Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes

Abstract

Metabolomic studies aimed to dissect the connection between the development of type 2 diabetes and obesity are still scarce. In the present study, fasting serum from sixty-four adult individuals classified into four sex-matched groups by their BMI [non-obese versus morbid obese] and the increased risk of developing diabetes [prediabetic insulin resistant state versus non-prediabetic non-insulin resistant] was analyzed by LC- and FIA-ESI-MS/MS-driven metabolomic approaches. Altered levels of [lyso]glycerophospholipids was the most specific metabolic trait associated to morbid obesity, particularly lysophosphatidylcholines acylated with margaric, oleic and linoleic acids [lysoPC C17:0: R=-0.56, p=0.0003; lysoPC C18:1: R=-0.61, p=0.0001; lysoPC C18:2 R=-0.64, p<0.0001]. Several amino acids were biomarkers of risk of diabetes onset associated to obesity. For instance, glutamate significantly associated with fasting insulin [R=0.5, p=0.0019] and HOMA-IR [R=0.46, p=0.0072], while glycine showed negative associations [fasting insulin: R=-0.51, p=0.0017; HOMA-IR: R=-0.49, p=0.0033], and the branched chain amino acid valine associated to prediabetes and insulin resistance in a BMI-independent manner [fasting insulin: R=0.37, p=0.0479; HOMA-IR: R=0.37, p=0.0468]. Minority sphingolipids including specific [dihydro]ceramides and sphingomyelins also associated with the prediabetic insulin resistant state, hence deserving attention as potential targets for early diagnosis or therapeutic intervention.

Metabolomic Profiles Associated with BMI, Waist Circumference, and Diabetes and Inflammation Biomarkers in Women

“…Numerous metabolites were associated with BMI and WC. These metabolites included many previously associated with BMI and other measures of adiposity, including urate, the BCAAs and other amino acids, several acyl‐carnitines, and glycerophospholipids . Several novel associations were also found, including for specific sphingolipids, nucleotides, modified FAs (hydroxylated or carboxylated), and bile acids.…”

“…One approach to identify those that do is to examine their relationship to parameters used to define metabolic health. The parameters that have been investigated to date include blood pressure , cholesterol, lipoprotein, and triglyceride levels , body composition , glucose, insulin and insulin sensitivity , adipokine levels , and inflammation markers . These studies have provided support for the involvement of some metabolites in processes related to metabolic diseases, such as the BCAAs in the development of insulin resistance , but the role of many of the metabolites associated with BMI remains undefined.…”

Elevated metabolites of acetaminophen in cord blood of children with obesity

“…Reported here are UCB metabolite profiles associated with childhood obesity at ages 3–5 years. The metabolomics array revealed 46 metabolites at significantly higher levels in the cord blood of children with obesity including 25 lipid species similar to those identified in individuals affected by metabolic diseases . Additionally, an unexpected association was found between acetaminophen metabolites at birth and childhood obesity.…”

Form(ul)ation of adipocytes by lipids

“…On one hand, clinical insulin resistance and diabetes are associated with higher plasma diglycerides (DG) and cholesteryl esters (CE), which are abundant in low-density lipoproteins. [14][15][16][17] On the other hand, they are associated with lower plasma levels of lysophosphatidylcholines (LyPC), which are abundant in high-density lipoproteins.…”

“…These changes in SL composition include higher plasma levels of ceramides and altered composition of sphingomyelin (SM) species. [15][16][17][18]21 Lipidomics of blood samples has been also performed following regimens of weight loss by diet, exercise, bariatric surgery or drug therapy. 19,22,23 The results demonstrate that weight loss produces a characteristic lipid signature that is in part opposite to the characteristic lipid signature of patients with diabetes.…”