D-Lactate and its related metabolic intermediates: Potential biomarkers for diabetic vascular complications

Micro- and macrovascular diseases are the main causes of mortality and morbidity among patients with Type 2 Diabetes Mellitus (DM2). Routine surveillance for vascular complications in these individuals is important to optimize their health outcomes. Endothelial dysfunction is one of the known root causes of micro- and macrovascular problems of all patients including diabetic patients, yet endothelial function is not directly tested in diabetic individuals. Intracellular Adhesion Molecule (ICAM), Vascular Adhesion Molecule (VCAM), and E-selectin are three important research biomarkers of endothelial function. D- and L-Lactate and methylglyoxal are three natural glucose metabolites and have known toxicity to the endothelium. We aimed to explore the correlation of these three key glucose metabolites in diabetic patients with the biomarkers of endothelial dysfunction to determine if glucose control is reflective of endothelial health. Metformin, a common oral diabetic medication, may increase D-lactate levels in serum and may directly damage endothelium, which was also explored in this study. The study involved an open label randomized design with four unique groups of participants. Two groups were patients with a DM2 diagnosis who either were prescribed metformin (DM2 plus MET) or were not treated with metformin (DM2 no MET). The remaining two control groups did not have DM2, but one group was prescribed metformin for unrelated indications (i.e. women with PCOS) (NonDM plus MET) and the other group was not prescribed metformin (NonDM no MET). Multiple fasting blood samples were collected from each individual over the 1-year study at the Royal University Hospital in Saskatoon. In total 76 persons participated in the study, 6 in DM2 plus MET, 1 in DM2 no MET, 39 in NonDM plus MET and 30 in NonDM no MET groups. In the non-DM2 groups, 35 of 39 participants were women treated for >6 months with metformin for polycystic ovarian syndrome (PCOS) and were originally recruited as part of another study. We hypothesized that the hyperglycemia associated with DM2 correlates with relatively high levels of glucose metabolites and endothelial damage markers. To test this correlation, fasting glucose, hemoglobin A1C, and fasting insulin levels of all participants were measured. All these measurements revealed that levels of these factors among diabetic patients are higher than non-diabetic patients consistent with their underlying hyperglycemia. The mean for fasting glucose levels was 9.4 mmol/L for diabetic participants and 5.0 mmol/L in non-diabetic participants over three independent testing times. The mean levels for HbA1C were 7.2% in the diabetic groups and 5.2% for non-diabetic participants (normal <7%). These findings revealed suboptimal long- (reflected by HbA1c) and short-term (fasting glucose) glucose control among diabetic participants. As predicted, the levels of three glucose metabolites, D-lactate, L-lactate, and methylglyoxal, were higher in the diabetic population than in non-diabetic participants. We did not detect D-lactate elevations above normal for any of our individual cases or in grouped analysis including those taking metformin. However, the mean D-lactate level in diabetic participants was significantly higher than non-diabetic participants (P-value <0.05), although still in the normal range and less than 0.5 nmol/µL. This important finding included our study group using metformin for diabetic control. This was one of the major concerns for metformin users and led us to formally assess this. The average L-lactate level in diabetic participants was significantly higher than in non-diabetic participants (P-value <0.05), yet the methylglyoxal level in diabetic participants was not statistically different from non-diabetic participants (P-value >0.05). Our fasting samples did not provide enough examples of hyperglycemia to conduct a comparison between the levels of D-lactate, L-lactate, and methylglyoxal among participants with high and normal levels of blood glucose. To address if the levels of the glucose metabolite, D-lactate, directly correlated with markers of endothelial damage, we explored the association of three endothelial biomarkers, ICAM, VCAM, and E-selectin with D-lactate levels. We detected a significant positive association between D-lactate and both ICAM and E-selectin (P-value <0.05), but not VCAM and D-lactate (P-value >0.05). This positive correlation of 2 out of 3 markers of endothelial dysfunction with D-lactate levels provides opportunity to consider D-lactate as a potential biomarker for endothelial dysfunction in diabetic patients. Measuring D-lactate needs simpler instruments and in general can improve access for monitoring cardiovascular consequences in DM2 patients. In addition, except for a few differential diagnoses, D-lactate may provide a reliable opportunity for identification of the cardiovascular consequences. A number of limitations existed in this study included the small number of recruited patients as the demographic and health-related differences of diabetic and non-diabetic patients, including sex, age, race, weight, and BMI all of which have the potential to affect the results of the study. All the NonDM plus MET group were women so that the sex was not equally represented and may impact the outcomes. Furthermore, we need to consider that the diabetic participants were much older than the control group which can influence the results. These exciting and novel results in our pilot study will require a larger study to confirm the generalizability of D-lactate as a potential biomarker of endothelial damage.

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