Metabonomic Profiling Reveals Difference in Altered Metabolic Pathways Between Chronic Kidney Disease and High-Fat-Induced Insulin Resistance in Rats

Background/Aims: Chronic kidney disease (CKD) is closely correlated with the development of insulin resistance (IR). Until now, the underlying molecular mechanisms remain to be elucidated. This study aimed to identify metabolites and molecular pathways unique to CKD-induced IR. Methods: Ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS) analysis coupled with orthogonal partial least square discriminant analysis (OPLS-DA) were performed to profile metabolites in the serum, liver, and muscle tissues and to analyze molecular pathways in relation to CKD- and high fat diet (HFD)-induced IR in the rats. Results: At 18 weeks after the 5/6 Nx operation, CKD induction was demonstrated by renal histology and biochemical tests. Furthermore, both CKD-induced IR and HFD-induced IR rats showed significantly greater levels of fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). In the UPLC-MS in combination with OPLS-DA analysis, we identified 101, 59, and 41 differential metabolites in the serum, liver, and muscle, which were associated with the CKD-induced IR, while 58, 38, and 17 differential metabolites in the serum, liver, and muscle were revealed in the HFD-induced rats compared to controls. Moreover, compared to HFD-induced IR rats, those with CKD-induced IR exhibited abnormal pathways primarily in the tryptophan metabolism, arginine metabolism, and trimethylamine oxide metabolite. Interestingly, altered metabolites in the CKD-induced IR and HFD-induced IR displayed an opposite direction. Conclusion: Alterations in metabolites and relevant pathways were significantly different between the CKD- and HFD-induced IR rats. These findings may offer important information regarding the pathogenesis specific to IR caused by the decline in the renal function