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Among the endocrinopathies, diabetes mellitus occupies a unique position. In Addison's d i s e a s e , hypothyroidism, hypoparathyroidism, hypopituitarism a n d o t h e r deficiency s t a t e s , there i s a clear correlation between a hormonal deficiency and the pathologic anatomy. In diab e t e s mellitus, however, t h i s i s not the c a s e . T h e pancreas may b e relatively normal from a morphologic point of view ' 0 l 7 except for minor changes which a r e thought by many t o b e due t o overstimulation of the beta cells. 1 9 5 * 4 0 * 4 1 * 4 6One explanation for this incongruity could be that insulin i s p r o d u c e d normally i n diabetics but destroyed in a n accelerated manner. Since insulin i s elaborated into t h e portal circulation a n d must p a s s t h r o u g h t h e hepatic vascular bed, considerable attention h a s been focused on t h e liver a s a s i t e of insulin degradation.7. 2 4 -2 7 , 3 8 , 4 3 . 4 4T h e possibility that p a s s a g e through the liver obtunds or a l t e r s effectiveness of insulin h a s potential surgical significance. If t h e concept were proved, procedures for diversion of pancreatic venous drainage into systemic venous channels could be devised, thereby making more insulin available for peripheral t i s s u e s .The present study w a s undertaken to t e s t the relative effectiveness of physiologic d o s e s of insulin administered into t h e s y s t e m i c circulation a s compared t o administration directly into the liver via the portal vein. Comparison w a s made of slow, constant insulin infusions alternately administered to a large s e r i e s of d o g s by t h e s e two routes. T h e results were analyzed s t a t i s t i c a l l y u s i n g a n electronic digital computer. METHODSA total of 83 experiments were performed in 24 adult, healthy, mongrel dogs, from 12 t o 20 kg., on which portacaval transposition had been done two or more months previously. At the time of transposition, a l l venous tributaries t o the vena c a v a were ligated from the inguinal ligaments to t h e d i a p h r a g m , excepting only the renals. 3 4 With this preparation, injections or infusions into t h e vena cava or i t s tributaries p a s s into t h e portal vein and then through t h e liver. 3 4 In the present study, such a n infusion i s termed "intraportal."T h e hypoglycemic res p o n s e to intraportal infusions w a s compared t o t h a t obtained with forelimb (systemic) insulin infusions.T h e animals were fed a standard kennel ration of commercial dried dog food supplemented with ground meat. Examinations were carried out after withholding food for 12 to 16 hours. In s e v e n dogs, experiments were carried out on s u c c e s s i v e days, u s i n g a randomized order of JSR