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Modelling pancreatic beta-cell inflammation in zebrafish identifies a natural product for human beta-cell protection

ABSTRACT: To assess the effect of chronic inflammation on the beta-cells transcriptome, we conducted RNA-sequencing, from 3 months old zebrafish transgenic line Tg(ins:IL1B) animals and WT siblings The total RNA from FACS sorted Beta-cells was isolated using Quick-RNA MicroPrep kit (R1050 Zymo Research) and following the manufacturer instructions. The sequencing was made on llumina HiSeq2500 in 2x75bp paired-end mode. method Results:Two replicates for controls and two for IL1B expressing beta cells were sequenced. About 40 million sequence reads per sample were mapped to the Zebrafish genome. We identify around 19 thousand genes per sample. Approximately 6% of the genes were differentially expressed. 1,245 genes with a FDR of 5 showed a fold change ≥0.7 and adjusted p-value <0.05. Conclusions: Hierarchical clustering by Pearson correlation of differentially expressed genes uncovered the expression of alpha-cell related genes in beta-cells. This provides a possible impairment of beta-cell identity reflected in RNA expression profiles.

ORGANISM(S): Danio rerio

PROVIDER: GSE123036 | GEO | 2018/11/29

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Modelling pancreatic beta-cell inflammation in zebrafish identifies a natural product for human beta-cell protection

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