Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice.
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 ( approximately 10-fold) levels of plasma glucagon. No changes were observed in pancreatic islet cytoarchitecture, islet size, or alpha-cell number. However, alpha-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.
Liang
Yin
Y
Endocrine Therapeutic and Metabolic Disorders, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, USA. yliang@prdus.jnj.com
Osborne
Melville C
MC
Monia
Brett P
BP
Bhanot
Sanjay
S
Gaarde
William A
WA
Reed
Chantal
C
She
Pengxiang
P
Jetton
Thomas L
TL
Demarest
Keith T
KT
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D005943:Gluconeogenesis; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D018027:Receptors, Glucagon / Q000235:genetics*; D014158:Transcription, Genetic
D001786:Blood Glucose; D016376:Oligonucleotides, Antisense; D018027:Receptors, Glucagon; D000242:Cyclic AMP