Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 OC8

University of Edinburgh, Edinburgh, UK.


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.

Volume 15

Society for Endocrinology BES 2008

Society for Endocrinology 

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