title: Human monoclonal antibodies against glucagon receptor improve glucose homeostasis by suppression of hepatic glucose output in diet-induced obese mice.
abstract: OBJECTIVE
  Glucagon is an essential regulator of hepatic glucose production (HGP), which provides an alternative therapeutic target for managing type 2 diabetes with glucagon antagonists. We studied the effect of a novel human monoclonal antibody against glucagon receptor (GCGR), NPB112, on glucose homeostasis in diet-induced obese (DIO) mice.
  
  
  METHODS
  The glucose-lowering efficacy and safety of NPB112 were investigated in DIO mice with human GCGR for 11 weeks, and a hyperinsulinemic-euglycemic clamp study was conducted to measure HGP.
  
  
  RESULTS
  Single intraperitoneal injection of NPB112 with 5 mg/kg effectively decreased blood glucose levels in DIO mice for 5 days. A significant reduction in blood glucose was observed in DIO mice treated with NPB112 at a dose ≥5 mg/kg for 6 weeks, and its glucose-lowering effect was dose-dependent. Long-term administration of NPB112 also caused a mild 29% elevation in glucagon level, which was returned to the normal range after discontinuation of treatment. The clamp study showed that DIO mice injected with NPB112 at 5 mg/kg were more insulin sensitive than control mice, indicating amelioration of insulin resistance by treatment with NPB112. DIO mice treated with NPB112 showed a significant improvement in the ability of insulin to suppress HGP, showing a 33% suppression (from 8.3 mg/kg/min to 5.6 mg/kg/min) compared to the 2% suppression (from 9.8 mg/kg/min to 9.6 mg/kg/min) in control mice. In addition, no hypoglycemia or adverse effect was observed during the treatment.
  
  
  CONCLUSIONS
  A novel human monoclonal GCGR antibody, NPB112, effectively lowered the glucose level in diabetic animal models with mild and reversible hyperglucagonemia. Suppression of excess HGP with NPB112 may be a promising therapeutic modality for the treatment of type 2 diabetes.
authors.affiliation: Department of New Drug Discovery, Neopharm Co, Ltd, Daejeon, Korea.
authors.forename: Wook-Dong
authors.initials: WD
authors.lastname: Kim
authors.forename: Yong-ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Kim
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Jung
authors.forename: Woo-Chan
authors.initials: WC
authors.lastname: Son
authors.forename: Seon-Joo
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Byung-Wan
authors.initials: BW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000915:Antibody Affinity; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018027:Receptors, Glucagon / Q000276:immunology*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon; D005947:Glucose