Abstract
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.
Highlights
Decreased functional β-cell mass in the face of insulin resistance is a hallmark of type 2 diabetes (T2D)[1]
Previous studies have shown the presence of macrophages in islets of patients with T2D17, 18
We observed that mainly IL-1β, and IL-6 and TNFα decreased the expression of differentiation markers in cultured islets
Summary
Immune cell infiltration in pancreatic islets of patients with type 2 diabetes. Previous studies have shown the presence of macrophages in islets of patients with T2D17, 18. There were no differences in plasma insulin levels in anti-IL-1β antibody treated groups compared to controls (data not shown), ex vivo isolated islets from mice with IL-1β antagonism had an improved insulin secretion capacity in response to glucose and comparable insulin content (Fig. 3f,g). (m,n) GSIS, corresponding fold insulin secretion and insulin content of isolated islets from DIO/STZ mice ± sodium salicylate treatment. TNF inhibitor etanercept improved glycaemia in an ipGTT in DIO/STZ mice (Fig. 3o), while insulin levels remained comparable in treatment and control groups (data not shown). Islets isolated from DIO/STZ mice showed lower expression of Ins[2], Slc2a2, Nkx[] and Foxo[1] compared to HFD alone, while expression of inflammatory factors Cxcl[1], Ptprc, IL1β and TNFα were higher (Fig. 4a). The combination of IL-1β- and TNFα-antagonism significantly reduced the inflammatory gene response, while the expression of β-cell identity genes were similar to TNFα-antagonism alone (Fig. 4e)
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