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Sulaj, A.* ; Nguyen, B.H.P. ; Poschet, G.* ; Kliemank, E.* ; Fleming, T.* ; Henke, L.* ; Neibig, W.* ; Kopf, S.* ; Hell, R.* ; Longo, V.D.* ; Herzig, S. ; Nawroth, P.P. ; Menden, M.P. ; Szendroedi, J.

Periodic fasting induced reconstitution of metabolic flexibility improves albuminuria in patients with type 2 diabetes.

Mol. Metab. 102:102257 (2025)

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OBJECTIVE: Metabolic inflexibility has been shown to be associated with type 2 diabetes (T2D) and diabetic nephropathy (DN). However, data are lacking, proving that reconstitution of metabolic flexibility by using a 6-month periodic fasting (PF) regimen may improve albuminuria. RESEARCH DESIGN AND METHODS: In this post hoc analysis of a randomized-controlled trial, we investigated whether the PF regimen enhanced metabolic flexibility in individuals with T2D and DN showing improvement of albuminuria (responders) compared to non-responders. Participants followed every month either a 5-day fasting-mimicking diet or a Mediterranean diet for 6 months. LC-MS/MS-based comprehensive metabolic profiling was performed in plasma samples before, during, and after the intervention. Changes in metabolomic patterns and enriched signalling pathways were analysed between study groups. RESULTS: PF induced a sustained shift toward enhanced fatty acid oxidation, lipid utilization, and amino acids turnover, particularly in responders. Responders exhibited persistent elevations in short-chain acylcarnitines and cholesteryl esters, indicating more efficient lipid oxidation and tighter integration of lipid metabolism with the tricarboxylic acid cycle. Increased glycine and serine levels suggested enhanced cellular maintenance, a protein-sparing effect, and a metabolic shift favouring lipid over carbohydrate. In contrast, non-responders demonstrated only transient and limited metabolic shifts. Unsupervised clustering identified distinct metabolic response patterns, reinforcing the potential of personalized dietary interventions. CONCLUSIONS: These findings demonstrate that diet-induced restoration of metabolic flexibility is associated with improved albuminuria in T2D, suggesting broader implications for precise nutritional strategies in diabetes management.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Albuminuria ; Metabolic Flexibility ; Periodic Fasting ; Type 2 Diabetes; Glycine Metabolism; Insulin-resistance; Nephropathy; Progression; Mechanisms; Expression; Subgroups; Nutrition; Disease; Risk

ISSN (print) / ISBN 2212-8778

e-ISSN 2212-8778

Journal Molecular Metabolism

Quellenangaben Volume: 102, Article Number: 102257

Publisher Elsevier

Publishing Place Amsterdam

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Computational Biology (ICB)

Grants Olympia Morata funding program of the Medical Faculty Heidelberg
(German Diabetes Society)
Deutsche Diabetes Gesellschaft
German Center for Diabetes Research)
Deutsches Zentrum fr Diabetesforschung (DZD