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Glucose load following prolonged fasting increases oxidative stress-linked response in individuals with diabetic complications.

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posted on 2024-06-21, 17:21 authored by Ekaterina von Rauchhaupt, Claus Rodemer, Elisabeth Kliemank, Ruben Bulkescher, Marta Campos, Stefan Kopf, Thomas Fleming, Stephan Herzig, Peter P Nawroth, Julia Szendroedi, Johanna Zemva, Alba Sulaj

Objective: Prolonged catabolic states in type 2 diabetes (T2D), exacerbated by excess substrate flux and hyperglycaemia, can challenge metabolic flexibility and antioxidative capacity. We investigated cellular responses to glucose load after prolonged fasting in T2D.

Research Design and Methods: Glucose-tolerant individuals (CON, n=10), T2D individuals with (T2D+, n=10) and without diabetic complications (T2D-, n=10) underwent oral glucose tolerance test before and after a 5-day fasting-mimicking diet. Peripheral blood mononuclear cells’ (PBMC) resistance to ex-vivo dicarbonyl methylglyoxal (MG) exposure after glucose load was assessed. Markers of dicarbonyl detoxification, oxidative stress, and mitochondrial biogenesis were analyzed by qPCR, with mitochondrial complex protein expression assessed by western blotting.

Results: T2D+ exhibited decreased PBMC resistance against MG, while T2D- resistance remained unchanged, and CON improved post-glucose load and fasting (-19.0% vs. -1.7% vs. 12.6%; all P=0.017). T2D+ showed increased expression in dicarbonyl detoxification (mRNA glyoxalase-1, all P=0.039), oxidative stress (mRNA glutathione-disulfide-reductase, all P=0.006) and mitochondrial complex V protein (all P=0.004) compared to T2D- and CON post-glucose load and fasting. Citrate synthase activity remained unchanged, indicating no change in mitochondrial number. Mitochondrial biogenesis increased in T2D- compared to CON post-glucose load and fasting (mRNA HspA9, P=0.032). T2D- compared to CON, exhibited increased oxidative stress post-fasting, but not post-glucose load, with increased mRNA expression in antioxidant defences (mRNA forkhead-box-O4, P=0.036, and glutathione-peroxidase-2, P=0.034), and compared to T2D+ (glutathione-peroxidase-2, P=0.04).

Conclusions: These findings suggest increased susceptibility to glucose-induced oxidative stress in individuals with diabetic complications after prolonged fasting and might help in diet interventions for diabetes management.

Funding

This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; project number 236360313–SFB 1118). E.R. was supported by the Friedrich-Fischer-Estate. J.Z. was supported by the Olympia Morata funding program of the Medical Faculty Heidelberg. A.S was supported by the Deutsches Zentrum für Diabetesforschung (DZD; German Center for Diabetes Research; project number 82DZD07C2G), by the Deutsche Diabetes Gesellschaft (DDG, German Diabetes Society) and by the Olympia Morata funding program of the Medical Faculty Heidelberg.

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