Interferons are key cytokines acting on pancreatic islets in type 1 diabetes.

AIMS/HYPOTHESIS: The proinflammatory cytokines IFN-α, IFN-γ, IL-1ß and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. METHODS: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. RESULTS: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1ß and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. CONCLUSIONS/INTERPRETATION: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.

Mining the transcriptome of target tissues of autoimmune and degenerative pancreatic ß-cell and brain diseases to discover therapies.

Target tissues of autoimmune and degenerative diseases show signals of inflammation. We used publicly available RNA-seq data to study whether pancreatic ß-cells in type 1 and type 2 diabetes and neuronal tissue in multiple sclerosis and Alzheimer's disease share inflammatory gene signatures. We observed concordantly upregulated genes in pairwise diseases, many of them related to signaling by interleukins and interferons. We next mined these signatures to identify therapies that could be re-purposed/shared among the diseases and identified the bromodomain inhibitors as potential perturbagens to revert the transcriptional signatures. We experimentally confirmed in human ß-cells that bromodomain inhibitors I-BET151 and GSK046 prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1ß and interferon-γ and at least some of the effects of the metabolic stressor palmitate. These results demonstrate that key inflammation-induced molecular mechanisms are shared between ß-cells and brain in autoimmune and degenerative diseases and that these signatures can be mined for drug discovery.

The association of uncoupling proteins 1, 2, and 3 with weight loss variability after bariatric surgery: a systematic review.

BACKGROUND: Bariatric surgery is currently the most effective treatment for patients with severe obesity. Uncoupling proteins (UCP) 1, 2, and 3 play key roles in the regulation of energy balance and weight. Previous studies have suggested that changes in UCP1-3 genes could influence weight loss after bariatric surgery. However, it is still unclear if these UCPs are indeed involved in weight loss variability after surgery. Therefore, we performed a systematic review aiming to summarize the results of studies on this subject. METHODS: A literature search was performed for all studies that evaluated associations of UCP1-3 expressions and their polymorphisms with obesity-related outcomes after bariatric surgery. RESULTS: Twenty-six studies were eligible for inclusion in this systematic review. Among them, 18 evaluated UCP1-3 expressions while 8 studies investigated the association between UCP1-3 polymorphisms and weight loss after bariatric surgery. In general, UCP2 and UCP3 expressions in adipose tissue and skeletal muscle seem to be affected by metabolic changes of bariatric surgery, which might be influenced by the surgery type. Data on UCP1 expression in adipose tissue is still inconclusive. Only few studies investigated the association between polymorphisms in UCP1-3 genes and weight loss after bariatric surgery, with contradictory results. CONCLUSION: Available studies suggest that changes caused by bariatric surgery could influence UCP2 and UCP3 expressions in adipose tissue and muscles, consequently affecting weight loss. However, because of the reduced number of studies, further studies are needed to confirm whether these UCPs and their polymorphisms are indeed involved in weight loss after bariatric surgery.