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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.

SUBMITTER: Wiklund P

PROVIDER: S-EPMC4832240 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Wiklund Petri P Zhang Xiaobo X Pekkala Satu S Autio Reija R Kong Lingjia L Yang Yifan Y Keinänen-Kiukaanniemi Sirkka S Alen Markku M Cheng Sulin S

Scientific reports 20160415

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 spectrosc ...[more]

PMID: 27080554

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Project description:BackgroundObesity is characterized by adipose tissue dysregulation and predisposes individuals to insulin resistance and type 2 diabetes. At the molecular level, adipocyte dysfunction has been linked to obesity-triggered oxidative stress and protein carbonylation, considering protein carbonylation as a link between oxidative stress and metabolic dysfunction. The identification of specific carbonylated proteins in adipose tissue could provide novel biomarkers of oxidative damage related to metabolic status (i.e prediabetes). Thus, we aimed at characterizing the subcutaneous and omental human adipose tissue carbonylome in obesity-associated insulin resistance.Methods2D-PAGE was used to identify carbonylated proteins, and clinical correlations studies and molecular biology approaches including intracellular trafficking, reactive oxygen species assay, and iron content were performed using in vitro models of insulin resistance.ResultsThe carbonylome of human adipose tissue included common (serotransferrin, vimentin, actin, and annexin A2) and depot-specific (carbonic anhydrase and α-crystallin B in the subcutaneous depot; and α-1-antitrypsin and tubulin in the omental depot) differences that point out the complexity of oxidative stress at the metabolic level, highlighting changes in carbonylated transferrin expression. Posterior studies using in vitro prediabetic model evidence alteration in transferrin receptor translocation, linked to the prediabetic environment. Finally, ligand-receptor molecular docking studies showed a reduced affinity for carbonylated transferrin binding to its receptor compared to wild-type transferrin, emphasizing the role of transferrin carbonylation in the link between oxidative stress and metabolic dysfunction.ConclusionsThe adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance.

Project description:BackgroundInsulin resistance is a hallmark of type 2 diabetes mellitus (T2DM) and is associated with metabolic disorders. Adipose tissue plays a crucial role in regulating whole-body energy balance and glucose homeostasis. Mitogen-inducible gene 6 (Mig-6) is a negative feedback regulator of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR). This study aims to evaluate the role of Mig-6 in white adipose tissue (WAT) and its impact on systemic glucose homeostasis using Mig-6 transgenic mice.MethodsHuman visceral fat samples were obtained from four obese and three lean women undergoing hysterectomy. Adipocyte-specific Mig-6 knock-in (Mig-6AdKI) mice were generated and maintained on either a high-fat diet (HFD) or normal chow diet (NCD). Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed. We conducted histological examinations to observe tissue morphology and used quantitative PCR to assess adipokine mRNA expression.ResultsMig-6 expression was significantly reduced in the adipose tissue of obese mice and humans. Mig-6AdKI mice exhibited improved glucose tolerance and insulin sensitivity under both NCD and HFD conditions, without changes in body weight or fat mass. The improvement in glucose homeostasis under NCD conditions was particularly noteworthy. Increased adiponectin mRNA levels were observed in the WAT of Mig-6AdKI mice. Meanwhile, histological analysis did not observe any changes in adipose tissue morphology that could explain the improvement in systemic glucose homeostasis, although there were tendencies towards increased adipocyte size and inflammation in HFD-fed Mig-6AdKI mice.ConclusionAdipose-specific overexpression of Mig-6 improves systemic glucose tolerance and insulin sensitivity, suggesting its potential as a target for both the treatment and prevention of diabetes. These findings provide a reference for further research targeting EGFR or Mig-6 in adipose tissue, highlighting the metabolic role of Mig-6 in glucose homeostasis.

Dataset Information

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

Publications

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

Similar Datasets

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