Statin-Induced Insulin Resistance Through Inflammasome Activation: Sailing Between Scylla and Charybdis

Elevated LDL cholesterol is an independent risk factor for cardiovascular disease (CVD), and current clinical guidelines recommend aggressive reduction as the preferred course of treatment (1). Type 2 diabetes (T2D) also is a major and independent risk factor for development of CVD (2). A plethora of clinical data exists substantiating the beneficial effects of treatment with inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductases—commonly known as statins—on cardiovascular morbidity and mortality in both nondiabetic people and those with T2D (3). While statin therapy clearly reduces cardiovascular events, accumulating evidence indicates that statins also may confer increased risk for T2D (4). Recent analyses of both clinical trials and population-based cohort studies suggest that the cardiovascular benefits of statin therapy outweigh the risk of developing T2D (5,6). Nevertheless, findings that suggest increased incidence of T2D in some high-risk patients (e.g., those with elevated fasting glucose [5]) or in certain populations (e.g., postmenopausal women [7]) may call for greater caution in statin use, particularly at a time when its over-the-counter availability is being considered (8).

Given the overwhelming consensus from both meta-analyses and prospective studies that statin treatment can result in an increased risk of developing T2D, it is critical to identify the underlying causes of this unfavorable side effect. It has been suggested that statins increase T2D risk by impairing β-cell insulin secretion and promoting insulin resistance (9), but the precise molecular mechanisms are still unknown. Numerous studies have demonstrated intimate involvement of the innate immune system in both obesity and the pathogenesis of T2D (10,11). In recent years, pattern recognition receptors of the innate immune system, such as Toll-like receptors and Nod-like receptors (NLRs), have been increasingly recognized as links between immune function and metabolism (12,13). The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly characterized of the inflammasomes. It has been shown to contain (among other activators) an NLR, the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) adaptor protein and caspase-1 (14). The NLRP3 inflammasome plays a central role in secretion of interleukin-1β (IL-1β) in response to various stimuli and therefore may prove to be a potential target for treatment in T2D. Indeed, it has been shown that subjects with the metabolic syndrome have increased activation of the NLRP3 inflammasome in adipose tissue macrophages (15). The clinical relevance of the NLRP3 inflammasome also is supported by recent data showing that T2D patients have elevated levels of the inflammasome proteins NLRP3 and ASC and increased caspase-1 activation prior to receiving treatment (16).

In this issue of Diabetes, Henriksbo et al. (17) provide evidence that various statins increase IL-1β secretion from macrophages through activation of the NLRP3 inflammasome. It is known that activation of the NLRP3 inflammasome requires priming (14). In the current report, none of the tested statins were able to stimulate IL-1β secretion without the presence of a priming agent, in this case the bacterial endotoxin lipopolysaccharide (LPS). Importantly, long-term treatment of obese mice with fluvastatin was found to promote insulin resistance in adipose tissue. Fluvastatin, in the presence of LPS priming, increased caspase-1 activity and IL-1β production in adipose tissue explants from wild-type mice, a result that was absent in NLRP3^−/− fat explants. Glyburide, a known inflammasome inhibitor and antidiabetes drug, prevented statin-induced caspase-1 activity and adipose tissue insulin resistance. Given that adipose tissue is a mixture of cell types and that the NLRP3 inflammasome is thought to be expressed predominantly in nonadipose cells in fat, the requirement of IL-1β and/or caspase-1 activity for statin-induced insulin resistance was further investigated in 3T3-L1 adipocytes. These studies revealed that combined fluvastatin and LPS treatment induced caspase-1 activation and impaired insulin signaling but without any concomitant increase in IL-1β secretion. This suggests that adipocytes are unlikely to be the cellular source of IL-1β production in adipose tissue of obese mice. Although these data further implicate that caspase-1 activation is sufficient to impair insulin signaling in adipocytes, even in the absence of IL-1β, whether inhibition of inflammasome activation with glyburide could prevent statin-induced insulin resistance in this clonal adipocyte model was not investigated. Moreover, given that IL-1β was not the mediator of insulin resistance in these cells, the molecular mechanisms by which activation of the NLRP3 inflammasome by statins causes insulin resistance in fat cells remain elusive.

