Inhibition of the prostaglandin D2–GPR44/DP2 axis improves human islet survival and function

Abstract

Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D2 (PGD2) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD2 or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1β. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD2 or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1β in human islets. This was accompanied by activation of the Akt–glycogen synthase kinase 3β signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-α and growth-regulated oncogene-α/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.

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“…PGD2 /DP2 receptor signaling is thought to play a role in fibrosis. PGD2 /DP2 receptor signaling exerts direct pro-apoptotic and pro-fibrotic actions on various cells, including islet cells, cardiomyocytes, and osteoclasts [201][202][203]. Moreover, PGD2/DP2 receptormediated IL-13 release is a significant inducer of fibrosis by stimulating the IL-13Rα2 receptor expressed on macrophages to release TGF-β1 [204].…”

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“…IL-13 has been recently reported to stimulate hyaluronan accumulation in mouse lungs [74 & ]. PGD 2 /DPr2 signaling also exerts pro-apoptotic and profibrotic actions on a variety of cells including islet cells, cardiomyocytes and osteoclasts [75][76][77]. PGD 2 /DPr2 signaling promotes apoptosis of cultured pig kidney cells [78].…”

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“…GPR44 has been reported to be highly expressed in beta cells of the human pancreas or other large animals, such as non-human primates and pigs, but not in the exocrine nor other endocrine tissues of the pancreas [ 67 ]. Activation of the GPR44 signaling pathway was assumed to inhibit insulin secretion, but oral administration of a GRP44 inhibitor showed no major impact on insulin secretion in patients with type 2 diabetes [ 68 ], albeit demonstrated improvement of islet function under inflammatory and hyperglycemic stress [ 69 ]. Inhibition of GPR44 has been well studied in inflammatory processes responsible for allergy and asthma [ 70 ], leading to the development of numerous GPR44 antagonists for the treatment of asthma and other allergic diseases, some of them even reaching late clinical phase drug development [ 71 ].…”