Aberrant activation of the innate immune system in metabolic disorders such as type 2 diabetes has been recognized to be an important mechanism of disease pathogenesis (1–3). Emergence of a chronic proinflammatory state driven by the activation of myeloid lineage innate immune cells, such as macrophages and neutrophils, has been directly linked to the emergence of insulin resistance (4, 5). Until recently, the identity of specific innate immune pattern recognition receptors or sensors that recognize diverse metabolic “danger signals” to initiate a proinflammatory cascade during obesity and diabetes was unknown. Pioneering studies from Tschopp and colleagues (6) identified that “inflammasomes,” the multiprotein cytosolic molecular platforms in myeloid cells, can sense damage-associated molecular patterns (DAMPs) and control the secretion of proinflammatory cytokines interleukin (IL)-1β and IL-18 in metabolic stress. Structurally, inflammasomes consist of a Nod-like receptor (NLR), the apoptosis-associated speck-like protein containing a CARD (ASC) adaptor protein, and caspase-1 (6). Several NLR molecules including NLRP1, NLRP3, and NLRC4 control caspase-1 activation, which controls the cleavage and secretion of pro–IL-1β and pro–IL-18 into bioactive cytokines (6). Several studies using genetically modified mice that lack inflammasome components Nlrp3, Asc, and caspase-1 provided initial evidence that activation of the Nlrp3 inflammasome is a key mechanism that induces metabolic inflammation and insulin resistance (7–10). Deactivation of the Nlrp3 inflammasome in obese type 2 diabetic patients that lose excess weight through lifestyle intervention is coupled with improved glucose homeostasis, suggesting that inflammasome may be a clinically relevant mechanism that links inflammation with type 2 diabetes (7). However, there is scant clinical evidence that myeloid cells of type 2 diabetic patients have elevated Nlrp3 inflammasome activation, and it is not clear whether the mechanism of inflammasome activation observed in rodent models applies to human metabolic disease. In this issue of Diabetes, Lee et al.(11) report that monocytes derived from newly identified untreated type 2 diabetic patients display elevated expression of inflammasome components Nlrp3 and Asc, along with increased caspase-1 activation. Consistent with elevated Nlrp3 inflammasome activation in myeloid cells, the drug-naïve type 2 diabetic patients (n= 47) had significantly high serum levels of IL-1β and IL-18 compared with healthy subjects (n= 57). The studies from knock-in reporter mice in which Nlrp3 coding sequence is substituted with green fluorescent protein demonstrate that the Nlrp3 inflammasome is predominantly active in myeloid cells (12). In the current article, Lee et al. demonstrate that monocytes derived from peripheral blood of type 2 diabetic patients have increased basal Nlrp3 inflammasome activation (11). In addition, compared with cells from healthy participants, the myeloid cells of type 2 diabetic patients respond with elevated caspase-1 activation and produce higher levels of IL-1β and IL-18 when exposed to metabolic danger signals such as urate, free fatty acids, and extracellular ATP (11)(Fig. 1). The increased levels of elevated free fatty acids that induce lipotoxicity (7, 8) and higher uric acid levels (13) are known to increase the risk of development of diabetes and its complications. The release of ATP from necrotic cells is also a potent trigger of inflammasome activation (14). Therefore, it is possible that these metabolic DAMPs that are produced as a result of metabolic dysfunction trigger the activation the Nlrp3 inflammasome …