High-Coverage Targeted Lipidomics Reveals Novel Serum Lipid Predictors and Lipid Pathway Dysregulation Antecedent to Type 2 Diabetes Onset in Normoglycemic Chinese Adults

Abstract

Comprehensive assessment of serum lipidomic aberrations before type 2 diabetes mellitus (T2DM) onset has remained lacking in Han Chinese. We evaluated changes in lipid coregulation antecedent to T2DM and identified novel lipid predictors for T2DM in individuals with normal glucose regulation (NGR). RESEARCH DESIGN AND METHODSIn the discovery study, we tested 667 baseline serum lipids in subjects with incident diabetes and propensity score-matched control subjects (n = 200) from a prospective cohort comprising 3,821 Chinese adults with NGR. In the validation study, we tested 250 lipids in subjects with incident diabetes and matched control subjects (n = 724) from a pooled validation cohort of 14,651 individuals with NGR covering five geographical regions across China. Differential correlation network analyses revealed perturbed lipid coregulation antecedent to diabetes. The predictive value of a serum lipid panel independent of serum triglycerides and 2-h postload glucose was also evaluated. RESULTSAt the level of false-discovery rate <0.05, 38 lipids, including triacylglycerols (TAGs), lyso-phosphatidylinositols, phosphatidylcholines, polyunsaturated fatty acid (PUFA)-plasmalogen phosphatidylethanolamines (PUFA-PEps), and cholesteryl esters, were significantly associated with T2DM risk in the discovery and validation cohorts. A preliminary study found most of the lipid predictors were also significantly associated with the risk of prediabetes. Differential correlation network analysis revealed that perturbations in intraclass (i.e., non-PUFA-TAG and PUFA-TAGs) and interclass (i.e., TAGs and PUFA-PEps) lipid coregulation preexisted before diabetes onset. Our lipid panel further improved prediction of incident diabetes over conventional clinical indices. CONCLUSIONSThese findings revealed novel changes in lipid coregulation existing before diabetes onset and expanded the current panel of serum lipid predictors for T2DM in normoglycemic Chinese individuals.

Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes

“…Of note, 1deoxysphingolipids have also been found to be elevated in individuals with type 2 diabetes and in non-diabetic individuals with the metabolic syndrome [28]. Moreover, 1-deoxysphingolipid levels were also increased in individuals with type 2 diabetes who had polyneuropathy, when compared with healthy individuals, but there were no correlations between these levels and peripheral nerve function tests or the clinical neuropathy stages [12]. In an open-label clinical trial in individuals with primary hypercholesterolemia or mixed dyslipidaemia, treatment with fenofibrate for 6 weeks resulted in lowering of plasma 1deoxysphingolipid levels [29].…”

“…Higher concentrations of specific SMs have recently been found to predict incident type 2 diabetes in prospective sphingolipidomics studies over 6 and 11 years, respectively [26,27]. The formation of atypical neurotoxic deoxysphingolipids has been identified to play a causative role in the development of hereditary sensory and autonomic neuropathy type 1 (HSAN1) [12]. Of note, 1deoxysphingolipids have also been found to be elevated in individuals with type 2 diabetes and in non-diabetic individuals with the metabolic syndrome [28].…”

“…The past decade has witnessed novel technologies such as metabolomics aimed at the extensive characterisation and quantification of global metabolites from both endogenous and exogenous sources in the context of insulin resistance, the metabolic syndrome and type 2 diabetes [8][9][10][11]. As a subfield of metabolomics, lipidomics emerged to investigate the relationship of dysregulation in lipid metabolism and pathogenesis of type 2 diabetes [12] and diabetic neuropathy [13].…”

Noncanonical regulation of phosphatidylserine metabolism by a Sec14-like protein and a lipid kinase

“…Phospholipids were analyzed by liquid chromatography/mass spectrometry. In brief, phospholipids were separated on a Phenomenex Luna Silica 3-µm column (internal diameter 150 × 2.0 mm; Lu et al, 2019 ). Individual polar lipid species were quantified by referencing to spiked internal standards including PtdCho (14:0/14:0), PtdEtn (14:0/14:0), d31-PtdSer (16:0/18:1), PtdSer (17:0/20:4), PtdOH (17:0/17:0), PtdOH (17:0/20:4), and phosphatidylglycerol (14:0/14:0) obtained from Avanti Polar Lipids.…”

Independent and Opposite Associations Between Branched-Chain Amino Acids and Lysophosphatidylcholines With Incident Diabetes in Thais

“…In addition to BCAAs, the composition of the lipidome has been shown to differ according to glycemic status [8], and phospholipids such as lysophosphatidylcholines (LPCs) have been demonstrated to be associated with obesity and diabetes [9]. In a study in the Chinese population, lipids, including triacylglycerols, lyso-phosphatidylinositols, phosphatidylcholines, polyunsaturated fatty acid-plasmalogen phosphatidylethanolamines, and cholesteryl esters, were shown to be related to the future development of type 2 diabetes [10]. Moreover, it has been suggested that LPCs may mediate the metabolic effects of metformin [11,12].…”