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Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

¹ Isis Pharmaceuticals, Carlsbad, California
² Endocrine Discovery, Lilly Research Laboratories, Indianapolis, Indiana

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 75 and 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by 65% decrease in fed and 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and 20 and 35% decrease in plasma resistin and tumor necrosis factor- 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 40% decrease in fed and fasted glucose levels and 50% reduction in plasma triglycerides. In ZDF and high-fat diet–fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused 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.

Abbreviations: ASO, antisense oligonucleotide; GC, glucocorticoid; GCCR, glucocorticoid receptor; HFD-STZ, high-fat diet–fed streptozotocin-treated; HMG, 3-hydroxy-3-methylglutaryl; HPA, hypothalamic-pituitary-adrenal; POMC, proopiomelanocortin; STZ, streptozotocin; TAT, tyrosine aminotransferase; TNF, tumor necrosis factor

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