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A new role for neuregulin-1 in type 2 diabetes

Commented by Wolfgang A. Linke

Diabetes and the Heart
Basic Science - Cardiac Diseases - Heart Failure
ESC Working Groups
Signal Transduction, Mechano-Transduction

Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1

Hopf AE et al.

The giant protein titin in the contractile units of the heart (sarcomeres) is essential for myocardial structure and function. In addition to other functions, titin defines the elasticity and stiffness of the cardiomyocytes and supports their dynamic adaptation to changing conditions [1]. Diabetes mellitus chronically impairs the passive extensibility of the heart muscle cells [2-4]. Clinically, increased left ventricular cardiac stiffness is considered the earliest manifestation of diastolic left ventricular dysfunction caused by type 2 diabetes mellitus (T2DM) [5]. In addition to changes in the extracellular matrix, increased myocardial stiffness is due to changes in the elastic properties of titin. Researchers led by Anna-Eliane Hopf and Martina Krüger at the University Hospital Düsseldorf (HHU) investigated the short-term fine-tuning of the elasticity of titin, which occurs via post-translational modifications, in particular phosphorylation. Well-characterized phosphorylation sites are in located in two elastic elements of the titin spring termed N2-B and PEVK. While cardiomyocyte elasticity increases with phosphorylation of the N2-B domain, phosphorylation of the PEVK region results in a decrease in elasticity. Together with their co-operation partners, the scientists showed that patients with T2DM have impaired insulin homeostasis, as a result of which increased activity of Ca2+-dependent protein kinase C (PKCα) and increased phosphorylation of the titin-PEVK region occurs. At the same time, human muscle biopsies showed decreased phosphorylation of the titin N2-B region by cGMP-dependent protein kinase G (PKG). Both changes caused reduced elasticity of the cardiomyocytes. Additionally, researchers investigated on animal models the effects of antidiabetic and hypoglycemic agent metformin, as well as that of neuregulin-1, on titin-based properties of the cardiomyocytes. In contrast to metformin, neuregulin-1 was able to reverse the diabetes-induced posttranslational changes of titin. Moreover, the passive properties of the cardiomyocytes from diabetic animals could be normalized by neuregulin-1. In addition to hypoglycemic medications, chronic administration of neuregulin-1 may thus be a promising approach to normalizing pathologically increased ventricular stiffness and may represent a new therapeutic option for patients with diabetes-induced diastolic dysfunction.


  1. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114:1052–1068. doi:10.1161/CIRCRESAHA.114.301286.
  2. van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43–51. doi:10.1161/CIRCULATIONAHA.107.728550.
  3. Falcao-Pires I, Hamdani N, Borbely A, et al. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation. 2011;124:1151–1159. doi:10.1161/CIRCULATIONAHA.111.025270.
  4. Hamdani N, Hervent AS, Vandekerckhove L, et al. Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4. Cardiovasc Res. 2014;104:423–431. doi:10.1093/cvr/cvu223.
  5. Boyer JK, Thanigaraj S, Schechtman KB, Perez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol. 2004;93:870–875. doi:10.1016/j.amjcard.2003.12.026.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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