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Immunoneutralization of Endogenous Glucagon Reduces Hepatic Glucose Output and Improves Long-Term Glycemic Control in Diabetic ob/ob Mice

¹ Diabetes Research Unit, Novo Nordisk, Måløv, Denmark
² Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
³ Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark

Address correspondence and reprint requests to Heidi Sørensen, Novo Nordisk Park, 2760 Måløv, Denmark. E-mail: hesn{at}novonordisk.com

Abbreviations: FFA, free fatty acid; HGO, hepatic glucose output; mAb, monoclonal antibody; OGTT, oral glucose tolerance test

In type 2 diabetes, glucagon levels are elevated in relation to the prevailing insulin and glucose levels. The relative hyperglucagonemia is linked to increased hepatic glucose output (HGO) and hyperglycemia. Antagonizing the effects of glucagon is therefore considered an attractive target for treatment of type 2 diabetes. In the current study, effects of eliminating glucagon signaling with a glucagon monoclonal antibody (mAb) were investigated in the diabetic ob/ob mouse. Acute effects of inhibiting glucagon action were studied by an oral glucose tolerance test (OGTT) and by measurement of HGO. In addition, the effects of subchronic (5 and 14 days) glucagon mAb treatment on plasma glucose, insulin, triglycerides, and HbA_1c (A1C) levels were investigated. Glucagon mAb treatment reduced the area under the curve for glucose after an OGTT, reduced HGO, and increased the rate of hepatic glycogen synthesis. Glucagon mAb treatment for 5 days lowered plasma glucose and triglyceride levels, whereas 14 days of glucagon mAb treatment reduced A1C. In conclusion, acute and subchronic neutralization of endogenous glucagon improves glycemic control, thus supporting the contention that glucagon antagonism may represent a beneficial treatment of diabetes.

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