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Metabolomics Workbench ST000075 - GNPS - Combined Metabolomics and Lipidomics of Type 1 Diabetes (QTOF)

ABSTRACT: This West Coast Metabolomics Center pilot and feasibility project granted to Graeme Bell (University of Chicago) and collaborator Manami Hara uses a multi-omics approach to investigate the metabolome (primary metabolites), lipidome (complex lipids) and signaling lipids (oxylipins) in the plasma of Non-obese Diabetic (NOD) mice which progressed to Type 1 Diabetes Mellitus (T1D) and those that did not. NOD Mice (n=71) were assessed as diabetic or non-diabetic based on their fasting (4hr) blood glucose levels at sacrifice, which defined 30 hyperglycemic (glucose = 250 mg/dL) and 41 normoglycemic animals. The primary objective of this study was to identify candidate biomarkers associated with beta-cell destruction/survival and T1D progression.

INSTRUMENT(S): Q-TOF - NEGATIVE, Q-TOF - POSITIVE

ORGANISM(S): Mus Musculus

SUBMITTER: Oliver Fiehn

PROVIDER: MSV000082715 | GNPS | Thu Aug 02 17:17:00 BST 2018

REPOSITORIES: GNPS

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Project description:Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus. Excessive activation of the canonical Wnt/β-catenin pathway contributes to the development of cardiomyopathy in type 1 diabetes mellitus (T1DM). Transcription factor 7-like 2 (TCF7L2) is the main β-catenin partner of the TCF family in adult human hearts. In this study, we investigated the role of Wnt/β-catenin in the development of cardiomyopathy in type 2 diabetes mellitus (T2DM) by using streptozotocin (STZ)/high-fat diet (HFD)-induced diabetic mice and high glucose-stimulated neonatal rat cardiomyocytes (NRCMs) as in-vivo and in-vitro models of T2DM, respectively. Compared with the control mice, the T2DM mice exhibited increased myocardial β-catenin and TCF7L2 expression that was concentrated in the nucleus. Treatment of diabetic mice with the β-catenin/TCF7L2 bipartite inhibitor iCRT14 prevented myocardial remodeling and improved cardiac dysfunction. iCRT14 also prevented high glucose-induced hypertrophy in NRCMs, while the β-catenin stabilizer SKL2001 worsened hypertrophy. Immunoprecipitation experiments confirmed the formation of the β-catenin/TCF7L2 bipartite in the control and T2DM mouse cardiomyocytes. Moreover, carbonic anhydrase 2 (CA2) was upregulated in T2DM cardiomyocytes in vitro and in vivo. TCF7L2 overexpression upregulated CA2, while iCRT14 treatment or TCF7L2 knockdown downregulated CA2. Chromatin immunoprecipitation (ChIP) experiments revealed an increased interaction between β-catenin/TCF7L2 and the transcription initiation region of CA2 in the heart tissue of T2DM mice. CA2 knockdown ameliorated NRCM hypertrophy induced by high glucose and SKL2001. A luciferase reporter assay confirmed that CA2 is directly regulated by the β-catenin/TCF7L2 bipartite. Collectively, these results indicate that the canonical Wnt/β-catenin pathway upregulates CA2 via TCF7L2 to promote cardiomyopathy in T2DM. This research sheds new light on the pathogenesis of DCM and presents new potential therapeutic targets for this disease.

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Metabolomics Workbench ST000075 - GNPS - Combined Metabolomics and Lipidomics of Type 1 Diabetes (QTOF)

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