Glucagon Immunoneutralization in Diabetic Rats Normalizes Urea Synthesis and Decreases Nitrogen Wasting

Abstract

To study the effect of glucagon neutralization on urea synthesis in diabetic rats, animals with newly induced (75 mg/kg streptozocin) experimental diabetes mellitus were divided into two groups. One group was given one weekly injection of nonimmune rabbit serum (n = 6), and the other group was given one weekly injection of a specific high-titer antibody against pancreatic glucagon (n = 6). Four weeks later, serum-treated diabetic rats had fasting glucagon concentrations 2–3 times higher than nondiabetic controls given one weekly injection of saline (control). Plasma glucagon binding capacity of diabetic rats given glucagon antibodies was 10–15 times higher than the glucagon concentration. A second group of nondiabetic controls were given nonimmune serum. Blood glucose concentration and urinary glucose output were identical in both groups of diabetic animals. Food intake doubled in both groups of diabetic rats. In control rats, the accumulated nitrogen balance, determined weekly for 4 wk, was positive at 81 ± 3.1 mmol/96 h; in serum-treated diabetic rats, the accumulated nitrogen balance was negative, −8.3 ± 2.4 mmol/96 h throughout the 4 wk, whereas it was higher at 4.7 ± 2.3 mmol/96 h in the glucagon antibody-treated diabetic rats (P < 0.05). The capacity of urea synthesis determined after 4 wk in both groups of nondiabetic controls was 8.4 ± 1.6 μmol · min−1 · 100 g−1 body wt; in the serum-treated diabetic group, it was 21.3 ± 1.9 μmol · min−1 · 100 g−1 body wt (P < 0.01 vs. control); and in the glucagon antibody–treated diabetic group, it was 8.6 ± 0.7 μmol · min−1 · 100 g−1 body wt (P < 0.01 vs. serum-treated diabetic). In the serum-treated diabetic group, the nitrogen content of muscle and heart fell significantly to 56 and 81% of control rats, respectively (P < 0.05). In the glucagon antibody–treated diabetic group, muscle and heart nitrogen content fell significantly less, i.e., to 67 and 88%, respectively (P < 0.05 vs. serum-treated diabetic). The results demonstrate that glucagon immunoneutralization in diabetic rats normalizes the capacity for hepatic aminonitrogen-to-urea conversion and reduces diabetic nitrogen loss by 25% without affecting hyperglycemia.