Longitudinal Plasma Lipidome and Risk of Type 2 Diabetes in a Large Sample of American Indians With Normal Fasting Glucose: The Strong Heart Family Study

Abstract

<strong>OBJECTIVE:</strong> Comprehensive assessment of alterations in lipid species preceding T2D is largely unknown. We aimed to identify plasma molecular lipids associated with risk of T2D in American Indians. <p><strong>RESEARCH DESIGN AND METHODS</strong>: Using an untargeted LC-MS, we repeatedly measured 3,907 fasting plasma samples from 1,958 participants who attended two exams (~5.5 year apart) and were followed up to 16 years in the Strong Heart Study. Mixed-effect logistic regression was used to identify lipids associated with risk of T2D adjusting for traditional risk factors. Repeated measurement analysis was performed to examine the association between change in lipidome and change in continuous measures of T2D adjusting for baseline lipids. Multiple testing was controlled by false discovery rate at 0.05.</p> <p><strong>RESULTS:</strong> Higher baseline level of 33 lipid species, including TAGs, DAGs, PEs, and PCs, was significantly associated with increased risk of T2D (odds ratio [OR] per SD increase in log2-transformed baseline lipids: 1.50-2.85) at 5-year follow-up. Of these, 21 lipids were also associated with risk of T2D at 16-year follow-up. Aberrant lipid profiles were also observed in prediabetes (OR per SD increase in log2-transformed baseline lipids: 1.30-2.19 for risk lipids; 0.70-0.78 for protective lipids). Longitudinal changes in 568 lipids were significantly associated with changes in continuous measures of T2D. Multivariate analysis identified distinct lipidomic signatures differentiating high from low risk groups. </p> <p><strong>CONCLUSIONS:</strong> Lipid dysregulation occurs many years preceding T2D, and novel molecular lipids (both baseline level and longitudinal change over time) are significantly associated with risk of T2D beyond traditional risk factors. Our findings shed light on the mechanisms linking dyslipidemia to T2D and may yield novel therapeutic targets for early intervention tailored to American Indians.</p>

Lipidomics Analysis of Impaired Glucose Tolerance and Type 2 Diabetes Mellitus in Overweight or Obese Elderly Adults

“…TGs and DGs showed the most signi cant association with T2D and IGT. Our analysis is in line with those of previous studies, which showed that TG(46:1), TG(48:1), TG(48:2), TG(51:1), and TG (52:1) were positively associated with T2DM and prediabetes in an American Indian cohort [27], and positively associated with T2DM in Chinese[26] and Caucasian cohorts [32].…”

“…In young adults (aged 18-34 years), independent of age and BMI, PI (16:0/16:0) and PI (16:0/16:1) were positively associated with insulin AUC in men and homeostatic model assessment of insulin resistance (HOMA-IR) in both women and men [40]. PI (16:0/16:1) was also found to be positively associated with prediabetes over a 5-year follow-up period [27].…”

“…We found that the levels of multiple glycerophospholipids, including PC (10:0/11:4), PC (14:0/10:1), PS (11:0/16:0), PS (11:0/18:0), PI (16:0/16:0), and PI (16:0/16:1), changed signi cantly in individuals with IGT and T2DM. Although previous studies have reported associations of PC, PE, PS, and PI species with IR, T2D, and related traits [26,27,35,40], some studies have shown inconsistent results as PCs and PEs were increased in some studies [41,42] but were decreased in others [30,31]. In young adults (aged 18-34 years), independent of age and BMI, PI (16:0/16:0) and PI (16:0/16:1) were positively associated with insulin AUC in men and homeostatic model assessment of insulin resistance (HOMA-IR) in both women and men [40].…”

“…To identify associations between lipids and T2DM incidence, several large-scale lipidomic cohort studies have been performed in adults [25][26][27][28]. Given the large number of obese older adults with T2DM, this study only included overweight/obese elderly adults with NGT, IGT, and T2DM and presented a comprehensive lipidomic evaluation.…”

Lipidomics of cyclophosphamide 4‐hydroxylation in patients receiving post‐transplant cyclophosphamide

“…Profiling of free fatty acids (FFAs) and complex lipids from several classes, including ceramides (CER), sphingomyelins (SM), cholesteryl esters (CE), lyso‐ and phospholipids that is, phosphatidyl ethanolamines (PE), lyso‐PE (LPE), phosphatidyl cholines (PC), lyso‐PC (LPC), and phosphatidyl inositols (PI), mono‐, di‐, and triacylglycerols (DG and TG), and acylcarnitines have been described previously 18 . Details on sample extraction, laboratory protocols, and data preprocessing have been described previously 19 . A total of 409 lipids were detected in at least 90% of samples for cohort 1 and 387 in cohort 2.…”