Glycolytic lactate in diabetic kidney disease
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 eu...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/179738 |
| _version_ | 1811684768929021952 |
|---|---|
| author | Darshi, Manjula Kugathasan, Luxcia Maity, Soumya Sridhar, Vikas S. Fernandez, Roman Limonte, Christine P. Grajeda, Brian I. Saliba, Afaf Zhang, Guanshi Drel, Viktor R. Kim, Jiwan J. Montellano, Richard Tumova, Jana Montemayor, Daniel Wang, Zhu Liu, Jian-Jun Wang, Jiexun Perkins, Bruce A. Lytvyn, Yuliya Natarajan, Loki Lim, Su Chi Feldman, Harold Toto, Robert Sedor, John R. Patel, Jiten Waikar, Sushrut S. Brown, Julia Osman, Yahya He, Jiang Chen, Jing Reeves, W. Brian de Boer, Ian H. Roy, Sourav Vallon, Volker Hallan, Stein Gelfond, Jonathan A. L. Cherney, David Zi Sharma, Kumar |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Darshi, Manjula Kugathasan, Luxcia Maity, Soumya Sridhar, Vikas S. Fernandez, Roman Limonte, Christine P. Grajeda, Brian I. Saliba, Afaf Zhang, Guanshi Drel, Viktor R. Kim, Jiwan J. Montellano, Richard Tumova, Jana Montemayor, Daniel Wang, Zhu Liu, Jian-Jun Wang, Jiexun Perkins, Bruce A. Lytvyn, Yuliya Natarajan, Loki Lim, Su Chi Feldman, Harold Toto, Robert Sedor, John R. Patel, Jiten Waikar, Sushrut S. Brown, Julia Osman, Yahya He, Jiang Chen, Jing Reeves, W. Brian de Boer, Ian H. Roy, Sourav Vallon, Volker Hallan, Stein Gelfond, Jonathan A. L. Cherney, David Zi Sharma, Kumar |
| author_sort | Darshi, Manjula |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:33:53Z |
| format | Journal Article |
| id | ntu-10356/179738 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:33:53Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1797382024-08-25T15:38:06Z Glycolytic lactate in diabetic kidney disease Darshi, Manjula Kugathasan, Luxcia Maity, Soumya Sridhar, Vikas S. Fernandez, Roman Limonte, Christine P. Grajeda, Brian I. Saliba, Afaf Zhang, Guanshi Drel, Viktor R. Kim, Jiwan J. Montellano, Richard Tumova, Jana Montemayor, Daniel Wang, Zhu Liu, Jian-Jun Wang, Jiexun Perkins, Bruce A. Lytvyn, Yuliya Natarajan, Loki Lim, Su Chi Feldman, Harold Toto, Robert Sedor, John R. Patel, Jiten Waikar, Sushrut S. Brown, Julia Osman, Yahya He, Jiang Chen, Jing Reeves, W. Brian de Boer, Ian H. Roy, Sourav Vallon, Volker Hallan, Stein Gelfond, Jonathan A. L. Cherney, David Zi Sharma, Kumar Lee Kong Chian School of Medicine (LKCMedicine) Khoo Teck Puat Hospital Saw Swee Hock School of Public Heath, NUS Medicine, Health and Life Sciences Diabetic nephropathy Glucose intake 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. National Medical Research Council (NMRC) Published version See Supplemental Acknowledgments for CRIC study investigators and KPMP collaborators details. The author’s work was supported by NIH RO1DK112042, R01DK106102, R01HL142814, RF1AG061296, and O’Brien Center for Acute Kidney Injury Research Grant P30DK079337 (VV); Singapore Alexandra Health Fund Research Program (JW); STAR grant 20201 (JJL); Singapore NMRC MOH-000066, 0000714, and OFLCG/001/2017 (SCL); and NIH DP3DK094352, RO1DK110541, and JDRF (MD, DM, VRD, JJK, RM, LN, and KS). The KPMP (www.kpmp.org) is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937 (KS, SSW, CL, MD, GZ, RT, JRS, and IHDB). KS is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (2U01DK114920-06), a Veterans Affairs Merit Award (2I01BX001340-09A1), and a subaward from the National Heart, Lung, and Blood Institute via New York University and a NIH Small Business Innovation Research subaward to SygnaMap (1R43DK130732-01A1). DZIC is supported by a Department of Medicine and the University of Toronto Merit Award and receives support from the Canadian Institutes of Health Research, Diabetes Canada, and the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research. DZIC is also the recipient of a 5-year CIHR-Kidney Foundation of Canada Team Grant award. 