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 1

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GCGR ASOs decrease GCGR mRNA and lower plasma glucose in ob/ob mice. Mou...
GCGR ASOs decrease GCGR mRNA and lower plasma glucose in ob/ob mice. Mouse (A) or rat (B) primary hepatocytes were treated with the indicated ASO concentration for 4 hours as described in Methods. Following oligonucleotide treatment, cells were cultured for an additional 16–18 hours. Total RNA was extracted, and GCGR mRNA expression was assessed by RT-PCR. GCGR expression was normalized to total RNA in the same samples using Ribogreen. Data are expressed as percent of saline-treated controls. (C) Nonfasted plasma glucose in 8-week-old male ob/ob mice treated twice per week (every 3.5 days) by subcutaneous injection with saline (filled squares), GCGR ASO 148359 (open triangles), GCGR ASO 180475 (open circles), or control ASO 141923 (filled inverted triangles) for 4 weeks. All ASOs were administered at 25 mg/kg. Data are the mean values ± SEM of eight mice per treatment group. In overall comparisons, glucose lowering in animals treated with GCGR ASO 148359 and GCGR ASO 180475 was significantly different compared individually with saline- and control ASO–treated animals (P < 0.05 adjusted using Tukey's t test). (D) Liver GCGR mRNA reduction in ob/ob mice. GCGR mRNA was measured by real-time quantitative RT-PCR from livers of ob/ob mice treated for 4 weeks [i.e., end of the treatment period described in (C)] with saline (black bar), GCGR ASO 148359 (light gray bar), GCGR ASO 180475 (white bar), and control ASO 141923 (dark gray bar). GCGR mRNA was normalized to total RNA in the same samples using Ribogreen. Data are the mean values ± SEM of four mice per treatment group (P < 0.05 using Student’s t test).