Synergistic action of glucagon and insulin in regulation of hepatic regeneration

Abstract

Rats eviscerated of portal splanchnic organs and deprived of a portal blood supply were maintained by continuous intravenous infusion; when given only electrolytes and glucose they were capable of a regenerative response to partial hepatectomy, as evidenced by a significant rise in the rate of hepatic DNA synthesis, but this response was delayed by about 24 hr and diminished by about two-thirds in comparison to normal controls. Addition of insulin (with glucose) or glucagon (with FreAmine) had little effect when given separately. In combination, however, the two hormones were capable of fully restoring the DNA biosynthetic rate to normal, even when the start of the hormone treatment was delayed for 6–7 hr after the partial hepatectomy. The modest but significant regenerative activity inducible in the near total absence of pancreatic hormones, and the non-deleterious effect of delaying insulin and glucagon treatment for 6–7 hr in eviscerated rats, both suggest that, despite the profound influence of these hormones, additional hormonal or humoral agents may be involved in the initial activation of hepatic regeneration. The precipitous fall in portal vein insulin levels to near zero that we observed during the first several hours of regeneration in normal (non-eviscerated) rats further supports this view, as does the preliminary finding that infusion of insulin and glucagon into eviscerated but non-hepatectomized control rats failed even minimally to excite DNA synthesis in intact livers. Thus, although there is a likelihood that other agents may serve to initiate and even to sustain regeneration, the pancreatic hormones, acting in synergy, appear to be the major regulators of the rate and possibly also of the magnitude of the proliferative process.