Sex-Specific Differences in the Revascularization of Grafted Pancreatic Islets

Islet transplantation can improve glycemic control in a subset of patients with type 1 diabetes mellitus (T1DM). This therapeutic approach is often limited by scarcity of adequate donor islets and an insufficient revascularization capacity of grafted islets. Recent findings reveal that sex is an important determinant for the outcome of islet transplantation. However, it is still unknown how the biological sex of islet donors and recipients affects the revascularization of the grafts during the initial ischemic post-transplantation phase. In this study, we observed in a mouse dorsal skinfold chamber model a higher revascularization capacity of female islets transplanted in female or male recipient mice when compared to male islets transplanted in female or male recipients. To mimic the ischemic in vivo conditions ex vivo, we subjected isolated female and male islets to oxygen-glucose deprivation. Under these conditions female islets expressed and secreted significantly more glucagon (GCG). By a panel of functional angiogenesis assays, we could further demonstrate that GCG exhibits a strong pro-angiogenic function. This effect was pronounced in blood vessels as well as endothelial cells and pericytes of female origin due to a higher expression of GCG receptor. Taken together, these results not only confirm the clinical observation that transplantation of female islets improves the outcome of islet transplantation but also indicate that this is mediated by an accelerated GCG-driven islet engraftment.