Chronic kidney disease is associated with attenuated plasma metabolome response to oral glucose tolerance testing

Authors: AHMADI, ARMIN - University Of California, Davis; HUDA, M. NAZMUL - University Of California, Davis; Bennett, Brian; GAMBOA, JORGE - Vanderbilt University; ZELNICK, LEILA - University Of Washington; SMITH, LUCAS - University Of California, Davis; CHONDRONIKOLA, MARIA - University Of California, Davis; RAFTERY, DANIEL - University Of Washington; DE BOER, IAN - Puget Sound Institute; ROSHANRVAN, BABACK - University Of California, Davis

Submitted to: Journal of Renal Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2022
Publication Date: 10/18/2022
Citation: Ahmadi, A., Huda, M., Bennett, B.J., Gamboa, J., Zelnick, L., Smith, L.R., Chondronikola, M., Raftery, D., de Boer, I.H., Roshanrvan, B. 2022. Chronic kidney disease is associated with attenuated plasma metabolome response to oral glucose tolerance testing. Journal of Renal Nutrition. 33(2):316-325. https://doi.org/10.1053/j.jrn.2022.09.013.
DOI: https://doi.org/10.1053/j.jrn.2022.09.013

Interpretive Summary: Chronic kidney disease (CKD) is a major public health problem. In this study, we performed targeted metabolomics analysis of blood samples obtained from 41 moderate-to-severe non-diabetic CKD patients and 20 healthy controls before and after 2h of 75g oral glucose load (OGTT). Compared to controls, participants with CKD had higher Lactate: Pyruvate ratio both at fasting and after the oral glucose challenge. Total energy production was impaired in CKD patients. Moreover, CKD patients had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to a glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients.

Technical Abstract: Chronic kidney disease (CKD) is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of the response to oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. Using targeted metabolic profiling, we examined plasma metabolome in 41 moderate-to-severe non-diabetic CKD patients with estimated glomerular filtration rate (eGFR)<60ml/min per 1.73m2 (38.9±12.7) and 20 healthy controls with normal eGFR (87.2±17.7) before and after 2h of 75g oral glucose load. Compared to controls, participants with CKD had higher Lactate: Pyruvate ratio both at fasting and after oral glucose challenge. Total energy production estimated through GTP:GDP ratio was impaired during OGTT despite similar fasting GTP:GDP ratio. CKD group had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into the incretin response in patients with CKD and the impact of incretin mimetics on energy metabolism.