Antidiabetic drug glyburide modulates depressive-like behavior comorbid with insulin resistance

Abstract

BackgroundAbundant reports indicated that depression was often comorbid with type 2 diabetes and even metabolic syndrome. Considering they might share common biological origins, it was tentatively attributed to the chronic cytokine-mediated inflammatory response which was induced by dysregulation of HPA axis and overactivation of innate immunity. However, the exact mechanisms remain obscure. Herein, we mainly focused on the function of the NLRP3 inflammasome to investigate this issue.MethodsMale C57BL/6 mice were subjected to 12 weeks of chronic unpredictable mild stress (CUMS), some of which were injected with glyburide or fluoxetine. After CUMS procedure, behavioral and metabolic tests were carried out. In order to evaluate the systemic inflammation associated with inflammasome activation, IL-1β and inflammasome components in hippocampi and pancreases, as well as corticosterone and IL-1β in serum were detected separately. Moreover, immunostaining was performed to assess morphologic characteristics of pancreases.ResultsIn the present study, we found that 12 weeks’ chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Furthermore, antidiabetic drug glyburide, an inhibitor of the NLRP3 inflammasome, was discovered to be effective in preventing the experimental comorbidity. In brief, it improved behavioral performance, ameliorated insulin intolerance as well as insulin signaling in the hippocampus possibly through inhibiting NLRP3 inflammasome activation by suppressing the expression of TXNIP.ConclusionsAll these evidence supported our hypothesis that chronic stress led to comorbidity of depressive-like behavior and insulin resistance via long-term mild inflammation. More importantly, based on the beneficial effects of blocking the activation of the NLRP3 inflammasome, we provided a potential therapeutic target for clinical comorbidity and a new strategy for management of both diabetes and depression.

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

“…the improvement of metabolic parameters induced by prolonged administration of Met in mice fed an HFD were accompanied by a reduction of both anxiety and despair, whereas fluoxetine, the conventional antidepressant drug used herein as a positive control, failed to exert beneficial effects in the EPM. These results concur with previous preclinical studies pointing out that different classes of antidiabetic agents or adiponectin, a hormone exerting insulin-sensitizing action, produces antidepressant-like activities (Ho et al, 2012;Liu et al, 2012;Gupta et al, 2014;Su et al, 2017). In humans, a recent study also reported that Met favors depression recovery in patients with comorbid diabetes unveiling a strong correlation between improvement in plasma glycated hemoglobin levels and depression score (Guo and Lu, 2014).…”

“…In marked contrast, insulin-sensitizing strategies exert neuroprotective/neurotrophic effects in rodents (Zhong et al, 2018). This has been reported with the antidiabetic agents liraglutide, glyburide, and metformin Su et al, 2017;Weina et al, 2018). Given the beneficial role of the serotonin (5-HT) system in the enhancement of brain plasticity (Quesseveur et al, 2013), the possibility that deficits in 5-HT neurotransmission underlie the comorbidity between T2D/IR and depression, has been raised.…”

P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes

“…Studies have shown that by inhibiting the activation of NLRP3 inflammasome, some hypoglycemic drugs exhibit antidepressant effects, whereas antidepressants exhibit the effect of regulating glucose metabolism. Glibenclamide is not only a sulfonylureas antidiabetic drug but also an effective inhibitor of NLRP3 inflammasome, which can regulate metabolic disorders caused by chronic stress and alleviate depressor-like behaviors by inhibiting the production of inflammasomes in the circulatory system [56,57]. Fluoxetine, a selective serotonin reuptake inhibitor, acts as an antidepressant and blood glucose regulator by inhibiting NLRP3 inflammasome to reduce inflammatory cytokines and regulate insulin signaling [58,59].…”

“…The serum levels of IL-1β and homoeostatic model assessment-insulin resistance increase in patients with depression, and neuroinflammation and insulin resistance induced by metabolic imbalance can induce depressive disorder [78,79]. The activation of NLRP3 inflammasomes to produce IL-1β leads to the coexistence of depressive-like behavior and insulin resistance in CUMS mice [57].…”

Depression and Metabolic Syndrome: Two Sides of the Same Coin

“…Some studies have found a strong association between depression and MetS [1][2][3][4][5][6][7][8]. While patients who suffer from depression have been found to have a two-fold increased risk of developing MetS [4,[9][10][11] one study [12] showed that those who suffered from twelve weeks of 'chronic stress' developed depressive symptoms, which over time became comorbid with insulin resistance. There is general agreement that insulin resistance is one of the principal contributing factors in the development of MetS.…”