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Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice

Yin Liang1, Melville C Osborne, Brett P Monia

  • 1Endocrine Therapeutic and Metabolic Disorders, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, USA. yliang@prdus.jnj.com

Diabetes
|January 30, 2004
PubMed

Insights

This study shows that a glucagon receptor antisense oligonucleotide (GR-ASO) effectively lowers blood glucose and improves metabolic markers in diabetic mice. GR-ASO treatment reduces glucagon receptor expression without causing hypoglycemia.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Pharmacology

Background:

  • Hyperglucagonemia, characterized by elevated glucagon levels, is a key driver of hyperglycemia in type 2 diabetes.
  • Targeting the glucagon receptor pathway offers a potential therapeutic strategy to manage blood glucose levels in diabetic patients.

Purpose of the Study:

  • To investigate the antidiabetic effects of a specific glucagon receptor antisense oligonucleotide (GR-ASO).
  • To evaluate the impact of GR-ASO on glucagon receptor expression and downstream signaling in a mouse model of type 2 diabetes.

Main Methods:

  • Quantitative real-time RT-PCR was used to confirm GR-ASO's ability to inhibit glucagon receptor mRNA expression in primary mouse hepatocytes.
  • GR-ASO was administered intraperitoneally to db/db mice for 3 weeks at 25 mg/kg twice weekly.
  • Measurements included glucagon receptor mRNA, glucagon-stimulated cAMP production, blood glucose, triglyceride, free fatty acid levels, glucose tolerance, and hyperglycemic response to glucagon.

Main Results:

  • GR-ASO treatment significantly decreased hepatic glucagon receptor mRNA and reduced glucagon-stimulated cAMP production.
  • DB/DB mice treated with GR-ASO exhibited reduced blood glucose, triglyceride, and free fatty acid levels, alongside improved glucose tolerance.
  • A diminished hyperglycemic response to glucagon challenge was observed, with no instances of hypoglycemia in treated mice. Plasma glucagon levels increased approximately 10-fold, while alpha-cell glucagon levels also increased significantly.

Conclusions:

  • Antagonism of glucagon receptors via GR-ASO demonstrates significant potential for improving glycemic control in type 2 diabetes.
  • GR-ASO effectively reduces hyperglycemia and associated metabolic dysfunctions without inducing hypoglycemia.
  • The findings support the therapeutic concept of targeting glucagon receptors for diabetes management.

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