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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GCGR ASO treatment affects gluconeogenic and glycogenolytic enzyme gene ...
GCGR ASO treatment affects gluconeogenic and glycogenolytic enzyme gene expression and glycogen content in liver. (A) Expression of genes encoding gluconeogenic and glycogenolytic enzymes in GCGR ASO–treated SD rats. Real-time quantitative RT-PCR was used to profile gene expression from the livers of SD rats treated with GCGR ASO 180475 or saline for 4 weeks. Hepatic GCGR, glucose-6-phosphatase catalytic subunit (G-6-Pase [cat]), phosphoenolpyruvate carboxykinase, cytosolic isoform (PEPCK-C), fructose-1,6-bisphosphatase (F-1,6-Bpase), and glycogen phosphorylase (GP) mRNA levels showed significant differences when compared to control ASO–treated animals (P < 0.05 using the Student’s t test). Differences in the mRNA levels of GK and PPARγ were not observed. Rat 36B4 ribosomal phosphoprotein mRNA was measured and used to normalize RNA input. Data are the mean values ± SEM of 5 rats per treatment group. (B) Expression of genes encoding gluconeogenic and glycogenolytic enzymes in GCGR ASO–treated ZDF rats. Real-time quantitative RT-PCR was used to profile gene expression from livers of ZDF rats treated as described in (A). (C) Glycogen was measured as described in Methods in liver samples from 11-week-old db/db mice (n = 5 per treatment group), which had been treated twice per week (every 3.5 days) by subcutaneous injection with saline (black bar), GCGR ASO 180475 (white bar), or control ASO 141923 (gray bar) for 9 total doses. ASOs were administered at 25 mg/kg. GCGR ASO–treated mice had increased liver glycogen in the fasted state (P < 0.05) with no significant change in the fed state.