Endothelial cell signalling supports pancreatic beta cell function in the rat

Abstract

Aims/hypothesis The proximity of endothelial cells and beta cells in islets by necessity means that they are exposed to each other's products. Whereas islet endothelial cells require signals from beta cells to function properly, endothelin-1, thrombospondin-1 and laminins, among others, have been identified as endothelial-derived molecules, although their full effects on beta cells have not been explored. We tested the hypothesis that islet endothelialderived products affect beta cell function. Methods Endothelial cells from rat islets were proliferated and purified. Endothelium-conditioned culture medium (ECCM) was obtained by maintaining the endothelial cells in culture medium. Islet function was evaluated following exposure of cultured islets to standard culture medium or ECCM. Changes in mRNA levels for key beta cell metabolic enzymes were also measured in islets after ECCM exposure.Results Glucose-stimulated insulin release and islet insulin content were markedly enhanced by exposure to ECCM. This was at least partly explained by improved mitochondrial function, as assessed by glucose oxidation and an upregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]), combined with upregulation of the rate-limiting enzyme in the glycolysis, glucokinase, in the islets. The intracellular degradation of insulin was also decreased in the islets. Islet endothelial cells produced laminins, and the positive effects of islet endothelial cells were prevented by addition of a neutralising antibody to the β1-chain of laminin. Addition of exogenous laminin stimulated islet function. Conclusions/interpretation This study provides proof of principle that endothelial cells can affect the function of beta cells in their vicinity and that this is at least partially mediated by laminins.

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

“…This is in accordance with previous studies demonstrating that the revascularisation of smaller islets after transplantation is more efficient than that of larger islets [37], an effect that is likely to be amplified by the large aggregates formed in our islet-alone grafts. The re-establishment of a blood supply is of obvious importance for the survival and function of the islets, but it is also clear that paracrine interactions between beta cells and endothelial cells are important in maintaining beta cell function [38]. The improved recovery of these interactions in the islet+MSC grafts may account for some beneficial effects of the MSC co-transplant in our model.…”

Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets

“…The normally low oxygenation of transplanted islets may affect islet survival and function, because it means that their metabolism tends to be much more anaerobic than that of endogenous islets and results in lactate formation and tissue acidosis (48). Several recent reports also indicate that endothelial cell signaling may be important for ␤-cell function and growth (19,49,50).…”

“…The perfusions were concluded by a 15-min perfusion with medium containing 2.8 mmol/l glucose. A 1.0-ml sample was collected at 14,15,16,17,18,19,20,22,25,30,35,40,45,50,55, and 60 min. The insulin concentrations of the effluent samples were measured by ELISA (Mercodia).…”

Betacellulin Overexpression in Mesenchymal Stem Cells Induces Insulin Secretion In Vitro and Ameliorates Streptozotocin-Induced Hyperglycemia in Rats

“…In this way, b-cells are exposed to other cell-derived molecules that can affect the physiological regulation of glucose-induced insulin secretion. It was demonstrated that endothelial-derived molecules, like endothelin-1, thrombospondin-1, and laminins, among others, can improve b-cell function [45][46][47]. These data show the importance of soluble factors secreted by islet vicinity, suggesting that the addition of soluble factors can also interfere in cell differentiation.…”

“…The pancreatic islets in the adult are among the most vascularized of all organs in the body, with a unique dense glomerular-like angioarchitecture [45]. In this way, b-cells are exposed to other cell-derived molecules that can affect the physiological regulation of glucose-induced insulin secretion.…”