A Distinct Role Of STING In Regulating Glucose Homeostasis Through Insulin Sensitivity And Insulin Secretion

Background:Glucose homeostasis is maintained mainly by the precise regulation of insulin secretion from β-cells and insulin action in the insulin target tissues.Genetic and environmental factors that impair insulin secretion and/or action can disrupt glucose homeostasis and lead to metabolic diseases,including type 2 diabetes mellitus(T2D).Over the past decades,the prevalence of T2 D has been dramatically rising largely due to overnutrition and low physical activity induced obesity.However,the underlying mechanisms of obesity induced metabolic diseases remains to be elucidated.In most mammals,metabolic homeostasis and immune system interact and influence each other in multiple manners.Overnutrition can activate immune response and induce low-grade aseptic inflammation,which is now recognized as an important etiological component in the development of insulin resistance and β-cell dysfunction.Stimulator of interferon genes(STING)mediates type I interferon inflammatory responses in immune cells to lead to the activation of a protective,antiviral signaling cascade.In addition to pathogen-derived DNA from microbial infection,recent studies have suggested that under certain pathological conditions,the STING signal pathway could also recognize self DNAs exposed in the cytoplasm of cells,including DNA leaked from the nucleus and cytosolic mitochondrial DNA,and caused autoimmune or auto-inflammatory diseases.More importantly,accumulating evidence suggests an important role of the STING pathway in regulating energy homeostasis and metabolic pathways.However,the role of STING in regulating glucose homeostasis is not yet understood.Aim:To explore the role and mechanism of STING in regulating glucose homeostasis.Method: 1.Animal model: Global STING knockout mice,β-cell specific STING knockout mice,db/db mice(type 2 diabetes animal model),NOD mice(type 1 diabetes animal model),Akita mice(monogenic diabetes animal model).2.Glucose metabolism related experiments: Intraperitoneal glucose tolerance test(IPGTT),intraperitoneal insulin tolerance test(IPITT),to observe the overall glucose metabolism level of mice.3.Islet related experiments: islet extraction,islet perfusion,glucose-stimulated insulin secretion experiment(GSIS),islet calcium imaging,q RT-PCR and western blot analysis,to evaluate the function of β-cells.4.Immunofluorescence and immunohistochemistry: to detect the expression and distribution of STING and insulin in the pancreas.5.Transcriptome analysis: to analyze the gene expression of islets of islets from the mice.6.Cell model: Use different glucose concentrations to induce islets and rat β cell line(INS-1),to observe the relationship between STING and glucose.7.Statistical analysis: using Student’s t-test,p <0.05 is considered statistically different.Results: 1.Global STING knockout alleviated glucose intolerance and insulin resistance,and increased intracellular insulin content,whereas impaired glucose-stimulated insulin secretion in the mice.2.STING decreased in islets of db/db mice and patients with T2 D.3.The expression of STING in islets of various types of diabetes is different.4.The expression of STING in INS-1 cells and islets is gradually down-regulated with the increase of glucose concentration and the extension of the action time.5.β-cell specific STING knockout causes glucose intolerance and impaired GSIS,while does not affect insulin sensitivity and insulin content.Transcriptome analysis found that β-cell specific STING knockout resulted in significant differences in the expression of glucose-stimulated insulin-related genes.Conclusion: This study is the first time to uncover a pivotal role of STING in insulin secretion from β-cells.Given the fact that STING has a distinct role in β-cells and the peripheral insulin target tissues,it would be important to maintain fine-tuned STING signaling in different tissues.And therefore,tissue-specific targeting STING pathway may be a novel therapeutic target for preventing T2 D development and progression.