Opposing effects of IL-1β/COX-2/PGE2 pathway loop on islets in type 2 diabetes mellitus

Abstract

The cyclooxygenase2 (COX-2) enzyme catalyzes the first step of prostanoid biosynthesis, and is known for its crucial role in the pathogenesis of several inflammatory diseases including type 2 diabetes mellitus (T2DM). Although a variety of studies revealed that COX-2 played a role in the IL-1β induced β cell dysfunction, the molecular mechanism remains unclear. Here, using a cDNA microarray and in silico analysis, we demonstrated that inflammatory responses were upregulated in human T2DM islets compared with non-diabetic (ND) islets. COX-2 expression was significantly enhanced in human T2DM islets, correlated with the high inflammation level. PGE2, the catalytic product of COX-2, downregulated the functional gene expression of PDX1, NKX6.1, and MAFA and blunted the glucose induced insulin secretion of human islets. Conversely, inhibition of COX-2 activity by a pharmaceutical inhibitor prevented the β-cell dysfunction induced by IL-1β. COX-2 inhibitor also abrogated the IL-1β autostimulation in β cells, which further resulted in reduced COX-2 expression in β cells. Together, our results revealed that COX-2/PGE2 signaling was involved in the regulation of IL-1β autostimulation, thus forming an IL-1β/COX-2/PGE2 pathway loop, which may result in the high inflammation level in human T2DM islets and the inflammatory impairment of β cells. Breaking this IL-1β/COX-2/PGE2 pathway loop provides a potential therapeutic strategy to improve β cell function in the treatment of T2DM patients.

Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

“…In our study, we demonstrated that elevated expression of IL-1b and TNF-a can activate MSCs to secrete IL-1Ra, a requirement for MSCs to restore the function of hT2DM islets. Moreover, IL-1Ra has been shown to inhibit the IL-1 signaling transduction pathway, subsequently preventing damage caused by intermediates such as COX-2 [19] and NF-kB [46,47]. IL-1Ra was also found to reduce the endogenous production of IL-1b in hT2DM islets, possibly due to a feedback loop blockade in IL-1b signallng [48].…”

“…Diacerein, which decreases both IL-1b and TNF-a demonstrated improved insulin secretion of T2DM patients [17,18]. Moreover, the COX-2 inhibitor Celecoxib was shown to improve insulin secretion of human islets [19]. Together, these studies suggest that targeting the inflammatory response is critical in mitigating b cell dysfunction.…”

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

“…COX 1 and 2), which catalyze the intermediate conversion of PGH2 to PGE2. Elevated islet expression of specific PGE2 synthetic enzymes and/or islet PGE2 excretion has been observed in islets from T2D animals and humans (2,5,6,8,9,20,37). Yet, in this study, PGE2 production was not enhanced in HGOB islets above the levels observed in either lean or NGOB.…”

“…Based on the traditional role of Gi/o proteins to block adenylate cyclase activity and reduce cAMP production, EP3γ activity may reduce NGOB β-cell cAMP levels from an even higher theoretical baseline. Numerous signaling changes have been demonstrated in β-cell compensation and failure, such as those mediated by β-cell stress pathways (6,9,38,39), many of which converge on cAMP (14,31,(40)(41)(42). In this scenario, EP3γ up-regulation may be a compensatory adaptation to dampen β-cell stress and promote β-cell survival.…”

“…Previous work by our group and others identified enhanced signaling through the prostaglandin EP3 receptor (EP3), a cAMP-inhibitory G protein-coupled receptor (GPCR) encoded by the PTGER3 gene, in islets isolated from T2D mice and humans as compared to non-diabetic controls (2)(3)(4)(5)(6). The most abundant natural ligand of EP3 is prostaglandin E2 (PGE2), an eicosanoid derived from arachidonic acid whose islet production is similarly increased in the pathophysiological context of T2D (2,(6)(7)(8)(9)(10). EP3 agonists reduce, while EP3 antagonists potentiate glucose-stimulated insulin secretion (GSIS) of islets from T2D mice and humans, while having little to no effect on islets from wild-type or non-diabetic subjects (2,8,10).…”