Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic
glucose output. Whereas systemic GC inhibition can alleviate
hyperglycemia in rodents and humans, it results in
adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized
antisense oligonucleotides (ASOs) to cause selective reduction of the
glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in
glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in approximately 75 and approximately 40% reduction in GCCR
mRNA expression in liver and WAT, respectively. This was accompanied by approximately 65% decrease in fed and approximately 30% decrease in fasted
glucose levels, a 60% decrease in plasma
insulin concentration, and approximately 20 and 35% decrease in plasma
resistin and
tumor necrosis factor-alpha levels, respectively. Furthermore, GCCR ASO reduced hepatic
glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and
dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused approximately 40% decrease in fed and fasted
glucose levels and approximately 50% reduction in plasma
triglycerides. In ZDF and high-fat diet-fed
streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused approximately 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted
glucose levels and a robust reduction in plasma
triglyceride,
cholesterol, and
free fatty acids. No change in circulating
corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with
dexamethasone after treating with GCCR ASO.
Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in
dexamethasone-induced PEPCK expression in the liver without causing any change in the
dexamethasone-induced
lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the
metabolic syndrome.