Diabetes mellitus (DM) is a primary metabolic disorder and the impact of this entity on maladaptive tissue and organ responses may be mediated through alter metabolomic profile and signatures at steady state or at stress. To this point of view Beckman et al. (Clin. Sci. (Lond.) (2020) 134, 2369–2379), in a hypothesis-generated study, investigated how metabolomic profile is affected following branchial artery ischemia. Interestingly, they found that there is a dynamic and altered change of metabolites associated with energy substrate and with glycolysis/glyconeogenesis in patients with DM. This evidence may shed light on the impaired muscle tolerance in subjects with DM and on impaired vasoreactivity. However, these data lack the ability to be conclusive and further steps should be explored to understand how metabolomic profile is implicated in the response of muscle tissue to ischemia and to the clinical profile of subjects with DM.
Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia and defect in metabolism of energy substrate—carbohydrate, fat and protein . Most organs and systems are affected including brain, heart, kidney, eyes, nervous system, liver, skin etc. In this morbid cycle, cardiovascular disease and accelerated atherosclerosis contribute the most to the diabetes-attributed mortality .
Atherosclerotic lesions and obstructive artery disease are the underlying pathophysiologic background of peripheral arterial disease (i.e. lower extremities artery disease, upper extremities artery disease, mesenteric artery disease, carotid and vertebral artery disease) and of coronary artery disease including heart failure of ischemic etiology . Abundance of data in DM subjects have documented the role of inflammatory and oxidative milieu on endothelial cell dysfunction, on accumulation and oxidation of lipoproteins, on macrophages chemotaxis and foam cells formation . At early stages of the disease course, endothelial dysfunction precedes atherosclerotic lesions. However, impaired vascular tone and smooth muscle cells response to stress and ischemia cannot fully be explained based on NO reduced bioavailability .
However, the impact of DM on cardiovascular diseases extends beyond accelerated atherosclerosis. Insulin resistance impairs the use of energy substrate by cardiac myocytes and prioritizes utilization of free fatty acid instead of glucose, adversely affecting cardiac contractility and diastolic function and leads to energetic insufficiency . Free fatty acid utilization affects production of mitochondrial uncoupling proteins and disrupts mitochondrial proton gradient and adenosine triphosphate (ATP) production .
Advanced glycation end products are linked to cardiac hypertrophy and fibrosis through up-regulation of hypertrophy associated genes . The role of phosphatidylinositol 3-kinases up-regulated by hyperglycemia may be also implicated in myocardial dysfunction . Furthermore, the so-called diabetic cardiomyopathy is an entity less well-defined with microvascular dysfunction only partially responsible for heart failure progression and functional deterioration . DM may also change the expression of calcium handling proteins in cardiomyocyte leading to intracellular decay of calcium impaired systolic function and left ventricle remodeling . Importantly, reduced functional capacity of DM subjects may be attributed to either impairment at the peripheral muscle level or at the cardiomyocyte level.
To this point of view changes in the metabolic profile at the vascular level may shed further light on the mechanism underlying vascular responses to stress and ischemia and a further step on the mechanisms involved on exercise impairment in subjects with DM. Evolvement on the field of metabolomics allowed the systematic study of the ‘fingerprints’ that variable cellular and biochemical processes leave under specific circumstances and may allow to further understand the biochemical and biological phenotype.
Accordingly, Beckman et al.  based on a rather small sample size, in a hypothesis generated study, investigated the metabolic profile and how this has affected following branchial artery ischemia. Firstly, they documented that subjects with DM have altered metabolic profile compared with healthy subjects especially concerning homocysteine and cardiometabolic parameters (β-alanine, glyconic acid, dimethylguanidin, valeric acid etc.).
In the second step, they studied the metabolomic profile immediately and at 1 min after ischemia release. Interestingly, there was a dynamic change. Metabolites associated with glycolysis/glyconeogenesis (pyruvic acid, lactic acid and sugar) were changed immediately after ischemia release in patients with DM and returned to baseline levels 1 min after. These data may support the hypothesis that inappropriate metabolism and handling of energy substrate in patients with DM significantly affect the skeletal muscle vasculature and may shed light on the underlying pathology of reduced exercise capacity in this population.
Additive to these observations, they found association between baseline metabolomic profile and metabolites levels post-ischemia in patients with DM although there was no such correlation in healthy subjects. These data may support the hypothesis that altered metabolism under pathologic conditions is responsible for impaired muscle tolerance and adjustment to ischemia and finally for the functional impairment. However, it is rather unexplained why in healthy subjects there was no correlation between baseline and post-ischemia metabolites’ signatures.
Interestingly, they also documented an association between altered response of muscle metabolic profile following ischemia with impaired flow-mediated dilation and endothelial function providing further links to the mechanism underlying accelerated atherosclerosis in subjects with DM. However, the only metabolite (phosphocholine) found associated with endothelial-dependent vasodilation in both, healthy subjects, and subjects with DM, was correlated in an opposite direction (positive vs. negative) in the two studied groups raising further questions on the role of metabolomic profile in vascular wall properties.
Unequivocally, the study by Beckman et al. can be considered as only hypothesis generated . It may provide evidence on the altered metabolism and response to ischemia in subjects with DM. Unfortunately, the design of the study does not allow cause–and–effect relationships and even more multiple comparisons weaken statistical significance. Indeed, unanswered questions merit further research (Figure 1). Firstly, is there a straightforward link of altered muscle metabolism with vascular function and what is the role of oxidative milieu on vascular smooth muscle cells properties. Secondly, how repetitive cycles of ischemia and dysfunctional metabolism may affect peripheral muscle function similar to hibernating myocardium. How altered metabolism of cardiac myocytes may lead microvascular coronary changes and diabetic cardiomyopathy in subjects with DM. What are our efforts to restore metabolic imbalance in subjects with DM and how this procedure may beneficially affect prognosis and symptoms of DM patients?
Schematic representation of the altered muscle metabolism in subjects with DM with possible direct and indirect effects
Although our knowledge on the complicated mechanism underlying the systematic course of DM has been amplified recently, several steps should be further taken to target the whole syndrome and especially the cardiovascular impairment associated with this metabolic disorder.
The authors declare that there are no competing interests associated with the manuscript.