Adenylate cyclase and insulin action. Effect of insulin, nonsuppressible insulin-like material, and diabetes on adenylate-cyclase activity in mouse liver.

Abstract

Activation of adenylate cyclase in a particle preparation from mouse liver was studied after previous exposure to synthetic glucagon and NaF, and following extensive washing of the preparation. Activation by glucagon was maintained, but fully abolished when GTP was preincubated with the hormone. ATP reduced the effect of glucagon and NaF. The effect of submaximal concentrations of glucagon was significantly inhibited in the presence of physiological amounts of insulin (50–100 μU/ml). Increasing the concentration of insulin led to a disappearance of this effect. Whereas reduction of the basal adenylate cyclase activity was observed, no effect was obtained under maximal stimulation by NaF. Nonsuppressible insulin‐like material, a polypeptide with a molecular weight of approx. 7000, which mimics insulin in a number of metabolic effects, was also found to inhibit the basal as well as the glucagon‐stimulated adenylate cyclase. In contrast to insulin, no paradoxical decrease was seen with higher concentrations. The effects of high concentrations of NaF were not inhibited by insulin‐like material. After previous incubation with insulin‐like material its effect was maintained in the subsequent assay suggesting that the substance binds to liver membranes. In mouse myocardium, insulin‐like material caused no reduction in norepinephrine‐stimulated adenylate cyclase activity. Cyclic‐AMP phosphodiesterase activity, as measured with 1.13 μM substrate, was not influenced by insulin or insulin‐like material. It is unlikely that increased breakdown of cyclic AMP during the adenylate cyclase reaction is responsible for the observed effect of insulin or insulin‐like material. Diabetes, induced by streptozotocin, led to a marked increase in the sensitivity of the adenylate cyclase system to maximal glucagon stimulation. In contrast, the sensitivity of the system to NaF remained unchanged. Insulin treatment of diabetic animals in vivo led to a reversal of the glucagon effect towards the values in the control group. It is suggested that both insulin and insulin‐like material directly affect the adenylate cyclase system by interference with the transmission of the glucagon signal between the receptor and the catalytic enzyme unit. This effect may be of fundamental physiological significance in the mechanism of action of insulin.