اكتشاف جين جديد يساهم في الإصابة بمرض السكري و يؤثر في استقلاب الغلوكوز

الملخص EN

Background: Type 2 diabetes (T2D) is a multifactorial polygenic disease with an unclear causative mechanism.

Close to 140 genetic variants are associated with T2D, but they only explain 10% of the heritability.

Aim: In this study, we employed a novel approach to identify novel genes involved in the pathophysiology of T2D and insulin secretion.

Methods: We analyzed RNA-sequencing data from human pancreatic islets at a global level.

Furthermore, we performed a serial of functional experiments in rat pancreatic β-cells to validate the potential role of the candidate gene including siRNA silencing, insulin secretion, cell viability, apoptosis, QPCR, and western blot expression of the key molecule in β-cells.

Results: Differential expression analysis reveals those 231 genes are significantly (P<0.05) downregulated in diabetic islets compared to nondiabetics.

However, the number of genes was restricted to 37 genes by applying a cutoff of (P<0.01).

Of these genes, PPP1R1A was selected as a candidate gene due to its strong correlation with HbA1c and high expression in human pancreatic islets.

Silencing of PPP1R1A in INS-1 cells was markedly reduced, insulin secretion while cell viability and apoptosis were not affected.

In addition, the expression of Insulin, PDX1, GLUT2, and INSR was significantly down-regulated in PPP1R1A-silenced cells.

Expression of NEUROD1 and GCK was not affected.

Conclusion: The study identifies PPP1R1A as a novel regulator of pancreatic β-cell function and insulin secretion.

Moreover, it introduces a list of potential genes to be explored for their role in the pathogenesis of T2D.