RT Journal Article
SR Electronic
T1 Long-Term Inhibition of the Glucagon Receptor with a Monoclonal Antibody in Mice Causes Sustained Improvement in Glycemic Control, with Reversible α-Cell Hyperplasia and Hyperglucagonemia
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 871
OP 881
DO 10.1124/jpet.109.157685
VO 331
IS 3
A1 Wei Gu
A1 Hai Yan
A1 Katherine A. Winters
A1 Renée Komorowski
A1 Steven Vonderfecht
A1 Larissa Atangan
A1 Glenn Sivits
A1 David Hill
A1 Jie Yang
A1 Vivian Bi
A1 Yuqing Shen
A1 Sylvia Hu
A1 Tom Boone
A1 Richard A. Lindberg
A1 Murielle M. Véniant
YR 2009
UL http://jpet.aspetjournals.org/content/331/3/871.abstract
AB Uncontrolled hepatic glucose output (HGO) contributes significantly to the pathological hyperglycemic state of patients with type 2 diabetes. Glucagon, through action on its receptor, stimulates HGO, thereby leading to increased glycemia. Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for the treatment of type 2 diabetes. We previously reported the generation and characterization of several high-affinity monoclonal antibodies (mAbs) targeting the glucagon receptor (GCGR). In the present study, we demonstrate that a 5-week treatment of diet-induced obese mice with mAb effectively normalized nonfasting blood glucose. Similar treatment also reduced fasting blood glucose without inducing hypoglycemia or other undesirable metabolic perturbations. In addition, no hypoglycemia was found in db/db mice that were treated with a combination of insulin and mAb. Long-term treatment with the mAb caused dose-dependent hyperglucagonemia and minimal to mild α-cell hyperplasia in lean mice. There was no evidence of pancreatic α-cell neoplastic transformation in mice treated with mAb for as long as 18 weeks. Treatment-induced hyperglucagonemia and α-cell hyperplasia were reversible after treatment withdrawal for periods of 4 and 10 weeks, respectively. It is noteworthy that pancreatic β-cell function was preserved, as demonstrated by improved glucose tolerance throughout the 18-week treatment period. Our studies further support the concept that long-term inhibition of GCGR signaling by a mAb could be an effective approach for controlling diabetic hyperglycemia.© 2009 by The American Society for Pharmacology and Experimental Therapeutics