TI - Discussion . AB - We have combined human physiology , genome -wide expression profiling , genetic association testing and cellular studies to spotlight TXNIP as a physiologic regulator of peripheral glucose uptake in humans . Our results build on murine studies that have established a role for this protein in the liver in the regulation of fasting : feeding transitions [44,45] and in beta cell toxicity [35] . While genetic variation in TXNIP does not predispose one's inherited risk for developing T2DM , TXNIP nonetheless appears to play a physiologic role in glucose homeostasis in muscle and in fat . Key novel results from the current study include the finding that TXNIP gene expression is reciprocally regulated by insulin and by glucose , that elevations in TXNIP can inhibit glucose uptake , and that TXNIP expression levels are consistently elevated in humans with T2DM and prediabetes . Our study shows that TXNIP is part of a negative feedback mechanism that regulates glucose uptake into cells (Figure 7A) . Such a mechanism may serve to prevent excess glucose uptake or metabolism [46] . At present , it is not clear whether TXNIP influences the metabolic fate of glucose--future studies will be required to address this important issue . Because TXNIP expression is suppressed by insulin signaling , it appears that TXNIP influences both insulin -dependent and insulin -independent arms of glucose uptake into cells . Of note , epidemiological studies have suggested roles for both insulin -dependent and insulin -independent pathways in the development of T2DM [4] . Recent genomic studies have pointed to mitochondrial dysfunction and to ROS as possible culprits in the etiology of insulin resistance [18,27,47,48] . At present , we do not know how mitochondrial dysfunction and ROS are related to each other in the pathogenesis of insulin resistance . The current study , in combination with other recent studies , suggests that TXNIP may lie upstream of both of these processes . First , TXNIP expression is induced by glucocorticoids [49] and by glucose and TXNIP elevations can stimulate ROS production [38] . Hence TXNIP represents a candidate intermediate linking diabetogenic stimuli to ROS production . Second , we have observed an inverse correlation in the expression of TXNIP and mitochondrial oxidative PHOSphorylation ( unpublished data ) , and previous studies have shown that TXNIP can serve as a transcriptional repressor [50] . Taken together , these data raise the hypothesis that TXNIP may lie upstream of the elevations in ROS and mitochondrial dysfunction that accompany insulin resistance . Importantly , our findings , in combination with recent studies focused on the pancreatic beta cell [40] , provide molecular insights into the pathogenesis of impaired insulin secretion and action (Figure 7B) that characterize the prediabetic state [1,51] . Hyperglycemia has long been known to exacerbate beta cell failure [52,53] and impaired skeletal muscle glucose uptake [54] via a process often termed glucose toxicity . At present the molecular basis for glucose toxicity is not known , although ROS represent a candidate mediator [46,47] . A recent study [40] reported that TXNIP is glucose inducible in pancreatic beta cells and may mediate beta cell death through apoptosis . Our present study has led to the novel finding that TXNIP also plays a role in controlling peripheral glucose uptake in humans and may be an important target mediating effects of insulin . Together , these studies suggest that TXNIP may be involved in glucose toxicity both in beta cells and in the periphery , helping to reconcile the dynamic relationship between insulin deficiency and impaired glucose uptake that is observed in the prediabetic state ( Figure 7B ) . Interventions aimed at modulating TXNIP activity may therefore help curtail this vicious cycle that eventually leads to overt T2DM .