Hyperglycemia Induces Apoptosis of Human Pancreatic Islet Endothelial Cells

Abstract

Pancreatic islet microendothelium and ␤ cells exhibit an interdependent physical and functional relationship. In this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1␤, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to highglucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. Intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 mol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1␤ and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to ␤ cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet function.

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

“…This may indicate an early activation of intraislet angiogenesis by AT that subsequently supported an increase in ␤-cell mass, particularly in smaller islets, and this was further supported by an increased percentage of proliferating EC after AT. An alternative explanation is that AT protected EC from developmental or STZ-associated apoptosis and would be supported by the reported ability of pravastatin to promote human pancreatic EC survival following a hyperglycemic challenge in vitro through an activation of the Akt survival pathway (12). Similarly, statin treatment has been shown to increase the survival and function of islet transplants (2).…”

Endoglin (CD105) is not a specific selection marker for endothelial cells in human islets of Langerhans

“…Macro-and microvascular endothelial cells (ECs) are certainly CD105-positive, but this accessory receptor is also highly expressed by a range of other cell types including bone marrow-and tissue-derived mesenchymal stromal cell (MSC)-like populations. In accordance with this, we have recently isolated from human islets, and expanded in vitro, a population of CD105-expressing cells that are clearly not MECs, but which share phenotypic characteristics with other cells that have been immuno-isolated on the basis of CD105 expression and identified as islet MECs for in vitro studies [1][2][3][4][5].…”

“…In this study, as in several previous studies [2][3][4][5], the MECs were expanded in vitro from a population that had been isolated from dispersed human islet cells using anti-CD105 immunobeads. CD105 (also known as endoglin) is a membrane glycoprotein that acts with transforming growth factor (TGF)-β receptors as an auxiliary binding protein for members of the TGF-β family, including activin, TGF-β1/β3 and bone morphogenic proteins.…”

Islet Endothelium: Role in Type 1 Diabetes and in Coxsackievirus Infections

“…Therefore, high glucoseinduced overexpression of CD40L on islet endothelial cells might accelerate the targeting and loss of the remaining -cell capacity during ongoing autoimmune insulitis. In fact, production of the vasoactive mediator NO by islet endothelium (Meier, 2008;Favaro et al, 2008) is increased in hyperglycaemic conditions and has an established direct cytotoxicity on islets and potentially impairs insulin release (Corbett JA et al, 1993). Islet microendothelial cells also are source of the proinflammatory cytokine IL-1 under hyperglycaemic conditions, independently of any viral or immune-mediated process.…”

“…In fact, production of the vasoactive mediator NO (Meier, 2008;Favaro et al, 2008) to upregulate CD40L expression in human islet microendetelial cells in vitro (Favaro et al, 2010). Functional CD40L is expressed on vascular endothelium (Mach et al, 1997) and contributes to B cell activation, isotype switching, costimulation in T cell mediated immunity, activation of extravasating monocytes (Yang & Wilson, 1996;Wagner et al, 2004), with an impact in atherosclerosis and in chronic inflammatory and autoimmune diseases.…”