SNW domain containing protein 1 (SNW1), a novel insulin resistant gene induces hyperglycemia via inducing gluconeogenesis and downregulating glucose uptake in gestational diabetic mother

Objective: Gestational Diabetes mellitus (GDM) is an emerging maternal health problem with increasing incidences. The lack of complete understanding of pathophysiological mechanism and novel regulatory biomarkers makes the early diagnosis difficult. Hence, the present study aims to decipher novel regulatory gene, which will help better understand the pathophysiology of GDM and serve as novel diagnostic and therapeutic biomarkers. Materials and Methods We performed high-throughput RNA sequencing on the Oxford Nanopore-MinION sequencing platform. Gene network analysis (STRING and Cytoscape), module extraction (MCODE), functional and pathway enrichment analysis (DAVID and Enrichr) were performed to identify the novel hub gene. Identified novel hub genes were validated through qRT-PCR and tested for their sensitivity and specificity. Serum metabolites were measured using 800MHz Bruker Avance NMR spectrometer and were compared between GDM and healthy control. PANC1 cells were transfected to validate the novel biomarkerand their possible regulatory mechanism. All expression and statistical analysis were carried out using Graph pad prism 9. Results Transcriptomic study leads to identification ofSNW1 as most sensitive and specific (AUC = 0.98; sensitivity = 96.7 and; specificity = 96.7; p < 0.001) biomarkerwhich isup-regulated (fold change = 1.09; p < 0.001) in GDM. Metabolomics study identified elevated gluconeogenesis which is evident from decreased level of amino acids like alanine (GDM = 397.5 ± 28.12; NGT = 515.1 ± 24.03) and elevated level of pyruvate (GDM = 17.35; NGT = 16.17) and glucose (GDM = 4.67; NGT = 3.25) in GDM and control respectively.SiRNA mediated knockdown of SNW1 causes significant downregulation of alanine aminotransferase (ALT/GPT), and insulin receptor substrate (IRS1) while significant upregulation of glucose transporter (GLUT2 and GLUT4) and insulin (INS) at mRNA as well as protein level both. Conclusion SNW1 is novel insulin resistant gene which induces hyperglycaemia via elevating gluconeogenesis and decreasing the glucose uptake. Hence SNW1 can be used as diagnostic biomarker for early diagnosis of GDM mother.