Regulation of hepatic regeneration in rats by synergistic action of insulin and glucagon.

Abstract

Rats were subjected to resection of the gastrointestinal tract, pancreas, and spleen, and maintained by continuous intravenous infusion. Such animals, receiving only electrolytes and glucose, and deprived of a portal blood supply, responded to 68% hepatectomy with a significant rise in hepatic DNA synthesis, which was, however, greatly delayed and diminished compared to normal controls. The activity was restored to normal by infusion of insulin and glucagon (supplemented with glucose and amino acids), but not by either hormone alone; it was not decreased by delaying the start of hormone treatment for 6-7 hr after partial hepatectomy. Infusion of insulin and glucagon into a small series of rats with intact livers did not appreciably elevate DNA synthesis. In normal rats partial hepatectomy is followed by an abrupt fall in portal vein insulin concentration. These findings are all consistent with the suggestion that agents other than insulin and glucagon may serve to initiate hepatic regeneration, but that these two hormones acting synergistically are major regulators of the rate and perhaps also the extent of the regenerative process.Although mitosis in the liver of the adult rat is a rare event, liver cells proliferate actively in response to partial hepatectomy. This growth process is under humoral control (1), and a variety of agents including hormones, polypeptides, and metabolites have been proposed as potential regulators.Increasingly, evidence has singled out portal venous blood as a likely source of such agents (2-11). Much of this evidence, though persuasive, is circumstantial, resting upon intricate surgical manipulations of the blood supply to the liver or to liver transplants; livers deprived of portal blood undergo partial atrophy. Starzl and his coworkers (2), on the basis of elaborate vascular transpositions in dogs, coupled with DNA labeling, and cyclic nucleotide and enzyme assays, implicated insulin or insulin plus glucagon. Orloff and his associates (3, 10), exploring effects of ablation or transplantation of various splanchnic viscera upon liver regeneration in rats, also designated the pancreatic hormones. Fisher et al. (8), however, on the basis of somewhat similar studies, considered the most likely origin of hepatotrophic factors to be the small intestine, especially the terminal part of the ileum.An approach permitting more direct evaluation of the role of portal blood factors is provided by portal splanchnic evisceration. Price and his coworkers studied hepatic regeneration in dogs, maintained by continuous intravenous alimentation, following resection of the gastrointestinal tract, pancreas, and spleen, with shunting of blood from the aorta or vena cava into the portal vein; partial hepatectomy induced a modest regenerative response, as evidenced by incorporation of labeled thymidine into hepatocyte DNA, and by mitotic activity (4, 5). We have made similar observations in rats, showing, in addition, that no portal blood flow is required (12). Although the experimental conditions ...

Proliferative effect of aqueous extract of Hyptis fructicosa on liver regeneration after partial hepatectomy in rats

“…The insulin together with glucagon stimulates the hepatocyte regeneration either in vitro 17 or in vivo 18,19 . The α2b interferon inhibits the hepatocyte proliferation when administered after 2 or 12h of the hepatectomy 20 .…”

Augmenter of Liver Regeneration: Its Place in the Universe of Hepatic Growth Factors

“…The emergence of insulin and the demonstration by Short and Lieberman (45) that hormone cocktails could drive r~sting livers into mitosis prompted a flurry of hormoneregulatory hypotheses to explain hepatic regeneration (45)(46)(47), supported by claims that glucagon was synergistic with insulin (48). However, the hypothesis was undermined by the inability to confirm a glucagon effect in the canine Eck fistula model (11,34) or in selective evisceration experiments in dogs (43,44), and by failure with the Eck fistula during the next 15 yr to add more hormones to the list ofhepatotrophic molecules with the possible exception of the weakly hepatotrophic thyroxin (T 3) (18).…”

O estresse oxidativo na regeneração hepática em ratos

“…No que se refere à glicemia, no entanto, significante aumento ocorreu no grupo teste. Tal hiperglicemia reflete principalmente a queda da concentração de insulina e do concomitante aumento do nível de glucagon, já experimentalmente comprovados 26 ,após hepatectomias parciais. A regeneração hepática é um fenômeno complexo.…”