Glycolytic lactate in diabetic kidney disease
Manjula Darshi, Luxcia Kugathasan, Soumya Maity, Vikas S. Sridhar, Roman Fernandez, Christine P. Limonte, Brian Grajeda, Afaf Saliba, Guanshi Zhang, Viktor R. Drel, Jiwan Kim, Richard Montellano, Jana Tůmová, Daniel Montemayor, Zhu Wang, Jianjun Liu, Jiexun Wang, Bruce A. Perkins, Yuliya Lytvyn, Loki Natarajan, Su Chi Lim, Harold I. Feldman, Robert Toto, John R. Sedor, Jiten Patel, Sushrut S. Waikar, Julia Brown, YAHYA M. OSMAN, Jiang He, Jing Chen, William Reeves, Ian H. de Boer, Sourav Roy, Volker Vallon, Stein Hallan, Jonathan Gelfond, David Z.I. Cherney, Kumar Sharma, for the Kidney Precision Medicine Project, and the CRIC Study Investigators
Abstract
Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.