Endocrine Abstracts

Insulin-resistant diabetes is characterised by progressive pancreatic β-cell dysfunction. Elevated pancreatic islet activity of the intracellular glucocorticoid amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was hypothesized to drive this process in genetically obese rodents. To determine the direct effects of elevated 11β-HSD1 on β-cell function in diabetes in vivo we created a transgenic model overexpressing 11β-HSD1 under the mouse insulin I promoter (MIP-HSD1 mice). As predicted, MIP-HSD1 mice showed a gene dose-dependent impairment of insulin secretion in vivo (area under curve in control diet: KsJ: 160±21, MIP-HSD1 tg/+: 140±17, MIP-HSD1 tg/tg: 88±9 P<0.05). However, unexpectedly, MIP-HSD1 mice completely reversed the β-cell failure and glucose intolerance caused by chronic high fat feeding in diabetes-prone C57Bl/KsJ mice (area under curve in high fat diet: KsJ: 2360±108, MIP-HSD1 tg/+: 2114±145, MIP-HSD1 tg/tg: 2115±162). MIP-HSD1 mice had increased islet number (control diet KsJ: 580±57, MIP-HSD1 tg/+: 1049±190 P<0.05, high fat diet KsJ: 384±27, MIP-HSD1 tg/+: 790±45 P<0.001) and improved islet function in vitro (insulin secretion rate area under curve in high fat diet: KsJ: 33.4±4.7, MIP-HSD1 tg/+: 53±5.4 P<0.05). Meanwhile as expected 11β-HSD1^−/− mice have appropriate insulin secretion for their improved peripheral insulin sensitisation (area under curve high fat diet C57Bl6: 629±159, 11β-HSD1^−/−: 415±123 P<0.01) correlated with a lower insulin production per islet in vitro (area under curve high fat diet C57Bl6: 20±2.4, 11β-HSD1^−/−: 15±2.7 P<0.05).

Our study shows that elevated β-cell 11β-HSD1 critically supports compensatory insulin hypersecretion. This suggests profound implications for the imminent clinical therapeutic targeting of 11β-HSD1 in diabetes.