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 HbA1c (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.