Abstract
Type 2 diabetes (T2D) has a strong genetic component. Most of the gene variants driving the pathogenesis of T2D seem to target pancreatic β-cell function. To identify novel gene variants acting at early stage of the disease, we analyzed whole transcriptome data to identify differential expression (DE) and alternative exon splicing (AS) transcripts in pancreatic islets collected from two metabolically diverse mouse strains at 6 weeks of age after three weeks of high-fat-diet intervention. Our analysis revealed 1218 DE and 436 AS genes in islets from NZO/Hl vs C3HeB/FeJ. Whereas some of the revealed genes present well-established markers for β-cell failure, such as Cd36 or Aldh1a3, we identified numerous DE/AS genes that have not been described in context with β-cell function before. The gene Lgals2, previously associated with human T2D development, was DE as well as AS and localizes in a quantitative trait locus (QTL) for blood glucose on Chr.15 that we reported recently in our N2(NZOxC3H) population. In addition, pathway enrichment analysis of DE and AS genes showed an overlap of only half of the revealed pathways, indicating that DE and AS in large parts influence different pathways in T2D development. PPARG and adipogenesis pathways, two well-established metabolic pathways, were overrepresented for both DE and AS genes, probably as an adaptive mechanism to cope for increased cellular stress. Our results provide guidance for the identification of novel T2D candidate genes and demonstrate the presence of numerous AS transcripts possibly involved in islet function and maintenance of glucose homeostasis.
Highlights
The pathogenesis of type 2 diabetes (T2D), which is characterized by chronically elevated blood glucose levels, is closely linked with obesity
Already at 3 weeks of age, on the day of the start of the high-fat diet (HFD) intervention, New Zealand Obese (NZO) animals exhibited significantly higher blood glucose levels compared to C3H mice (192 ± 5 mg/dl vs. 99 ± 3 mg/dl, P < 0.001; Fig. 1b)
These differences in glycemia were evident during HFD feeding
Summary
The pathogenesis of type 2 diabetes (T2D), which is characterized by chronically elevated blood glucose levels, is closely linked with obesity. The ability of the organism to generate different splice isoforms can be viewed as an adaptation process allowing to respond to distinct developmental and metabolic cues (Nilsen and Graveley 2010; Salomonis et al 2010) Consistent with this assumption, many key regulator genes of pancreatic β-cell function, including NO1, HNF1a, IPF-1, GCK, SUR1, TCF7L2, VEGF, and NOVA1, are known to be regulated by alternative splicing in humans (Dlamini et al 2017). We analyzed exon array data from pancreatic islets collected from T2D-prone NZO/Hl and T2D-resistant C3HeB/FeJ mice and fed with a high-fat diet with 45% calories from fat for three weeks This analysis revealed DE as well as AS genes between the two strains that may contribute to their different T2D susceptibilities and, represent novel candidate genes involved in early stages of T2D development. We performed pathway enrichment, gene network, as well as gene ontology enrichment analysis of the DE and AS genes
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