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.