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Review
. 2023 Dec 30;11(1):12.
doi: 10.3390/jcdd11010012.

Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target

Affiliations
Review

Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target

Abhishek Dattani et al. J Cardiovasc Dev Dis. .

Abstract

Type 2 diabetes (T2D) is a multisystem disease with rapidly increasing global prevalence. Heart failure has emerged as a major complication of T2D. Dysregulated myocardial calcium handling is evident in the failing heart and this may be a key driver of cardiomyopathy in T2D, but until recently this has only been demonstrated in animal models. In this review, we describe the physiological concepts behind calcium handling within the cardiomyocyte and the application of novel imaging techniques for the quantification of myocardial calcium uptake. We take an in-depth look at the evidence for the impairment of calcium handling in T2D using pre-clinical models as well as in vivo studies, following which we discuss potential novel therapeutic approaches targeting dysregulated myocardial calcium handling in T2D.

Keywords: calcium handling; diabetes; manganese-enhanced MRI.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Myocardial calcium handling and potential therapeutic targets. Left: within the myocardium, the cardiomyocyte is made up of myofibrils that are formed of sarcomeres, which are the contractile units. Right: Steps in the excitation-contraction coupling pathway: 1. Arrival of action potential; 2. Influx of sodium; 3. Influx of calcium via the LTCC; 4. Calcium binds to RyR2 on the SR; 5. Release of calcium from SR; 6. Contraction of cardiomyocyte. Abbreviations: LTCC = L-type Ca2+ channels; SR = sarcoplasmic reticulum; RyR2 = ryanodine receptor; SERCA-2 = sarcoplasmic reticulum Ca2+ ATPase-2, GLP-1 = glucagon-like peptide-1 receptor agonist, SGLT-2i = sodium glucose co-transporter 2 inhibitor, CaMK = calmodulin dependent protein kinase II. Block arrows show potential novel therapeutic targets for myocardial Ca2+ handling in type 2 diabetes. Created with BioRender.com, accessed on 23 October 2023.
Figure 2
Figure 2
Initial experiments showing abnormalities in calcium handling in the failing human heart. Biopsy samples from patients with end-stage HF showed various abnormalities of myocardial calcium handling. Created with BioRender.com, accessed on 23 October 2023.
Figure 3
Figure 3
Key features of abnormal myocardial calcium handling demonstrated by pre-clinical models. Abbreviations: ZDF = Zucker Diabetic Fatty, GK = Goto-Kakizaki, LTCC = voltage-gated L-type calcium channels, RyR2 = ryanodine receptor-2, SR = sarcoplasmic reticulum, SERCA-2 = SR calcium adenosine triphosphatase. Created with BioRender.com, accessed on 23 October 2023.
Figure 4
Figure 4
Manganese-enhanced magnetic resonance imaging. Serial T1 mapping using manganese-enhanced MRI can be used to assess calcium uptake in-vivo (A). T1 values can be entered into a Patlak model (B) to produce a manganese influx constant (Ki). Patients with T1D and T2D have reduced Ki compared to Controls (C). Abbreviations: T1D = type 1 diabetes, T2D = type 2 diabetes, Ki = manganese influx constant. Scale represents T1 times. Figure adapted with permission from Dattani et al. [93], Copyright 2023, Elsevier.

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