Pronounced changes in lifestyle and environment have made type 2 diabetes (T2D) a worldwide epidemic rapidly over the twenty-first century, and the accompanying complications constitute a main threat to global health [1]. Insulin resistance, a hallmark of T2D, is believed to be a fundamental pathologic event and underlying feature of T2D [2]. Although conventional insulin sensitizers, including metformin and rosiglitazone, have been proven to improve insulin sensitivity in target tissues, no pharmacologic agents exist which can be proven to treat diabetes completely. Hence, more efficacious strategies that can act via a new mechanism to promote insulin sensitivity are needed. Recently, insulin resistance is increasingly considered to be associated with low-grade systemic chronic inflammation, which has a central role in the pathogenesis of T2D [3, 4]. Since Hotamisligil et al. [5] first found that tumor necrosis factor (TNF)-α can be induced in a T2D rodent model, more attention has been focused on the connection between inflammation and insulin resistance. Another study in individuals revealed that, during obesity, elevated levels of C-reactive protein and interleukin (IL)-1β in the blood were predictive indicators of the development of T2D [6]. Therefore, chronic inflammation has been recognized as a critical inducer in the development of insulin resistance and T2D.

Consistent with these data, recent studies have shown that the nod-like receptor protein 3 (NLRP3) inflammasome plays a pivotal regulatory role in the mechanism that induces systemic inflammation and insulin resistance in obesity and T2D [7, 8]. The NLRP3 inflammasome can be triggered by both pathogen-associated molecular patterns and various danger-associated molecular patterns, including lipopolysaccharide (LPS) and saturated fatty acids, and further binds to its receptor on the cell surface, activating a proinflammatory pathway and inducing cytokine expression in various cell types [9, 10]. Structurally, a functional NLRP3 inflammasome is composed of NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1. NLRP3 interacts with ASC to activate caspase-1 and further regulates the maturation and secretion of proinflammatory cytokines IL-1β and IL-18, which are involved in the inflammation response [11, 12]. Indeed, multiple studies have demonstrated that inflammasome activation and the cleavage of inflammatory cytokines IL-1β and IL-18 induced by obesity in key metabolic tissues promote chronic inflammation and contribute to the development of T2D [7, 1315]. Other researchers reported that the elevated cytokines such as caspase-1, IL-1β, IL-6, and TNF-α produced by activation of the inflammatory signaling pathways can contribute to glucose uptake failure and insulin sensitivity by disrupting insulin signaling [1618]. Moreover, deficiency of protein in the NLRP3 inflammasome complex protects mice from high fat diet (HFD)-induced inflammation, alleviates insulin resistance, and promotes insulin signaling in insulin target tissues [8, 19, 20]. Notably, searching for an effective method to attenuate NLRP3 inflammasome-mediated inflammation will be a novel advance in treatment for insulin resistance and T2D.

Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewing capacities and low immunogenicity, which make them attractive for treating many diseases [21]. Interestingly, a recent paradigm shift suggests that MSCs have exhibited potential immunomodulation and anti-inflammatory properties through their paracrine effects [22]. In a renal medullary inflammation rat model, MSC transplantation could attenuate activation of the NLRP3 inflammasome and promote renal medullary function [23]. Moreover, MSCs have also been shown to downmodulate the inflammatory factors (IL-1β, TNF-α, and IL-6) through secreting prostaglandin E2 for therapies in osteoarticular diseases [24]. Additionally, promising results in a clinical trial have shown that MSCs reduce systemic inflammation in patients with T2D, and our previous study has confirmed that MSC administration alleviates insulin resistance in target tissues of HFD-treated T2D rats [25, 26]. Given the beneficial anti-inflammatory property of MSCs, it is imperative to test the possibility that MSCs could suppress NLRP3 inflammation activity to improve insulin resistance in a paracrine fashion.

In this study, we confirmed in vitro that the NLRP3 inflammasome was activated in an LPS and palmitic acid (PA)-induced inflammation model of insulin resistance in HepG2 cells. Human umbilical cord-derived MSCs (UC-MSCs) and their conditioned media (CM) could enhance insulin sensitivity through inhibiting the upregulation of NLRP3 inflammasome components with the elevated cleavage of IL-1β, IL-18, and TNF-α in insulin-resistant HepG2 cells. We also demonstrated that UC-MSCs repaired the glucose intolerance by suppressing inflammatory mediator release in insulin target tissues of the T2D animal model. Collectively, our studies provide evidence that MSC-mediated paracrine properties exert a protective effect on ameliorating insulin resistance through their immunomodulatory potency. This research further provides a rationale for the possible application of MSCs in the clinical treatment of insulin resistance and T2D.