Glucagon and Insulin Binding to Liver Membranes in a Partially Nephrectomized Uremic Rat Model

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Abstract
To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15±1 mg/100 ml, creatinine 0.7±0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30±2 mg/100 ml, creatinine 2.2±0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46±3 mg/100 ml, creatinine 4.20±0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95±4 vs. 125±11 mg/100 ml), plasma insulin (28±9 vs. 52±11 μU/ml), and plasma glucagon (28±5 vs. 215±18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals. In liver plasma membranes from nephrectomized rats, specific binding of 125I-glucagon was increased by 80-120%. Furthermore, glucagon (2 μM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of 125I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded 125I-glucagon and 125I-insulin to the same extent as control rats. These results demonstrate that: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.