The deleterious effect of chronic activation of the IL-1 system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1 in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1, in a glucose-dependent manner. Subsequently, IL-1 contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1 signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1 and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1 mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1 and insulin in the regulation of both metabolism and immunity. 30reactive oxygen species production, and NLRP3 inflammasome-mediated IL-1β secretion. 31Post-prandial inflammation is limited by normalization of glycemia and can be prevented by 32 inhibition of sodium-glucose cotransporter 2 (SGLT2). Our findings identify a physiological 33 role for IL-1β and insulin in the regulation of both metabolism and immunity.
Chronic inflammation impairs insulin secretion and sensitivity. β-cell dedifferentiation has recently been proposed as a mechanism underlying β-cell failure in T2D. Yet the effect of inflammation on β-cell identity in T2D has not been studied. Therefore, we investigated whether pro-inflammatory cytokines induce β-cell dedifferentiation and whether anti-inflammatory treatments improve insulin secretion via β-cell redifferentiation. We observed that IL-1β, IL-6 and TNFα promote β-cell dedifferentiation in cultured human and mouse islets, with IL-1β being the most potent one of them. In particular, β-cell identity maintaining transcription factor Foxo1 was downregulated upon IL-1β exposure. In vivo, anti-IL-1β, anti-TNFα or NF-kB inhibiting sodium salicylate treatment improved insulin secretion of isolated islets. However, only TNFα antagonism partially prevented the loss of β-cell identity gene expression. Finally, the combination of IL-1β and TNFα antagonism improved insulin secretion of ex vivo isolated islets in a synergistic manner. Thus, while inflammation triggered β-cell dedifferentiation and dysfunction in vitro, this mechanism seems to be only partly responsible for the observed in vivo improvements in insulin secretion.
Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.