Reduction in Glucagon Receptor Expression by an Antisense Oligonucleotide Ameliorates Diabetic Syndrome in db/db Mice

  1. Yin Liang, 1,
  2. Melville C. Osborne1,
  3. Brett P. Monia2,
  4. Sanjay Bhanot2,
  5. William A. Gaarde2,
  6. Chantal Reed2,
  7. Pengxiang She1,
  8. Thomas L. Jetton3 and
  9. Keith T. Demarest1
  1. 1Endocrine Therapeutic and Metabolic Disorders, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey
  2. 2Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California
  3. 3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Vermont, Burlington, Vermont
  1. Address correspondence and reprint requests to Yin Liang, MD, PhD, Endocrine Therapeutics & Metabolic Disorders, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, NJ 08869. E-mail: yliang{at}prdus.jnj.com

Abstract

Excess glucagon levels contribute to the hyperglycemia associated with type 2 diabetes. Reducing glucagon receptor expression may thus ameliorate the consequences of hyperglucagonemia and improve blood glucose control in diabetic patients. This study describes the antidiabetic effects of a specific glucagon receptor antisense oligonucleotide (GR-ASO) in db/db mice. The ability of GR-ASOs to inhibit glucagon receptor mRNA expression was demonstrated in primary mouse hepatocytes by quantitative real-time RT-PCR. Intraperitoneal administration of GR-ASO at a dosage of 25 mg/kg twice a week in db/db mice for 3 weeks resulted in 1) decreased glucagon receptor mRNA expression in liver; 2) decreased glucagon-stimulated cAMP production in hepatocytes isolated from GR-ASO–treated db/db mice; 3) significantly reduced blood levels of glucose, triglyceride, and free fatty acids; 4) improved glucose tolerance; and 5) a diminished hyperglycemic response to glucagon challenge. Neither lean nor db/db mice treated with GR-ASO exhibited hypoglycemia. Suppression of GR expression was also associated with increased (∼10-fold) levels of plasma glucagon. No changes were observed in pancreatic islet cytoarchitecture, islet size, or α-cell number. However, α-cell glucagon levels were increased significantly. Our studies support the concept that antagonism of glucagon receptors could be an effective approach for controlling blood glucose in diabetes.

Footnotes

    • Accepted October 27, 2003.
    • Received June 2, 2003.
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