Abstract:
Background. Fetal pig isletlike cell clusters (ICCs)
will differentiate when grafted into the thymus gland
of outbred immunosuppressed nondiabetic pigs for up
to 3 months. Whether these cells will survive for a
similar period in a diabetic recipient and will mature
with secretion of insulin to ameliorate the hyperglycemia
is unknown.
Methods. Between 40,000 and 125,000 ICCs (7,000 to
11,400 ICCslkg) were injected into the thymus gland
of five juvenile pigs immunosuppressed with cyclosporine
and deoxyspergualin, and the animals were
subsequently made diabetic by the injection of
streptozotocin. Insulin was administered subcutaneously,
with one pig dying from hypoglycemia. The
animal with the least number of ICCs transplanted
was killed 81 days later, and the graft was analyzed
histologically. Blood glucose levels and porcine C-
peptide in the remaining animals were monitored
for a median of 101 days.
Results. Histological analysis of the graft showed
numerous epithelial cell clusters; the percentage of
cells that contained insulin, glucagon, somatostatin,
and pancreatic polypeptide were 61%, 64%, 25%, and
18%, respectively. Some cells contained more than one
hormone. Porcine C-peptide was detected from 21
days after induction of diabetes but not before. In the
pig receiving the most ICCs, blood glucose levels were
lowered to nondiabetic levels 109 days after transplantation.
Plasma C.peptide levels in response to glucagon
in this pig steadily increased after grafting; peak
levels were 0, 0.21, 0.45, and 0.52 nglml at 4, 21, 49, and
80 days after induction of diabetes compared to 0.09
nglml in control diabetic pigs. The secretion of C-peptide in response to oral and intravenous glucose and
arginine also was greater than in untransplanted diabetic
pigs, the pattern of secretion being consistent
with developing fetal p cells as the source of the C-peptide. Pancreatic insulin content was 0.1 mU/mg, 4%
of that in nondiabetic pigs, and the number of /3 cells
per islet was 3 to 6 compared to 90 in nondiabetic
controls.
Conclusions. ICC's will differentiate and function
for up to 111 days when transplanted into outbred
immunosuppressed pigs rendered diabetic. Blood
glucose levels can be lowered to nondiabetic levels
when sufficient numbers of ICCs are grafted.
