Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

Abstract

OBJECTIVE— The pro-inflammatory cytokine interleukin-1β (IL-1β) generates pancreatic β-cells apoptosis mainly through activation of the c-Jun NH2-terminal kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone glucagon-like peptide 1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against cytokine-induced β-cell apoptosis, could interfere with the JNK pathway. RESEARCH DESIGN AND METHODS— Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1β. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. RESULTS— Ex-4 inhibited induction of the JNK pathway elicited by IL-1β. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin was concomitant with a rise in the levels of islet-brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1β. CONCLUSIONS— The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1β and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

“…Signalling mechanisms involved in exendin-4 inhibition of palmitate-mediated apoptosis IB1, a scaffold protein that tethers components of the JNK pathway acting as an endogenous blocker, has been suggested to mediate the protective actions of exendin-4 against apoptosis elicited by the cytokine, IL-1β [19]. Therefore, IB1 was next studied in the context of exendin-4 inhibition of NEFA-induced apoptosis.…”

“…GLP-1 receptor agonists can inhibit the proapoptotic pathways triggered by a variety of stimuli, including IL-1β, TNF-α and rapamycin, by interfering with JNK and possibly p38 MAPK activation [15,19,46]. The cAMP/PKA/CREB cascade represents a central mechanism of GLP-1 action, specifically when this relates to promotion of beta cell survival [47], even though other signalling mediators may also be implicated [48,49].…”

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

“…GLP-1RAs have protective effects on cytokine-induced apoptosis in beta cells by interfering with the JNK pathway. Exendin-4 also protects beta cells from interleukin-1 beta-induced apoptosis by interfering with the JNK pathway [77] . Zhang et al [78] treated mice on a high-fat diet with 1 mg/kg liraglutide twice a day, and after 8 wk, the results showed that JNK phosphorylation was significantly reduced.…”

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

“…However, the effects of immunomodulatory treatments are not limited to tissues involved in disease pathophysiology and thus might have unwarranted side effects. Moreover, current antidiabetes drugs may alleviate systemic and tissue-specific inflammation (4)(5)(6)(7)(8)(9)(10)(11)(12), and therefore the added value of using specific immunomodulatory treatments needs to be confirmed. Herein, we review the anti-inflammatory and metabolic effects of standard antidiabetes medications and of novel anti-inflammatory treatments.…”