Abstract
Studies involving the transplantation of human islets in Type I diabetics
have been of significant value both in documenting the potential
importance of islet transplantation as a therapeutic modality, and
in defining some of the problems which must be overcome before this
approach can be used in large numbers of patients. The currently
limited supply of adult human pancreatic glands, and the fact that
chronic immunosuppression is required to successfully transplant
islets into patients, indicate that techniques must be further developed
and refined for allo- and xenografting of isolated islets from human
and animal sources to diabetic patients. An increasing body of evidence
using microencapsulation techniques strongly suggests that this will
be achieved during the next few years. Data from our laboratory in
rodents and dogs indicate that these systems can function for extended
periods of time. In one study, insulin independence was achieved
in spontaneously diabetic dogs by islet microencapsulation inside
uncoated alginate gel spheres (Mr exclusion >600 kD). No synthetic
materials or membrane coatings were employed in this study. Spheres
containing canine islets were implanted into the peritoneum of 4
diabetic dogs. The animals received low-dose CsA (levels below readable
limits by HPLC at 3 weeks). Implantation of these spheres completely
supplanted exogenous insulin therapy in the dogs for 60 to >175 days.
Blood glucose concentration averaged 122+/-4 mg/dl for these animals
during the first 2 months. The glycosylated hemoglobin (HbAIC) levels
during this period dropped from 6.7+/-0.5% to 4.2+/-0.2% (P<0.001).
IVGTT K-values at 1 and 2 months postimplantation were 1.6+/-0.1
(P<0.002) and 1.9+/-0.1 (P<0.001), respectively compared with 0.71+/-0.3
before implantation. In a second group of studies, bovine islets
were immobilized inside a new type of selectively permeable "microreactor"
(Mr exclusion <150 kD) and implanted into the peritoneum of 33 STZ-induced
diabetic rats without any immunosuppression. Diabetes was promptly
reversed, and normoglycemia maintained for periods of several weeks
to months. Immunohistochemical staining of microreactors recovered
from these animals revealed well-granulated beta-cells consistent
with functionally active insulin synthesis and secretion. To test
further the secretory function of the islets, some of the explanted
microreactors were incubated in media containing either basal or
stimulatory concentrations of glucose. The islets responded with
an approximately 3- to 5-fold average increase above basal insulin
secretion. These results are encouraging, and may have important
implications in assessing the potential role of these microencapsulation
systems as therapy for human insulin-dependent diabetes.
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