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.