2024-08-20T02:40:54Z 2024-08-20T02:40:54Z 2024 Journal Article Darshi, M., Kugathasan, L., Maity, S., Sridhar, V. S., Fernandez, R., Limonte, C. P., Grajeda, B. I., Saliba, A., Zhang, G., Drel, V. R., Kim, J. J., Montellano, R., Tumova, J., Montemayor, D., Wang, Z., Liu, J., Wang, J., Perkins, B. A., Lytvyn, Y., ...Sharma, K. (2024). Glycolytic lactate in diabetic kidney disease. JCI Insight, 9(11), 168825-. https://dx.doi.org/10.1172/jci.insight.168825 2379-3708 https://hdl.handle.net/10356/179738 10.1172/jci.insight.168825 38855868 2-s2.0-85195628996 11 9 168825 en MOH-000066 MOH-0000714 OFLCG/001/2017 JCI Insight © 2024, Darshi et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Diabetic nephropathy Glucose intake Darshi, Manjula Kugathasan, Luxcia Maity, Soumya Sridhar, Vikas S. Fernandez, Roman Limonte, Christine P. Grajeda, Brian I. Saliba, Afaf Zhang, Guanshi Drel, Viktor R. Kim, Jiwan J. Montellano, Richard Tumova, Jana Montemayor, Daniel Wang, Zhu Liu, Jian-Jun Wang, Jiexun Perkins, Bruce A. Lytvyn, Yuliya Natarajan, Loki Lim, Su Chi Feldman, Harold Toto, Robert Sedor, John R. Patel, Jiten Waikar, Sushrut S. Brown, Julia Osman, Yahya He, Jiang Chen, Jing Reeves, W. Brian de Boer, Ian H. Roy, Sourav Vallon, Volker Hallan, Stein Gelfond, Jonathan A. L. Cherney, David Zi Sharma, Kumar Glycolytic lactate in diabetic kidney disease |
| title | Glycolytic lactate in diabetic kidney disease |
| title_full | Glycolytic lactate in diabetic kidney disease |
| title_fullStr | Glycolytic lactate in diabetic kidney disease |
| title_full_unstemmed | Glycolytic lactate in diabetic kidney disease |
| title_short | Glycolytic lactate in diabetic kidney disease |
| title_sort | glycolytic lactate in diabetic kidney disease |
| topic | Medicine, Health and Life Sciences Diabetic nephropathy Glucose intake |
| url | https://hdl.handle.net/10356/179738 |
| work_keys_str_mv | AT darshimanjula glycolyticlactateindiabetickidneydisease AT kugathasanluxcia glycolyticlactateindiabetickidneydisease AT maitysoumya glycolyticlactateindiabetickidneydisease AT sridharvikass glycolyticlactateindiabetickidneydisease AT fernandezroman glycolyticlactateindiabetickidneydisease AT limontechristinep glycolyticlactateindiabetickidneydisease AT grajedabriani glycolyticlactateindiabetickidneydisease AT salibaafaf glycolyticlactateindiabetickidneydisease AT zhangguanshi glycolyticlactateindiabetickidneydisease AT drelviktorr glycolyticlactateindiabetickidneydisease AT kimjiwanj glycolyticlactateindiabetickidneydisease AT montellanorichard glycolyticlactateindiabetickidneydisease AT tumovajana glycolyticlactateindiabetickidneydisease AT montemayordaniel glycolyticlactateindiabetickidneydisease AT wangzhu glycolyticlactateindiabetickidneydisease AT liujianjun glycolyticlactateindiabetickidneydisease AT wangjiexun glycolyticlactateindiabetickidneydisease AT perkinsbrucea glycolyticlactateindiabetickidneydisease AT lytvynyuliya glycolyticlactateindiabetickidneydisease AT natarajanloki glycolyticlactateindiabetickidneydisease AT limsuchi glycolyticlactateindiabetickidneydisease AT feldmanharold glycolyticlactateindiabetickidneydisease AT totorobert glycolyticlactateindiabetickidneydisease AT sedorjohnr glycolyticlactateindiabetickidneydisease AT pateljiten glycolyticlactateindiabetickidneydisease AT waikarsushruts glycolyticlactateindiabetickidneydisease AT brownjulia glycolyticlactateindiabetickidneydisease AT osmanyahya glycolyticlactateindiabetickidneydisease AT hejiang glycolyticlactateindiabetickidneydisease AT chenjing glycolyticlactateindiabetickidneydisease AT reeveswbrian glycolyticlactateindiabetickidneydisease AT deboerianh glycolyticlactateindiabetickidneydisease AT roysourav glycolyticlactateindiabetickidneydisease AT vallonvolker glycolyticlactateindiabetickidneydisease AT hallanstein glycolyticlactateindiabetickidneydisease AT gelfondjonathanal glycolyticlactateindiabetickidneydisease AT cherneydavidzi glycolyticlactateindiabetickidneydisease AT sharmakumar glycolyticlactateindiabetickidneydisease |