Growth of intraportally transplanted islets under liver regeneration stimulus and restoration of normoglycemia in streptozocin-diabetic rats.
BACKGROUND
Limitation of beta-cell growth after intraportal islet transplantation plays an important role in graft failure. To induce transplanted beta-cell proliferation, we studied the effect of compensatory liver growth in diabetic rats that had a subtherapeutic islet mass previously injected into the liver.


METHODS
Syngeneic rats were used as islet donors or recipients; diabetes was induced by streptozocin. Three groups of streptozocin-treated rats were studied. In group 1, 250 islets were selectively transplanted into the posterior liver lobes and 10 days later anterior portal branch ligation (PBL) was performed (n = 18); in group 2, 250 islets were transplanted into the posterior lobes and 10 days later sham PBL was performed (n = 13); in group 3, rats underwent a sham transplantation and PBL (n = 6). Nonfasting blood glucose levels and body weight were monitored. Six rats in groups 1 and 2 were killed 48 hours after PBL, liver sections were stained for proliferating cell nuclear antigen, and islet cell labeling index was calculated. The remaining rats were killed 30 days later. Liver compensatory growth or atrophy was calculated and morphometric determination of beta-cell area was assessed on insulin-immunostained sections of the liver.


RESULTS
In group 1 rats killed 48 hours after PBL, islet cell labeling index was significantly higher than in group 2 (p < 0.0001). After PBL, we observed normalization of nonfasting blood glucose levels in 10 of 12 rats. At 30 days, posterior liver lobes showed compensatory growth (218.5% +/- 18.6%) accompanied by atrophy of the anterior lobes; morphometric study of liver-engrafted islets showed a significant increase of individual beta-cell area, compared with group 2 (p < 0.0001). In groups 2 and 3, normoglycemia was not achieved.


CONCLUSIONS
In streptozocin-diabetic rats, normoglycemia was restored after transplantation of a sub-therapeutic islet mass, followed by PBL-induced liver regeneration. Histologic and morphometric results indicating islet cell proliferation suggest that compensatory liver growth might have induced a hypertrophic/hyperplastic response in the intraportally transplanted beta-cells.
Morsiani
E
E
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif., USA.
Fogli
L
L
Rozga
J
J
Ricci
D
D
Azzena
G
G
Demetriou
A A
AA
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology* / Q000601:surgery*; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000379:methods / Q000502:physiology*; D008099:Liver; D008102:Liver Circulation / Q000502:physiology; D008115:Liver Regeneration; D008297:Male; D011169:Portal Vein / Q000601:surgery; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011920:Rats, Inbred WF; D014183:Transplantation, Heterologous / Q000379:methods / Q000502:physiology; D014185:Transplantation, Isogeneic
D001786:Blood Glucose; D018809:Proliferating Cell Nuclear Antigen