Identifying Potential biomarkers of insulin sensitivity and insulin resistance in obese patients

Abstract

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain insulin sensitivity and show a lower risk of insulin resistance and T2DM. Our overall aim was to investigate the molecular mechanisms underlying the protective phenotype of obese insulin sensitive (OIS) individuals to help designing novel diagnostic and therapeutic strategies targeting obese insulin resistant (OIR) and T2DM counterparts. To achieve our aim, OMICS techniques, including metabolomics and lipidomics of blood and adipose tissues respectively, were utilized to investigate the molecular pathways differentiating OIS from OIR and T2DM. Blood metabolic profiling identified several metabolites associated with increased risk of T2DM including novel phospholipid metabolites. Adipose tissue lipidomics profiling revealed novel triacyclglycerols and fatty acids that were significantly altered with disease progression, including C12:0 and C18 fatty acids. Finally, we investigated the potential role of the prominent environmental pollutants polybrominated diphenyl ethers (PBDEs) in obesity-associated insulin resistance by measuring their bioaccumulation in adipose tissues from OIS and the OIR individuals. Our novel data indicated that PBDEs 99, 28, and 47 were significantly higher in OIR individuals compared to their OIS counterparts. Treatment of preadipocytes from OIS individuals with PBDE28 caused inhibition of insulin signaling, suggesting a functional role. The identified metabolites shed light on the molecular pathways potentially underlying the protective phenotype of OIS. Future studies will address the functionality of these metabolites in relation to insulin resistance and identify those that could potentially be used as diagnostic and/or therapeutic targets.