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.
Highlights
Abundant reports indicated that depression was often comorbid with type 2 diabetes and even metabolic syndrome
Glyburide abrogated depressive-like behavior induced by chronic unpredictable mild stress (CUMS) After acclimation and group assignment, the experimental mice were subjected to CUMS and drug administration simultaneously throughout the 12 weeks’ CUMS procedure (Fig. 1a)
Metabolic tests composed of IPGTT, insulin tolerance tests (ITT), GSIS, and HOMA-insulin resistance (IR) in our research indicated that stressed mice got insulin-resistant phenotypes, but were not obvious in hyperglycemia
Summary
Abundant 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. It is well known that depression and diabetes, especially type 2 diabetes (T2D), were among the leading causes of global disability-adjusted life-years (DALYs) [2]. According to reports from World Health Organization, more than 300 million human beings all over the world suffer from depression (refer to URL: http://www.who.int/mediacentre/ factsheets/fs369/en/), while approximately 422 million people worldwide have diabetes (refer to URL: http:// www.who.int/mediacentre/factsheets/fs312/en/).
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