Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function.
To learn more about islet vulnerability in the immediate posttransplant period, 400 syngeneic islets were transplanted under the kidney capsule of B6AF1 mice. Three groups of recipients were used: normal mice (normal), streptozotocin (STZ)-diabetic (diabetic), and STZ-diabetic kept hypo- or normoglycemic with insulin pellets (diabetic-normalized). Normoglycemia was achieved in all three groups 14 days after transplantation; however, in the diabetic and diabetic-normalized groups, blood glucose levels throughout the posttransplantation period were respectively higher and lower than in the normal group. Grafts were harvested 1, 3, 7, and 14 days after transplantation and analyzed for morphology, beta-cell death, beta-cell mass, insulin content, and insulin mRNA expression. In all groups, substantial damage in islet grafts was found on days 1 and 3 with apoptotic nuclei and necrotic cores; on day 3, beta-cell death was significantly higher in the diabetic group than in the other groups. Tissue remodelling occurred in all groups with stable graft appearance on day 14; the actual beta-cell mass of the grafts was lowest in the diabetic group. Graft insulin content decreased in all groups on day 1 and fell even further on days 3 and 7. Insulin mRNA levels of grafts retrieved from both the diabetic and diabetic-normalized group were lower than those from the normal group already by day 1 and remained lower on day 14. In conclusion, the first few days of islet transplantation, even under the most advantageous circumstances of excellent metabolic control, are characterized by dynamic changes, with substantial islet cell dysfunction and death followed by tissue remodelling and then stable engraftment.
Davalli
A M
AM
E.P. Joslin Laboratories, Joslin Diabetes Center, Boston, MA 02215, USA.
Scaglia
L
L
Zangen
D H
DH
Hollister
J
J
Bonner-Weir
S
S
Weir
G C
GC
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D016923:Cell Death; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000601:surgery*; D007328:Insulin / Q000032:analysis / Q000096:biosynthesis / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation / Q000473:pathology* / Q000502:physiology*; D007668:Kidney; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009336:Necrosis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013997:Time Factors; D014158:Transcription, Genetic; D014185:Transplantation, Isogeneic
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger