Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors
Kyle W. Sloop, … , Lynnetta M. Watts, M. Dodson Michael
Kyle W. Sloop, … , Lynnetta M. Watts, M. Dodson Michael
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1571-1581. https://doi.org/10.1172/JCI20911.
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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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Figure 4

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Hyperglucagonemia induced by GCGR ASO treatment is reversible. (A) Seven...
Hyperglucagonemia induced by GCGR ASO treatment is reversible. (A) Seven-week-old male db+/? mice were treated twice per week (every 3.5 days) by subcutaneous injection with saline (filled squares), GCGR ASO 180475 (open circles), or control ASO 141923 (filled inverted triangles). ASOs were administered at 25 mg/kg for the first 9 doses and at 10 mg/kg for an additional 18 doses (last treatment on day 91) followed by a treatment-free washout period of 8 weeks. Nonfasted plasma glucose was measured every two weeks, and the data are expressed as the mean ± SEM of 8 mice per treatment group. (B) Nonfasted plasma glucagon was measured every two weeks from the animals described in (A), and the data are expressed as the mean ± SEM of 8 mice per treatment group. (C) GCGR mRNA was measured by real-time quantitative RT-PCR from the livers of 5 animals removed from the study at the time points indicated. Eukaryotic 18S ribosomal RNA was measured and used to normalize RNA input. Data are the mean values ± SEM of 5 mice per treatment group (P < 0.05 using the Student’s t test).