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Islets of Langerhans from unrelated donor rhesus monkeys were transplanted into the portal vein of five rhesus monkeys which had been made diabetic by partial pancreatectomy and Streptozotocin. There was definite improvement of the diabetic state with an increase in the mean KT1/2 from 0.71 to 1.52 percent per minute. The islets were isolated by a more efficient digestion-filtration process than previously had been described. This process has allowed, for the first time, successful isolation of large masses of islets permitting islet transplants in subhuman primates.

Islets were isolated from human pancreases by the distention method and purified by centrifugation on Ficoll or Percoll gradients. The purity of the final preparations was 60% to 90% islets, making it possible to culture the islet preparations in vitro. Perifusion of the islet preparations after 1, 3, or 7 days of culture at 24 degrees C indicated that the islets were viable and would respond to glucose stimulation. If the islets were returned to 37 degrees C culture for 1 day, then the insulin secretory response at 7 days was comparable with the response during the first day of culture at 37 degrees C. Extending the culture period at 24 degrees C to 14 days damaged the islets as indicated by the lack of response to glucose stimulation. The Ficoll technique was a much more effective method for purifying the islets, since it provided approximately twice the yield of islets and insulin compared with the Percoll procedure. The mean yield of purified islets by the Ficoll technique was 2180 +/- 325 islets/gm of pancreas with a calculated islet mass of 3.7 +/- 0.8 mm3/gm. The findings that massive numbers of purified human islets can be obtained by centrifugation on Ficoll gradients and that the purified islet preparations remain morphologically and functionally intact during 7 days' culture at 24 degrees C make it possible to assess the function of donor islets before human islet transplantation, transplant the islets via the portal vein, and use low-temperature culture as a possible approach for altering the immunogenicity of donor human islets.

The extrahepatic diversion of essential splanchnic hepatotrophic factors may cause the liver atrophy and insufficiency that follows portacaval shunting. To investigate this, control dogs with end-to-side portacaval shunts (control-PCS, n = 6) were compared with dogs shunted 1 month after intraportal pancreatic islet autotransplantation (islet-Tx-PCS, n = 5). From the distal pancreas of each experimental dog, 1.95 +/- 0.49 X 10(5) islets were isolated by collagenase digestion and retransplanted within 3 hours. Assays of hepatocellular function (caffeine clearance) and hepatic blood flow (indocyanine green), conventional biochemical liver function tests, and glucose, insulin, and glucagon responses to intravenous glucose challenge were measured monthly and when dogs were killed. Four of six control-PCS dogs were killed 32 +/- 9 days after shunting because of more than 20% body weight loss; one control-PCS dog lost only 7% of body weight by day 56 and stabilized. No significant loss of body weight occurred in islet-Tx-PCS dogs (n = 5). Liver function test abnormalities seen in control-PCS dogs were absent in islet-Tx-PCS dogs. Both control-PCS and islet-Tx-PCS indocyanine green half-life measurements were significantly (p less than 0.05) prolonged at all times, indicating equally reduced hepatic blood flow after shunting for both groups. In contrast, islet-Tx-PCS caffeine half-life periods were significantly (p less than 0.05) shorter than in control-PCS dogs and were similar to those in normal dogs, indicating a protective effect of the transplanted islets on hepatocellular function. We conclude that intraportal pancreatic islet autotransplants prevent, by the local release of hepatotrophic factors within the liver, the metabolic abnormalities and loss of hepatic function after PCS.