The physiological significance of the secretion of endogenous insulin into the portal circulation. III. Evidence for a direct immediate effect of insulin on the balance of glucose across the liver.

There is at present general agreement, based upon abundant in vitro and in tvvo experimental evidence, that insulin exerts an immediate and profound effect on glucose utilization by muscle and adipose tissue (1-5). On the other hand, a direct hepatic action of insulin is disclaimed by most investigators since innumerable studies both in vitro and in vivo have failed to demonstrate clearly a consistent and reproducible effect of insulin upon hepatic glucose metabolism (5-12). Recent observations from this laboratory suggested that the site (13) and the rate (14) of insulin administration are important factors in eliciting a hepatic effect. However, in these as in all previous in vivo studies (11, 15-19), the conclusions regarding the hepatic action of insulin were inferential, since the net balance of glucose across the liver was not ascertained by direct measurement. Any experiments designed to elucidate the effect of insulin on hepatic carbohydrate metabolism should fulfill the following prerequisites: 1. Hepatic, in contrast to splanchnic, glucose metabolism should be measured. In view of the marked sensitivity of the extrahepatic splanchnic tissues to insulin (1-5, 11, 12), separation of the effects of insulin on these tissues from its effects on the liver is mandatory. This, in turn, re-