Human embryonic stem cell-derived cardiomyocytes as an in vitro model to study cardiac insulin resistance

Ilvy M. E. Geraets, Dipanjan Chanda, Florence H. J. van Tienen, Arthur van den Wijngaard, Rick Kamps, Dietbert Neumann, Yilin Liu, Jan F. C. Glatz, Joost J. F. P. Luiken, Miranda Nabben*

*Corresponding author for this work

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Abstract

Patients with type 2 diabetes (T2D) and/or insulin resistance (IR) have an increased risk for the development of heart failure (HF). Evidence indicates that this increased risk is linked to an altered cardiac substrate preference of the insulin resistant heart, which shifts from a balanced utilization of glucose and long-chain fatty acids (FAs) towards an almost complete reliance on FAs as main fuel source. This shift leads to a loss of endosomal proton pump activity and increased cardiac fat accumulation, which eventually triggers cardiac dysfunction. In this review, we describe the advantages and disadvantages of currently used in vitro models to study the underlying mechanism of IR-induced HF and provide insight into a human in vitro model: human embryonic stem cell derived cardiomyocytes (hESC-CMs). Using functional metabolic assays we demonstrate that, similar to rodent studies, hESC-CMs subjected to 16 h of high palmitate (HP) treatment develop the main features of IR, Le., decreased insulin-stimulated glucose and FA uptake, as well as loss of endosomal acidification and insulin signaling. Taken together, these data propose that HP-treated hESC-CMs are a promising in vitro model of lipid overload-induced IR for further research into the underlying mechanism of cardiac IR and for identifying new pharmacological agents and therapeutic strategies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
Original languageEnglish
Pages (from-to)1960-1967
Number of pages8
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Volume1864
Issue number5
DOIs
Publication statusPublished - 1 May 2018
EventAnnual Conference of the Society-for-Heart-and-Vascular-Metabolism - Beijing, PEOPLES R CHINA, Beijing
Duration: 1 May 2018 → …

Keywords

  • Human embryonic stem cells
  • In vitro models
  • Insulin resistance
  • Glucose and fatty acid uptake
  • Cardiomyocytes
  • HUMAN VENTRICULAR CARDIOMYOCYTES
  • FATTY-ACID UPTAKE
  • DIABETES-MELLITUS
  • CONTRACTILE DYSFUNCTION
  • HEART-FAILURE
  • CARDIOVASCULAR-DISEASE
  • FUNCTIONAL MATURATION
  • ACTION-POTENTIALS
  • PROGENITOR CELLS
  • DIFFERENTIATION

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