ArticleCardiovascular diabetology2023
Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion.
Article in Cardiovascular diabetology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 27 citations in OpenAlex.
- Big Job for the Small Titin: Don't Underestimate the "Little" Guy.Circulation research · 2026Article
- TBC1D4-Related Monogenic Diabetes: Molecular Mechanisms, Clinical Recognition, and Therapeutic Implications.Journal of diabetes · 2026Review
- mJournal of cardiothoracic surgery · 2026Article
- Article
- Metabolic regulation for the treatment of ischemic heart disease with stem cells and extracellular vesicles.NPJ cardiovascular health · 2025Review
- The regulatory role of exercise in heart failure and myocardial energy metabolism: A review.Biomolecules & biomedicine · 2025Review
- Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.bioRxiv : the preprint server for biology · 2025Article
- AS160 is a lipid-responsive regulator of cardiac CaNature communications · 2024Article
- TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype.Cell death & disease · 2024Article
- In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation.Cardiovascular diabetology · 2024Article
- Identification of rare variants in candidate genes associated with monogenic diabetes in polish mody-x patients.Journal of diabetes and metabolic disorders · 2024Article
- RICH1 is a novel key suppressor of isoproterenol‑ or angiotensin II‑induced cardiomyocyte hypertrophy.Molecular medicine reports · 2024Article
- Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas.Nature communications · 2024Article
- Cardiometabolic Modulation by Semaglutide Contributes to Cardioprotection in Rats with Myocardial Infarction.Drug design, development and therapy · 2024Article
- Insulin signaling and its application.Frontiers in endocrinology · 2023Review
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundType 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk. The study's aim was to investigate TBC1D4 function in cardiac substrate metabolism and adaptation to MI.
methodsCardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [
resultsTbc1d4-knockout abolished insulin-stimulated glucose uptake in ex vivo LV papillary muscle and in vivo cardiac glucose uptake after glucose injection, accompanied by a marked reduction of GLUT4. Basal cardiac glucose uptake and GLUT1 abundance were not changed compared to WT controls. D4KO mice showed mild impairments in glycemia but normal cardiac function. However, after I/R D4KO mice showed progressively increased LV endsystolic volume and substantially increased infarction area compared to WT controls. Cardiac transcriptome analysis revealed upregulation of the unfolded protein response via ATF4/eIF2α in D4KO mice at baseline. Transmission electron microscopy revealed largely increased extracellular matrix (ECM) area, in line with decreased cardiac expression of matrix metalloproteinases of D4KO mice.
conclusionsTBC1D4 is essential for insulin-stimulated cardiac glucose uptake and metabolic flexibility. Tbc1d4-deficiency results in elevated cardiac endoplasmic reticulum (ER)-stress response, increased deposition of ECM and aggravated cardiac damage following MI. Hence, impaired TBC1D4 signaling contributes to poor outcome after MI.
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