Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women

Abstract

Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays. High HOMA-IR subjects had higher serum branched-chain amino acid concentrations (BCAA) (p < 0.05 for both). Gene expression analysis of subcutaneous adipose tissue revealed significant down-regulation of genes related to BCAA catabolism and mitochondrial energy metabolism and up-regulation of several inflammation-related pathways in high HOMA-IR subjects (p < 0.05 for all), but no differentially expressed genes in skeletal muscle were found. In conclusion, in normoglycemic women insulin resistance was associated with increased serum BCAA concentrations, down-regulation of mitochondrial energy metabolism and increased expression of inflammation-related genes in the adipose tissue.

Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED Trial

“…These findings may explain in part our previous finding that, among participants of PREDIMED who were initially free of diabetes, the MedDiet+EVOO intervention significantly reduced risk of type 2 diabetes [16]. Our results are consistent with the findings from our systematic review on metabolomics and type 2 diabetes [6], other recent findings [5, 7–12, 25] and our previous observation on the association between plasma levels of BCAA and incident cardiovascular disease [26]. …”

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

“…In MSUD patients, high BCAA blood concentrations cause neurological damage associated with sustained inflammation including elevated serum levels of IL‐1β, IL‐6 and IFN‐γ 34. In normoglycemic women, insulin resistance was associated with increased serum BCAA concentrations, down‐regulation of mitochondrial energy metabolism and increased expression of inflammation‐related genes (CCL2‐CCL5) in the adipose tissue 35. Finally, our recent study demonstrated that elevated concentrations of BCAA induced inflammation and oxidative stress in PBMC 22.…”

Mechanism by which Metformin Influence Metabolic Changes in Human: A Systematic-Review

“…Phenylalanine and tyrosine are closely associated with each other and glutamate is associated with the above two AAAs through ammonia. Some studies have suggested that amino acids adjust insulin sensitivity through gluconeogenesis, especially impaired insulin sensitivity related to dysfunction of amino acid metabolism, and it may result in adiposity or diabetes [29,30]. Amino acids could modulate peripheral insulin sensitivity and eventually contribute to T2DM patients with insulin resistance [31].…”

“…Pharmacometabolomics could provide certain advantages compared to other "omics" fields because metabolites that intermediates and end products in metabolic pathway necessary to reflect better physiological dysfunctions, drug response and enable to diagnosis using biological fluids [25,[29][30][31][32][33][34][35][36][37][38]. A previous study reported the integration of metabolite levels of bio fluids and other biochemical information (e.g., glucose and HbA1c) could better reflect T2DM risk than a single established risk factor [29,[39][40][41][42][43][44][45][46].…”