Metabolic Profiling of Peripheral Blood Mononuclear Cells Respiration within High-Risk Prediabetes Clusters

Research question Reduced mitochondrial oxidative capacity has been associated with insulin resistance in diabetes. Peripheral blood mononuclear cells (pBMCs) offer a non-invasive means to assess mitochondrial function. This study investigates whether mitochondrial respiration in pBMCs differs between prediabetes clusters 5 and 6 and controls with normal glucose tolerance. These clusters, associated with elevated complications and mortality risks, differ in diabetes progression risk. Thus, exploring pBMC respiration as a potential early marker for patient stratification with respect to diabetes development.

Methodology Within the Heidelberg Diabetes Complications Study (HEIST-DIC ClinicalTrials.gov NCT0302272), 21 male participants were categorized into three groups: controls (n=8), prediabetes cluster 5 (n=6), and prediabetes cluster 6 (n=7) using the clustering tool at https://katsiaryna.shinyapps.io/clusters/. pBMCs were isolated via a blood density gradient and citric acid cycle (TCA)-linked respiration of pBMCs was measured using high-resolution respirometry (HRR). The O2 consumption rate was normalized to cell number and respiratory (RCR) and leak (LCR) control ratios were calculated as markers for mitochondrial coupling and proton leak, respectively.

Results In cluster 6, TCA-linked pBMC respiration, indicated by the O2 consumption rate AUC, was increased compared to both cluster 5 (1.3-fold, p<0.001) and controls (1.5-fold, p<0.0001). The RCR exhibited no significant differences, while the LCR increased by 1.1-fold in cluster 6 as compared to cluster 5 and controls (p<0.05). There were no significant differences with respect to age or BMI. However, clusters 5 and 6 showed a 1.5-fold increase in insulin AUC post-oral glucose tolerance test (OGTT) as compared to controls (p > 0.05). Only cluster 5 displayed a 1.5-fold increase in glucose AUC post-OGTT compared to controls (p<0.001). Whilst both clusters had elevating insulin levels, only cluster 6 maintained lower glucose levels after an OGTT.

Conclusion In both prediabetes clusters, only cluster 5 shows increased diabetes risk due to higher post-OGTT glucose levels and impaired insulin sensitivity compared to cluster 6. Cluster 6 exhibits elevated pBMC mitochondrial respiration, possibly due to enhanced substrate flux and insulin stimulation, but potentially leading to higher oxidative stress, supported by increased LCR. This heightened mitochondrial function in cluster 6 may stem from efficient glucose uptake and metabolism. Further experiments, including assessing reactive oxygen species production, are necessary to confirm this association. Exploring the correlation between pBMC respiration and that of glucose homeostasis-related tissues will deepen our understanding of metabolic dynamics.

 

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Interessenkonflikt

Authors have no conflict of interest to declare.

Publication History

Article published online:
18 April 2024