The metabolome as a diagnostic for maximal aerobic capacity during exercise in type 1 diabetes

Our aim was to characterise the in-depth metabolic response to aerobic exercise and the impact of residual pancreatic beta cell function in type 1 diabetes. We also aimed to use the metabolome to distinguish individuals with type 1 diabetes with reduced maximal aerobic capacity in exercise defined by \(\dot{V}{\text{O}}_{\text{2peak}}\).

Thirty participants with type 1 diabetes (≥3 years duration) and 30 control participants were recruited. Groups did not differ in age or sex. After quantification of peak stimulated C-peptide, participants were categorised into those with undetectable (<3 pmol/l), low (3–200 pmol/l) or high (>200 pmol/l) residual beta cell function. Maximal aerobic capacity was assessed by \(\dot{V}{\text{O}}_{\text{2peak}}\) test and did not differ between control and type 1 diabetes groups. All participants completed 45 min of incline treadmill walking (60% \(\dot{V}{\text{O}}_{\text{2peak}}\)) with venous blood taken prior to exercise, immediately post exercise and after 60 min recovery. Serum was analysed using targeted metabolomics. Metabolomic data were analysed by multivariate statistics to define the metabolic phenotype of exercise in type 1 diabetes. Receiver operating characteristic (ROC) curves were used to identify circulating metabolomic markers of maximal aerobic capacity (\(\dot{V}{\text{O}}_{\text{2peak}}\)) during exercise in health and type 1 diabetes.

Maximal aerobic capacity (\(\dot{V}{\text{O}}_{\text{2peak}}\)) inversely correlated with HbA_1c in the type 1 diabetes group (r²=0.17, p=0.024). Higher resting serum tricarboxylic acid cycle metabolites malic acid (fold change 1.4, p=0.001) and lactate (fold change 1.22, p=1.23×10⁻⁵) differentiated people with type 1 diabetes. Higher serum acylcarnitines (AC) (AC C14:1, F value=12.25, p=0.001345; AC C12, F value=11.055, p=0.0018) were unique to the metabolic response to exercise in people with type 1 diabetes. C-peptide status differentially affected metabolic responses in serum ACs during exercise (AC C18:1, leverage 0.066; squared prediction error 3.07). The malic acid/pyruvate ratio in rested serum was diagnostic for maximal aerobic capacity (\(\dot{V}{\text{O}}_{\text{2peak}}\)) in people with type 1 diabetes (ROC curve AUC 0.867 [95% CI 0.716, 0.956]).

The serum metabolome distinguishes high and low maximal aerobic capacity and has diagnostic potential for facilitating personalised medicine approaches to manage aerobic exercise and fitness in type 1 diabetes.