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

Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism Lynnetta M. Watts 1 , Vara Prasad Manchem 1 , Thomas A. Leedom 1 , Amber L. Rivard 1 , Robert A. McKay 1 , Dingjiu Bao 1 , Teri Neroladakis 1 , Brett P. Monia 1 , Diane M. Bodenmiller 2 , Julia Xiao-Chun Cao 2 , Hong Yan Zhang 2 , Amy L. Cox 2 , Steven J. Jacobs 2 , M. Dodson Michael 2 , Kyle W. Sloop 2 and Sanjay Bhanot 1 1 Isis Pharmaceuticals, Carlsbad, California 2 Endocrine Discovery, Lilly Research Laboratories, Indianapolis, Indiana Address correspondence and reprint requests to Sanjay Bhanot, MD, PhD, Executive Director, Antisense Drug Discovery, Isis Pharmaceuticals, 2292, Faraday Ave., Carlsbad, CA 92008. E-mail: sbhanot{at}isisph.com Abstract 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-α 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