Optimized angiogenesis of islet transplants resulted in greater availability of insulin caused by beta-cell proliferation and a significantly higher percentage (90% versus 20%) of mice cured from diabetes.

Summaryβ β β β -cell replacement is the only way to restore euglycaemia in patients with type-1 diabetes. Pancreatic tissue, processed for subsequent clinical islet transplantation, is exposed to ischaemia causing injury and death in a large number of islets before and after transplantation. In this review we summarize what is known on the sources of environmental stress for pancreatic islets, such as insufficient oxygen supply during pancreas procurement and in culture prior to intraportal transplantation, nutritional and oxygen deprivation during the isolation process, and the consequences of hyperglycaemia. An increasingly recognized role in the modulation of β β β β -cell function and these environmental stress factors plays the vascular network of the pancreatic islets. Islet revascularization by angiogenesis is relevant for the survival of the graft subsequent to transplantation. Potential strategies offered by therapeutic induction of revascularization to ameliorate the detrimental impact of these factors on the quality of islet transplants are discussed.

Middle T antigen (PymT) is the principal transforming component of polyomavirus, and rapidly induces hemangiomas in neonatal mice. PymT, a membrane‐associated scaffold, recruits and activates Src family tyrosine kinases, and, once tyrosine phosphorylated, binds proteins with PTB and SH2 domains such as ShcA, phosphatidylinositol 3‐kinase (PI3K) and phospholipase Cγ‐1 (PLCγ‐1). To explore the pathways required for endothelial transformation in vivo, we introduced PymT mutant forms into mice. PymT variants unable to bind PI3K and PLCγ‐1 directly induced hemangiomas similarly to wild type, but a mutant unable to bind ShcA was transformation compromised. Requirement for a ShcA PTB domain‐ binding site was suppressed by replacing this motif in PymT with YXN sequences, which bind the Grb2 SH2 domain upon phosphorylation. Surprisingly, PymT recruitment of ShcA and Grb2 correlated with PI3K activation. PymT mimics activated receptor tyrosine kinases by forming a ShcA—Grb2—Gab1 complex, thus inducing Gab1 tyrosine phosphorylation, which itself is associated with PI3K. Therefore, PymT activation of ShcA–Grb2 signaling is critical for endothelial transformation, and PymT can stimulate Grb2 signaling to both the MAP kinase and PI3K pathways.

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