Run for your life: can exercise be used to effectively target GLUT4 in diabetic cardiac disease?

Abstract

The global incidence, associated mortality rates and economic burden of diabetes are now such that it is considered one of the most pressing worldwide public health challenges. Considerable research is now devoted to better understanding the mechanisms underlying the onset and progression of this disease, with an ultimate aim of improving the array of available preventive and therapeutic interventions. One area of particular unmet clinical need is the significantly elevated rate of cardiomyopathy in diabetic patients, which in part contributes to cardiovascular disease being the primary cause of premature death in this population. This review will first consider the role of metabolism and more specifically the insulin sensitive glucose transporter GLUT4 in diabetic cardiac disease, before addressing how we may use exercise to intervene in order to beneficially impact key functional clinical outcomes.

Keywords: Cardiomyocyte; Diabetic cardiomyopathy; Exercise; GLUT4; Glucose.

Figure 1. Mechanisms of diabetic cardiomyopathy.

A range of contributory factors in the development of diabetic cardiomyopathy have been proposed. These include lipotoxicity, impaired insulin signalling, accumulation of advanced glycation end products, ER and oxidative stress. We focus on metabolic disturbance, specifically defects in the GLUT4 glucose transport system.

Figure 2. Trafficking of GLUT4 and CD36 in cardiomyocytes.

In the well-perfused healthy heart >95% of ATP is produced by oxidative phosphorylation and 60–90% of this is derived from metabolism of fatty acids which is the predominantly available substrate. The extraordinary high energetic demand of the heart is underpinned by an ability to adjust substrate preference to match the energetic demand with the levels of prevailing substrate in the circulation. The ability to ‘shift’ substrate preference is beneficial (Ritterhoff & Tian, 2017). For both fatty acids and glucose, flux analysis supports the contention that it is the delivery across the plasma membrane (PM) that controls the flux through the respective metabolic pathways. CD36 is a multifunctional protein which mediates ~70% of the uptake of fatty acids in cardiomyocytes. GLUT4 is the predominant glucose transporter in cardiomyocytes (Abel, 2004; Luiken et al., 2020). Both recycle between intracellular stores and the PM. In response to insulin or contraction, PM levels of CD36 and GLUT4 increase. (Note that different populations of intracellular GLUT4 are mobilised by insulin or contraction, but this is not shown here for simplicity). Once inside the cell, fatty acids are rapidly converted into fatty acyl CoA by fatty acyl CoA synthase which are then substrates for β-oxidation in mitochondria. Similarly, glucose is rapidly converted to glucose-6-phosphate and metabolised to pyruvate in the cytosol and then enters the TCA cycle. Reduced expression of the mitochondrial pyruvate carrier protein is associated with cardiac hypertrophy in human heart (Fernandez-Caggiano et al., 2020). Hence, cardiomyocyte metabolism is considered to be highly adaptive and tightly regulated by hormonal and contraction signals, coupling fuel use with available substrate and metabolic need.

Figure 3. Possible metabolic abnormalities leading to diastolic dysfunction.

Three possible mechanisms are discussed which may link impaired cardiomyocyte energy metabolism to diastolic dysfunction. These include changes in the balance of fuel use. Increased fatty acid transport and fatty acid cytosolic levels are associated with over-feeding and may lead to insulin resistance and starve the heart of the glucose that it needs to rapidly and efficiently generate the ATP that powers excitation contraction coupling. A high fat diet is known to increase cell surface CD36 levels and reduce levels of GLUT4 at the PM, giving rise to increased fatty acid metabolism and the accumulation of toxic lipid metabolites such as ceramide [1]. Impaired insulin signalling has also been posited as underlying diabetic cardiomyopathy [2]; ceramide is also known to inhibit insulin signalling pathways (see text). Although a relatively small contributor to total cardiac metabolism in the healthy heart (Ingwall, 2009; Ritterhoff & Tian, 2017), in this review, we focus on reduced glucose uptake and decreased levels of GLUT4 [3] as a key underpinning mechanism in diabetic cardiomyopathy and consider whether restoration of GLUT4 levels may be a useful therapeutic intervention.

Figure 4. Key mechanisms through which exercise may improve cardiac function in DCM.

Shown are several mechanisms through which exercise training may alleviate cardiac dysfunction associated with DCM. Firstly, exercise may normalise cardiac metabolism, which could directly enhance cardiac contractile function through increasing ATP availability. Similarly, exercise has been shown to alleviate impairments in cardiomyocyte calcium handling, which could directly enhance contractile function through more efficient use of ATP. It is unclear if these adaptive mechanisms occur independently or if there is a functional link. Finally, general global benefits of exercise training such as weight loss could reduce the burden on the diabetic heart, thus improving function. Please note that we have limited our discussion to what we consider to be key potential mechanisms; see main text for further details.