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

Abstract

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. Diabetes 55:2843-2848, 2006 I n type 2 diabetes, glucose-induced suppression of glucagon secretion is impaired, causing inappropriately elevated glucagon levels relative to the elevated glucose levels (1). Furthermore, endogenous glucose production is inappropriately increased in type 2 diabetes (2-4). Several studies have demonstrated a correlation between elevated glucagon levels and increased hepatic glucose production in both healthy subjects infused with exogenous glucagon (5-7) and type 2 diabetic patients (8 -10). Thus, reduction of glucagon levels is considered an interesting target for the treatment of type 2 diabetes, and therefore it is relevant to further characterize the relationship between hyperglucagonemia and the metabolic disturbances associated with type 2 diabetes.Immunoneutralization of endogenous glucagon with glucagon monoclonal antibodies (mAbs) provides a selective and complete suppression of glucagon action without directly affecting the secretion of other hormones. Studies using these antibodies have demonstrated significant blood glucose-lowering effects in diabetic animal models (11-13).In this study, monoclonal glucagon antibodies were used to provide isolated elimination of glucagon signaling in the ob/ob mouse, a commonly used model of type 2 diabetes displaying hyperglycemia, hyperinsulinemia, and insulin resistance (14 -16). With this approach, the aim was to gain further insight into the effects of glucagon on the regulation of hepatic glucose output (HGO) in an animal model of type 2 diabetes, both in the basal state and during the handling of a glucose load. Furthermore, the effects of prolonged elimination of glucagon signaling were studied. The results support the view that glucagon plays a prominent role in the hyperglycemia associated ...

cAMP-responsive Element-binding Protein (CREB)-regulated Transcription Coactivator 2 (CRTC2) Promotes Glucagon Clearance and Hepatic Amino Acid Catabolism to Regulate Glucose Homeostasis

“…3D). Because somatostatin affects the regulation of other glucoregulatory hormones in addition to glucagon (20) and reduces the splanchnic blood flow (21), the aforementioned results were confirmed by using an antibody specific for glucagon (22)(23)(24). After the injection of the glucagon-neutralizing antibody, fasting blood glucose concentrations were lower in the CRTC2 ASO group relative to the control ASO-treated rats (Fig.…”

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

“…This approach is also accompanied by an increase in GLP1 and insulin levels in Zucker diabetic fatty rats and db/db and ob/ ob mice (Sloop et al 2004). Furthermore, the use of high affinity, neutralizing glucagon monoclonal antibodies improved glycaemic control and reduced hepatic glucose production in diabetic ob/ob mice (Sorensen et al 2006). Therefore, these experimental results are a further support that glucagon antagonism may be beneficial for diabetes treatment.…”

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

“…These results further support the notion that presence or absence of glucagon did not matter for the hepatic glucose production during insulinopenia. This is in contrast to insulin-independent diabetes, where both glucagon antagonism and immunoneutralisation lowers blood glucose [8,16,17].…”

“…Glu-001, a monoclonal murine anti-glucagon antibody, or the inactive monoclonal antibody, anti-2, 4, 6-trinitrophenyl (designated control antibody), were administered i.p. at 4 mg/kg body weight at time −120 min [8]. The glucagon receptor antagonist, 25-2648, was administered by oral gavage as a suspension in a dose of 100 mg/kg body weight at time −180 min.…”

“…Glucagon action was blocked using neutralising antibodies [8] or an antagonist [9] (gifts from Novo Nordisk, Måløv, Denmark). Glu-001, a monoclonal murine anti-glucagon antibody, or the inactive monoclonal antibody, anti-2, 4, 6-trinitrophenyl (designated control antibody), were administered i.p.…”