Anti-Inflammatory Properties of Exenatide in Human Pancreatic Islets

作者：Cechin S R; Perez Alvarez I; Fenjves E; Molano R D; Pileggi A; Berggren P O; Ricordi C; Pastori R L^*

来源：Cell Transplantation, 2012, 21(4): 633-648.

DOI：10.3727/096368911X576027

• Human pancreatic islets
• Glucagon-like peptide-1
• Exenatide
• Inflammation
• Cytokines
• Proteinase inhibitor 9 (PI-9)
• Nude mice
• Islet transplantation

Exenatide is an analog of the incretin hormone glucagon-like peptide (GLP-1) that is used for the treatment of T2D for their metabolic effects. In addition to its insulinotropic effects, exenatide increases functional islet mass and improves their survival. Improved outcomes have been reported in recent clinical islet transplantation trials for the treatment of type 1 diabetes. The purpose of this study was to investigate whether exenatide has anti-inflammatory properties in human islets. Exenatide treatment improved islet function, significantly reduced content of inflammation-related molecules (tissue factor, IFN-gamma, IL-17, IL-1 beta, and IL-2) and caspase 3 activation, whereas increased phosphorylation of ERK1/2, STAT3, and Akt in vitro. Immunostaining showed expression of GLP-1R in beta-cells but not in alpha-cells. IL-1 beta colocalized with GLP-1R in beta-cells. Induction of serine proteinase inhibitor 9 (PI-9) was detected after exposure of human islets to exenatide in vitro and after transplantation into immunodeficient mice. GLP-1 induced PI-9 expression in vitro but to a lower extent than exenatide. This effect was partially blocked by the antagonist exendin-9 in vitro. As assessed by immunostaining PI-9 is mostly expressed in beta-cells but not in a-cells. In conclusion, we describe anti-inflammatory and cytoprotective properties of exenatide in human islets. Exenatide-mediated PI-9 expression, the only known granzyme B inhibitor, unveils potential immunoregulatory properties.

• 出版日期2012