Insulin and Glucagon-Receptor Interactions in the Genetically Obese Zucker Rat: Studies of Hormone Binding and Glucagon-Stimulated Cyclic AMP Levels in Isolated Hepatocytes1

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Abstract
Insulin and glucagon binding and glucagon-stimulated c[cyclic]AMP accumulation were studied in liver cells isolated from 12-15 wk old female Zucker rats (lean: Fa/-; obese: fafa). The specific binding of [125I]iodoinsulin and [125I]iodoglucagon was measured in cells isolated from 24 h fasted rats and from fed rats that received 3 g glucose/kg BW [body weight] i.p. 90 min prior to sacrifice. In all situations an apparent steady-state of binding was achieved after 60 min at 30.degree. C for both [125I]iodoinsulin and [125I]iodoglucagon. Studies of binding, over a wide range of hormone concentrations showed that the specific binding of insulin was lower in the obese than in the lean rats but only in 24 h fasted rats and at low insulin concentrations. In fed rats, no difference was observed between the fafa and the Fa/-. The specific binding of glucagon was similar in obese and in lean animals, but in both groups the binding was significantly higher in fed than in 24 h fasted rats; this was observed over a wide range of glucagon concentrations. In the presence of 1 mM theophylline, glucagon-stimulated cyclic AMP levels reached a maximum by 2 min at 30.degree. C. The level attained was higher and more sustained in fed obese than in fed lean rats. For a given amount of glucagon bound, cAMP levels were increased to a greater extent in fed obese rats than in other groups. In addition to the obese or non-obese state of the animal, dietary conditions may affect both the binding capacity of hormone receptors and glucagon-stimulated cAMP production. In this model of obesity (the Zucker rat), isolated liver cells do not exhibit the considerable insulin binding defect observed in other animal obesities. Glucagon binding and glucagon sensitivity are enhanced in fed rats as compared to fasted rats. Obesity appears to influence steps subsequent to glucagon-receptor interaction.