LONG-TERM METABOLIC CONTROL BY RAT ISLET GRAFTS DEPENDS ON THE COMPOSITION OF THE IMPLANT

This study examines whether the loss of metabolic control in initially normalized islet transplants can result from the inadequate compositi on of the donor tissue. Streptozotocin-induced diabetic rats were foll owed for 64 weeks after the intraportal injection of islet isografts w ith different composition. The implantation of 2.3 million beta-cells (10(7)/kg body wt) as particles (>100 pm diameter) of primarily insuli n-positive (70%) and glucagon-positive (20%) cells succeeded in a long -term normalization of 2-h fasting glycemia, glucose tolerance, and se rum fructosamine. The same metabolic control was achieved in animals w ith short and long durations of diabetes or when grafts were implanted under the kidney capsule. At posttransplantation (PT) week 64, insuli n reserves were 60% lower than those in age-matched controls, which ma y account for the glucose intolerance in a few old recipients. The sam e type of graft containing 0.7 million beta-cells (4 x 10(6)/kg body w t) corrected these metabolic parameters for more than 12 weeks; the pr oportionally lower insulin reserves were sufficient for the long-term correction of 2-h fasting glycemia, but did not avoid glucose intolera nce in older recipients. When the higher beta-cells number (10(7)/kg b ody wt) was injected as smaller particles (<100 mu m diameter) of lowe r purity (55% insulin-positive) and negligible glucagon content (<5% g lucagon-positive), the metabolic parameters were also corrected for 12 weeks PT but then progressively returned to overt diabetes (6 of 10) or glucose intolerance (4 of 10). We concluded that long-term metaboli c normalization can be achieved by islet implants in the liver or unde r the kidney capsule. The loss of metabolic control in older animals c an be caused by the inadequate composition of the graft, with the numb er of beta-cells, the proportion of other endocrine and nonendocrine c ells, and the particle size as influential variables.