Decreased glucocorticoid binding and receptor activation in brain of genetically diabetic (MDB/MDB) mice

Abstract

Binding of [ 3H]triamcinolone acetonide (TA) to cytosolic receptors and subsequent in vitro activation of glucocorticoid-receptor complexes were studied in whole brain and liver from misty diabetic mice ( mdb/mdb) and their control littermates (??/+ +). Binding was specific for glucocorticoid receptor (GcR) since the specific glucocorticoid, RU26988, was used to compete with [ 3H]TA for binding. Reduced [ 3H]TA binding was observed in whole brain and liver in diabetic animals when compared to control animals. Within the brain, binding was significantly ( P < 0.05) decreased in cortex, hippocampus, and hypothalamus. No significant differences in binding were found in the striatum or “midbrain”. GcR binding was similar in diabetic and control animals until 2 months of age when overt diabetic symptoms appeared and the GcR binding was lower in diabetic animals. Though GcR from mdb/mdb brain cytosol could be thermally activated, the extent of activation was significantly ( P < 0.05) less than that for controls. These data indicate that GcR in liver and brain cytosol are decreased in mdb/mdb mice and that the GcR available for binding in mdb/mdb brain cytosol appears less capable of undergoing activation and binding to DNA-cellulose than GcR from control brain cytosol. Decreased GcR activation in brain cytosol from mdb/mdb mice was associated with increased dissociation of [ 3H]TA from the GcR. These results suggest that the decreased negative feedback previously observed in diabetic animals may be due to decreased binding of hormones and a decreased level of activation of hormone bound receptor complexes.