Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes

Abstract

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α–independent peroxisome proliferator–activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.

Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, from Rhodomela confervoides

“…Thus, our study indicates that selective inhibition of PTP1B is not only beneficial for glycaemic control but also conducive to the proliferation and viability of pancreatic beta cells. A more recent study confirmed that the protective effect exerted by PTP1B on islets represents another mechanism of action of the enzyme: targeting of pancreatic islet PTP1B improved islet graft revascularization and transplant outcomes (Figueiredo et al, 2019).…”

Pleiotropic and Potentially Beneficial Effects of Reactive Oxygen Species on the Intracellular Signaling Pathways in Endothelial Cells

“…Increased insulin sensitivity was observed in mice deficient of PTP1B [56,57]. In a mouse model of pancreatic islet transplantation into eye, deletion of PTP1B, elevated revascularization of the graft islet, increased graft survival, facilitated recovery of normoglycemia, and improved glucose tolerance [58]. These effects of loss of PTP1B were mediated via an increase in the expression of VEGF-A by β cells, following activation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and the estrogen-related receptor α [58].…”

Direct reprogramming of human fibroblasts into insulin-producing cells by transcription factors

“…To assess vascularization and cell viability in ACE implants, iβ-like clusters were labeled with the long-term tracer for viable cells CFDA (Invitrogen) before transplantation. At day 10 post-transplantation, mice received an intravenous injection of RITC-dextran and in vivo imaging was used to assess functional vascularization and cell viability 34 . For determination of glucose-induced insulin secretion, mice were fasted for 5-6 h and then injected intraperitoneally with glucose (3g/Kg).…”