The new study by Henriksbo et al. (17) clearly shows that fluvastatin causes insulin resistance through activation of the NLRP3 inflammasome in murine adipose tissue explants. However, it remains to be seen whether statin therapy triggers the NLRP3 inflammasome in vivo and if it promotes insulin resistance in human adipose tissue. Future studies also should test whether statins induce inflammasome activation and insulin resistance in other metabolic tissues such as liver and skeletal muscle, as well as in pancreatic islets where NLRP3 inflammasome activation has been linked to enhanced IL-1β and T2D pathogenesis (18,19). Future work also should identify the priming “danger signals” that activate adipose NLRP3 inflammasome in obesity. Given the growing evidence that dysregulation of the gut microbiota leads to metabolic endotoxemia in obesity (20), it is tempting to conclude that LPS is the key priming agent (Fig. 1). However, it was found that LPS was not required for fluvastatin-mediated impairment of insulin signaling in fat explants (17), suggesting that other adipose-specific endogenous signals also may play a key role in priming the NLRP3 inflammasome in obesity. Indeed, several molecular triggers that are known to be elevated in the proinflammatory adipose tissue of obese subjects, such as saturated fatty acids, ceramides, and the products of hypoxic and necrotic fat cells, may all activate the NLRP3 inflammasome (13,14).

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Figure 1

Working model for statin-induced NLRP3 inflammasome activation and insulin resistance. The beneficial outcomes of statin therapy for the prevention of CVD are indisputable, but statins have been shown to increase the risk for T2D. Lowering of plasma LDL cholesterol (Chol) levels through aggressive lipid-lowering therapy leads to a decrease in morbidity and mortality from CVD. The study of Henriksbo et al. (17) shows that statins, in the presence of the endotoxin LPS, activate the NLRP3 inflammasome in macrophages as well as in adipose tissue explants, which causes insulin resistance in fat. Based on this study, it is proposed that in the obese dyslipidemic patient, a gut dysbiosis–linked rise in circulating LPS may provide the priming event, potentially along with other endogenous adipose priming danger signals, leading to statin-induced NLRP3 inflammasome activation and the subsequent secretion of IL-1β. Whether this proinflammatory cytokine is the mediator of insulin resistance remains elusive. This proinflammatory effect of statins may offset some of the positive effects of lipid-lowering therapy. In the nonobese dyslipidemic patient, statin therapy also may potentially increase insulin resistance and T2D through modest inflammasome activation in fat or other insulin target tissues (not illustrated), but it remains to be shown whether LPS, or other priming danger signals such as oxidized cholesterol or cholesterol crystals, are implicated.

It also should be mentioned that activation of the NLRP3 inflammasome may be tissue-specific and greatly influenced by the type of statin used. It was recently reported that atorvastatin, but not rosuvastatin, downregulates the NLRP3 inflammasome in Japanese patients with coronary artery disease (21). Although this conclusion was based on determination of NLRP3, IL-1β, and IL-18 levels and not confirmed by caspase-1 activity measurements, these data suggest that not all statins may increase the NLRP3 inflammasome, at least in certain populations. In fact, these coronary artery disease patients were not obese, and this may be a key factor to consider for statin-induced activation of the inflammasome. More studies are warranted to determine the effect of statin therapy on NLRP3 inflammasome activation in diverse cohorts, especially in obese insulin-resistant subjects who are at greatly increased risk for T2D.

In conclusion, the work of Henriksbo et al. (17) strengthens the argument that we need to better understand the relationship between statin treatment and insulin resistance and its potential contribution to the increased T2D risk in patients under lipid-lowering therapy with this class of drugs. While activation of the NLRP3 inflammasome appears to be a key mechanism underlying this undesirable statin side effect, it is now critical to identify the molecular drivers of this inflammatory pathway in adipose tissue and other key metabolic and vascular tissues. Further elucidation of the mechanism of action could influence the next generation of statins by avoiding these adverse effects on the NLRP3 inflammasome while preserving their lipid-lowering action. This also may help design novel combination therapies in which statins are used together with drugs (e.g., glyburide) or nutritional treatments that aim to limit inflammasome activation. In this regard, it is interesting to note that a recent study revealed that omega-3 fatty acids are potent suppressors of the NLRP3 inflammasome in obese insulin-resistant mice fed a high-fat diet (22). Any strategies that would limit the side effects of statins on this inflammatory mechanism are of paramount clinical significance given the number of people prescribed this therapy and the typical duration of treatment.

• © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.