Insulin-Like Growth Factor II Allows Prolonged Blood Glucose Normalization with a Reduced Islet Cell Mass Transplantation

Abstract

IGF-II has been reported to decrease neonatal islet cell apoptosis and in vitro adult islet cell necrosis and apoptosis, but the usefulness of IGF-II in a transplantation setting is unknown. We evaluated the effect of in vitro IGF-II incubations on microencapsulated rat islet survival both in vitro and in minimal mass transplantations into diabetic mice. After 6 d in culture, fresh examinations, histology, fluorescence microscopy, sodium 3'-[1-(phenyl-amino-carbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro)-benzene sulfonic acid hydrate assay, and apoptosis studies all indicated that IGF-II significantly improves islet cell viability in a dose-dependent fashion. IGF-II 100 ng/ml and 500 ng/ml induced a 51% and 83% increase of viable islets (P = 0.052, P < 0.01). A 20%, 29%, and 33% reduction of the apoptotic index was observed with 50, 100, and 500 ng/ml incubations respectively (P < 0.05; P < 0.005; P < 0.001). Ten weeks after transplantation of 150 encapsulated rat islet equivalents incubated with IGF-II 500 ng/ml, 80% of diabetic mice were normoglycemic. Without IGF-II preincubation, only 8% of the recipients remained normoglycemic with the transplantation of 150 islets and 42% with 300 islets (P < 0.05). In conclusion, IGF-II promotes islet cell survival, and allows successful transplantation using a smaller number of islets.

Co-encapsulation of bioengineered IGF-II-producing cells and pancreatic islets: effect on beta-cell survival

“…This number of islets was based on our previous experiments. 6 When non-encapsulated islets were used, only two out of five recipients became normoglycemic, and they maintained this normoglycemia only for a period of 12 and 31 days, respectively. When islets encapsulated alone were transplanted, normoglycemia was induced in 71% (5/7) of the recipients ( Figure 6).…”

“…5 We have investigated the use of IGF-II in a transplantation setting. 6 In vitro studies showed that IGF-II prevents the apoptosis and necrosis of microencapsulated mouse islet cells in a dose-dependent manner. In a marginal islet mass transplantation model, pre-transplantation IGF-II incubations allowed prolonged blood glucose normalization in a higher proportion (B200%) of diabetic mice, using a reduced (50%) amount of islets.…”

“…In a marginal islet mass transplantation model, pre-transplantation IGF-II incubations allowed prolonged blood glucose normalization in a higher proportion (B200%) of diabetic mice, using a reduced (50%) amount of islets. 6 Hill et al 7 have previously found that the massive b-cell apoptosis that occurs in the neonatal period is prevented in transgenic mice overexpressing the IGF-II gene. The beneficial effect of pancreatic duct cells, which produce IGF-II, on islet cell survival has also been supported by the finding of a significant correlation between a higher percentage of duct cell contamination in islet preparations and a positive outcome of clinical transplantations.…”

“…In our previous study, 6 islets were exposed to IGF-II for only 48 h in vitro, before being transplanted. Nonetheless, this procedure had a considerable impact on in vivo islet cell survival.…”

IGF2: an endocrine hormone to improve islet transplant survival

“…IGF2 has been shown to promote pancreatic b-cell survival against apoptotic stimuli in vitro and in vivo (Rabinovitch et al 1982, Swenne et al 1987, Hogg et al 1993, Ilieva et al 1999, Robitaille et al 2003, Jourdan et al 2011 and induce proliferation in a growth-arrested mouse b-cell line (Milo-Landesman & Efrat 2002). IGF2 protects pre-diabetic NOD mouse islets from the cytotoxic actions of IL1b by the mechanisms that include a reduction in apoptosis (Hill et al 1999b).…”