Pancreatic beta-cell replication in streptozotocin-diabetic rats: the effect of liver compensatory growth on intraportally engrafted islets

Abstract

Early studies showed that compensatory liver growth after anterior portal branch ligation (aPBL) may restore normoglycemia in streptozotocin (STZ)-diabetic rats, in which a subtherapeutic islet mass was previously transplanted into the liver. We hypothesized that this effect could be related to islet regeneration at the graft site. This study was designed to characterize the proliferative response of the intraportally transplanted islets, shortly after aPBL. Male Wistar-Furth rats were used as syngeneic islet donors and/or recipients. STZ-diabetic rats were divided in four groups: groups 1 and 2 underwent selective 250-islet transplantation (Tx) into the posterior liver lobes, followed by aPBL 10 days later; rats were killed 24 h (n = 9) and 48 h (n = 10) after aPBL, respectively; groups 3 and 4 underwent selective 250-islet Tx into the posterior liver lobes, followed by sham aPBL 10 days later; rats were killed 24 h (n = 3) and 48 h (n = 3) after aPBL, respectively. Two hours before killing, all animals were injected with 5'-bromo-2'-deoxyuridine (BrdU; 50 mg/kg, i.v.). Liver sections were immunostained for insulin and BrdU, and both hepatocyte and islet cell labeling index (LI) were calculated. Islet cell LI was 2.30+/-1.18% in group 1, 2.23+/-1.00% in group 2, 0.43+/-0.29% in group 3, and 0.39+/-0.21% in group 4 (group 1 vs. group 3: p<0.02; group 2 vs. group 4: p<0.01). Hepatocyte LI was 2.50+/-2.14% in group 1, 15.0+/-7.6% in group 2, 0.12 +/-0.04 in group 3, and 0.11+/-0.03% in group 4, respectively (group 1 vs. group 2: p<0.02; group 1 vs. group 3: p<0.001; group 2 vs. group 4: p<0.001). Our study showed that intraportally transplanted islets undergo a concurrent proliferative response after aPBL, although with a lower extent and a different timing when compared with the liver-cell response.