Ten nondiabetic dogs were submitted to a procedure called splanchnic division which directed the nutrient rich venous return from the intestines into the left lobes of the liver and the hormone rich pancreatico gastroduodeno splenic venous return into the right lobes. Two mth later, the right lobes had undergone the expected gross and microscopic hypertrophy. Compared with the abnormal shrunken and glycogen depleted hepatocytes of the left lobes, the large and otherwise normal hepatocytes of the right lobes had a higher rate of cell division as judged by microscopic examination, measurements of deoxyribonucleic acid synthesis and the results of autoradiography. Both sides had greater cell replication than in the livers of normal unaltered dogs. The dominance of the right lobes following splanchnic division was almost completely eliminated by the prior creation of alloxan induced diabetes in 4 dogs and by the performance of total pancreatectomy at the same time as splanchnic division in 6 dogs. In these 10 diabetic dogs, which were treated with Sc administered insulin for the 2 mth period of the postoperative study, hepatic lobar and cell size were nearly equal on both sides. By light and electron microscopy, the hepatocytes on both sides had abnormalities, somewhat less pronounced on the right. However, the most active cell division was now transferred to the left lobes. The results with alloxan induced diabetes were similar to those after total pancreatectomy, except that lipid deposits were less on both liver sides in the alloxan experiments, and the glycogen was selectively reduced in the right lobes. The latter finding presumably was due to the continued action of glucagon in dogs made diabetic with alloxan. 12 nondiabetic dogs had a procedure called partial portacaval transposition which directed systemic venous blood from the hindquarters, kidneys and adrenal glands into the left lobes of the liver and the total splanchnic venous return into the right lobes. Two mth later, the degree of relative hypertrophy and hyperplasia of the glycogen rich right lobes was even greater than after splanchnic division, as was the morphologic damage to the left lobar hepatocytes. The degree of right lobar hypertrophy following partial portacaval transposition was reduced but not eliminated by pre existing alloxan induced diabetes in 4 dogs and by concomitant total pancreatectomy in 6 more dogs. The dogs were Sc treated with insulin. Structurally, the hepatocytes on the right side after 2 mth were in better condition than were those on the left, although both were abnormal. The dominance of cell division on the right side was reduced, as judged by standard microscopy and by autoradiography, but there was not a shifting of sides. The biochemical analyses reflected the presence or absence of glucagon. These findings are consistent with the earlier multifactorial hypothesis which holds that portal hepatotrophic factors are mainly interreacting hormones generated by splanchnic organs and delivered straight to the liver and that the hormone interrelationships might have augmented significance because of the high concentration of nutritional substrate in the same venous blood. The observations also substantiate by direct testing the suggestion that insulin is the most important hepatotrophic factor and that it profoundly affects many aspects of liver cell structure, division and function
