A comparison of the hypoglycemic effect of insulin with systemic venous and portal venous administration

Abstract

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

Insulin Infusion Into the Portal and Peripheral Circulations of Unanaesthetized Dogs

“…With regard to effects on glucose metabolism, the results of this study agree with those of many other authors (Weisberg et al, 1949;Gambasi et al, 1956;Galansino et al, 1958;Tarding & Schambye, 1958;Martin et al, 1959) that portal administration is less effective than peripheral in producing hypoglycaemia. It may be noted that with one exception (Martin et al, 1959) all these authors worked with anaesthetized animals, and anaesthesia can therefore be discounted as an explanation for the fact that certain other authors (Madison & Unger, 1958;Shoemaker et el., 1959;Starzl et al, 1962Starzl et al, , 1963Erwald et al, 1974) have reported that the site of administration had no significant influence on the hypoglycaemic response.…”

Carbohydrate tolerance with portal and systemic venous drainage of the pancreas

“…In contrast to these findings, other investigators (Reemtsma et al, 1963;Chaya et al, 1966) have not seen hypoglycaemia. In addition, Starzl et al (1963) were unable to demonstrate any significant difference in the hypoglycaemic response to prolonged insulin infusion between infusions given into the portal vein and into the systemic veins. As part of their experiments to determine the effect of portacaval transposition on carbohydrate metabolism Waddell and Sussman (1967) diverted the venous drainage of the normal dog's pancreas into the inferior vena cava, and following this procedure observed significantly reduced peripheral venous concentrations of insulin while glucose tolerance was increased.…”

“…It has been suggested that the continuing occurrence of the vascular complications of diabetes in spite of apparently adequate insulin injections may be related to absorption from the injection site being to systemic rather than to hepatic portal veins. Half or more of the insulin in portal blood is normally removed by the liver (Izzo et al, 1972), andStarzl et al (1975) have shown that this insulin may exert a hepatotrophic effect. A study was planned to compare glucose tolerance following systemic venous drainage of the pancreas with glucose tolerance in animals having portal venous drainage of the pancreas.…”

Pattern of Postprandial Carbohydrate Metabolism and Effects of Portal and Peripheral Insulin Delivery

“…Despite the above line of reasoning, previous studies have failed to demonstrate a clearcut advantage of portal over peripheral insulin delivery on carbohydrate metabolism. Portal insulin infusion, if anything, produces less hypoglycemia for a given dose than systemic insulin infusion (5,6,12,16). Peripheral insulin infusion with either a computer-controlled infusion device or a predetermined waveform results in the same glycemic excursion as portal insulin infusion (10,15,17,22).…”

“…At least in theory, portal insulin delivery may preferentially regulate hepatic glucose metabolism, whereas systemic insulin delivery may predominantly stimulate glucose uptake by peripheral tissues. However, despite its intuitive appeal, previous investigations have failed to show a clear-cut advantage of portal over peripheral insulin delivery (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”