Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors
Kyle W. Sloop, Julia Xiao-Chun Cao, Angela M. Siesky, Hong Yan Zhang, Diane M. Bodenmiller, Amy L. Cox, Steven J. Jacobs, Julie S. Moyers, Rebecca A. Owens, Aaron D. Showalter, Martin B. Brenner, Achim Raap, Jesper Gromada, Brian R. Berridge, David K. B. Monteith, Niels Porksen, Robert A. McKay, Brett P. Monia, Sanjay Bhanot, Lynnetta M. Watts, M. Dodson Michael
Kyle W. Sloop, Julia Xiao-Chun Cao, Angela M. Siesky, Hong Yan Zhang, Diane M. Bodenmiller, Amy L. Cox, Steven J. Jacobs, Julie S. Moyers, Rebecca A. Owens, Aaron D. Showalter, Martin B. Brenner, Achim Raap, Jesper Gromada, Brian R. Berridge, David K. B. Monteith, Niels Porksen, Robert A. McKay, Brett P. Monia, Sanjay Bhanot, Lynnetta M. Watts, M. Dodson Michael
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Article Metabolism

Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

Abstract

Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2′-methoxyethyl–modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic β cell function.

Authors

Kyle W. Sloop, Julia Xiao-Chun Cao, Angela M. Siesky, Hong Yan Zhang, Diane M. Bodenmiller, Amy L. Cox, Steven J. Jacobs, Julie S. Moyers, Rebecca A. Owens, Aaron D. Showalter, Martin B. Brenner, Achim Raap, Jesper Gromada, Brian R. Berridge, David K. B. Monteith, Niels Porksen, Robert A. McKay, Brett P. Monia, Sanjay Bhanot, Lynnetta M. Watts, M. Dodson Michael

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GCGR ASO therapy improves pancreatic β cell function. (A) An intraperito...
GCGR ASO therapy improves pancreatic β cell function. (A) An intraperitoneal glucose challenge (2 g glucose/kg body wt) was performed on 9-week-old male SD rats (n = 5 per treatment group), which had been treated twice per week (every 3.5 days) by subcutaneous injection with saline (filled squares) or GCGR ASO 180475 (open circles) for 8 doses. ASOs were administered at 25 mg/kg. Blood samples were taken at the indicated time points, and plasma glucose levels were determined. Results are expressed as mean ± SEM. Inset depicts the log of the area under the glucose excursion curve (AUC) for saline (black bar) and GCGR ASO (white bar). P < 0.05. (B) Plasma insulin levels for the indicated time points during the glucose challenge described in (A). Results are expressed as mean ± SEM. Inset depicts the log of the area under the insulin excursion curve for saline (black bar) and GCGR ASO (white bar). P < 0.05. (C) An intraperitoneal glucose challenge (2 g glucose/kg body wt) was performed on 15-week-old male ZDF rats (n = 5 per treatment group), which had been treated as described in (A). Results are expressed as mean ± SEM. Inset depicts the log of the area under the glucose excursion curve for saline (black bar) and GCGR ASO (white bar). P < 0.05. (D) Plasma insulin levels for the indicated time points during the glucose challenge described in (C). Results are expressed as mean ± SEM. Inset depicts the log of the area under the insulin excursion curve for saline (black bar) and GCGR ASO (white bar). P < 0.05.