islets, the effects of 11β-HSD1 deficiency on insulin secretion and report the creation of a transgenic model of β-cell-specific 11β-HSD1 overexpression.

Pancreas and isolated islets from C57/BL6 and 11β-HSD1 deficient mice (11β-HSD1^−/−) were analysed by immunostaining with both 11β-HSD1 and insulin antibodies. 11β-HSD1 mRNA and oxo-reductase activity levels and dynamic insulin secretory capacity was measured in cultured isolated islets in vitro. 11β-HSD1 mRNA and activity (16.3±1.97% of [³H]dehydrocorticosterone (A) converted in [³H]corticosterone (B) n=9) levels were readily detected in isolated islets from C57BL/6J mice. 11β-HSD1 colocalised with insulin, suggesting that the enzyme is expressed in the β-cells. High fat feeding (HF) elicited an exaggerated insulin secretory response from wild type but not 11β-HSD1^−/− islets in vitro (AUC: 8.8±1.4 C57/BL6 HF versus 4.8±0.6 11β-HSD1^−/− HF, P<0.001). Conversely, to test the hypothesis that high β-cell 11β-HSD1 may trigger diabetes we created a glucose-inducible 11β-HSD1 expression ‘construct’ (MIP-11β-HSD1) that responds to high glucose (HG) concentrations in MIN6 β-cells (LG: 22.4±3% HG: 30.4±4% conversion A to B, P<0.05). To model the potential diabetogenic effects on high β-cell 11β-HSD1 in vivo, we created MIP-11β-HSD1 transgenic mice on the diabetes-prone C57BL/KsJ strain background. MIP-11β-HSD1 mice have increased glucose-stimulated 11β-HSD1 activity in their islets (22.6±2.6% vs 9.9±1.9% conversion A to B, n=3). Our data suggest 11β-HSD1 deficiency in pancreatic islets improves β-cell function. We now aim to see whether higher levels of the enzyme in the β-cells impair insulin secretion and trigger diabetes.