Abstract
Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophysiology and reveal potential roles of genetic predisposition. We have previously developed an obesity-induced diabetic zebrafish model that shares common pathological pathways with humans and may be used to identify putative pharmacological targets of diabetes. Additionally, we have previously identified several candidate genes with altered expression in T2DM zebrafish. Here, we performed a small-scale zebrafish screening for these genes and discovered a new therapeutic target, centromere protein X (CENPX), which was further validated in a T2DM mouse model. In zebrafish, cenpx knockdown by morpholino or knockout by CRISPR/Cas9 system ameliorated overfeeding-induced hyperglycemia and upregulated insulin level. In T2DM mice, small-interfering RNA-mediated Cenpx knockdown decreased hyperglycemia and upregulated insulin synthesis in the pancreas. Gene expression analysis revealed insulin, mechanistic target of rapamycin, leptin, and insulin-like growth factor 1 pathway activation following Cenpx silencing in pancreas tissues. Thus, CENPX inhibition exerted antidiabetic effects via increased insulin expression and related pathways. Therefore, T2DM zebrafish may serve as a powerful tool in the discovery of new therapeutic gene targets.
Highlights
Along with the epidemic of obesity, there is a parallel increase in the prevalence of diabetes worldwide (Haffner, 2006)
We performed knockdown screening to AB strain zebrafish using vivo-MO to investigate candidates that could reverse blood glucose elevation in Type 2 diabetes mellitus (T2DM) fish
We focused on cenpx and validated its potential as a novel therapeutic candidate gene for diabetes and homx1 was used as a positive control (Jais et al, 2014)
Summary
Along with the epidemic of obesity, there is a parallel increase in the prevalence of diabetes worldwide (Haffner, 2006). Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is primarily caused by pancreatic β-cell dysfunction and insulin resistance in target organs (Chatterjee et al, 2017). It is a complex disorder, and both genetic components, as well as environmental factors, are known to contribute to its pathogenesis (Ding et al, 2015). Even tighter glucose control does not reduce the incidence of macrovascular diseases, such as nephropathy in patients with T2DM (Ukpds, 1998). Early detection and intervention of impaired glucose tolerance, the preliminary stage of T2DM, have attracted attention as a prophylactic treatment strategy
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