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  • Several studies have shown that independently of body weight


    Several studies have shown that, independently of body-weight control, the central actions of leptin improve glycemic control in obese diabetic rat and mouse models [62]. For instance, restoration of OB-Rb expression in OB-Rb-deficient mice, and in particular in POMC neurons, was sufficient to normalize blood glucose levels although had little impact on body weight 63, 64. The mechanisms by which leptin signaling in the CNS improves glucose homeostasis are not completely understood, but include sensitization to insulin signaling in the hypothalamus [65], and in liver through the vagus nerve [66], in addition to insulin-independent pathways [67]. These findings combined with previous reports showing that suppression of EPAC1 improves hypothalamic leptin sensitivity 22, 23, suggest that EPAC1 inhibitors might improve glycemic control in the context of obesity/diabetes and leptin/insulin resistance. In addition, because EPAC1−/− mice are resistant to DIO, pharmacologic inhibition of EPAC1 might lead to weight loss, which further enhances insulin sensitivity. Another regulatory pathway that needs to be considered in the evaluation of EPAC therapeutic potential is the bidirectional insulin–leptin feedback loop (adipo-insular axis). Insulin increases leptin plasma levels by promoting its expression and production, whereas leptin decreases insulin expression and secretion [68]. It is thought that this bidirectional loop establishes a set-point to regulate insulin levels in relation to adiposity because rising leptin levels with increased fat stores serve to diminish insulin plasma concentrations, and subsequently its lipogenic effects [68]. Data from animal models and humans strongly suggest that dysregulation of the adipo-insular axis is a key factor in the development of T2DM. In obesity, hyperinsulinemia often precedes the development of insulin resistance; a phenomenon thought to occur because of leptin resistance in pancreatic β cells, and thus a self-perpetuating Finally ensues in which hyperinsulinemia contributes to insulin resistance and further increases leptin levels, which in turn exacerbate leptin resistance [68]. Because leptin exerts its effects through the same pathways in the brain and pancreas, and EPAC1 is expressed in β cells of the pancreatic islets 41, 43, albeit at low levels, it is conceivable that EPAC1 inhibitors might help in restoring normalcy to the adipo-insular axis. In fact, administration of leptin to lipoatrophic diabetes patients, who normally exhibit insulin resistance and low levels of leptin, dramatically improved glycemic control [69]. By contrast, leptin had minimal efficacy in T2DM patients who exhibit both insulin and leptin resistance [70]. Together, these clinical results support the notion that sensitization to leptin signaling, which can be achieved by inhibition of EPAC1, rather than administration of leptin, is an efficacious strategy to control hyperglycemia in obese patients. Given that EPAC2 functions downstream of GLP-1 and modulates KATP channels in pancreatic islets, activators of this protein may serve as effective antidiabetic drugs. These drugs might be particularly efficacious because EPAC2 mainly facilitate the early phase of GSIS, which becomes defective in the early stages of T2DM and plays a major role the development of glucose intolerance in most patients [71]. In addition, EPAC2 activators can potentially be used in combination with sulfonylureas (SFUs), which are a widely used class of anti-T2DM drugs that bind with high affinity to the sulphonylurea receptor SUR1 subunit of the KATP channel, leading to its closure, and subsequently Ca2+ influx and insulin Finally secretion. In fact, several recent studies have shown that EPAC2 potentiates the secretagog action of SFUs because the former is activated by the latter [72]. Although it is clear that SFUs activate EPAC2, the activation is most likely indirect and the exact mechanism by which SFUs activate EPAC2 remains undetermined 72, 108.