Stable Isotope Resolved Mass Spectrometry in Individuals with Type 1 Diabetes Reveals that Diminished Renal Mitochondrial Function Precedes Clinical Diabetic Kidney Disease
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Baek, Judy J., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- He, Chenchen, Agilent Technologies Inc, Santa Clara, California, United States
- Ang, Lynn, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Pop-Busui, Rodica, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Pennathur, Subramaniam, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
Significant metabolic reprogramming occurs in diabetic kidney disease (DKD). Metabolomics studies of murine models of DKD demonstrate increased glucose metabolism and urinary and kidney lactate production. However, whether such changes occur in individuals with type 1 diabetes (T1D), and the temporal nature of such reprograming with respect to clinical DKD has not been systematically investigated. Stable isotope resolved mass spectrometry using [U-C13] glucose allows dynamic measurement and tracing of relevant glucose-derived metabolic pathways. We performed glycemic clamp study with [U-C13] glucose to evaluate how kidney metabolism is altered in T1D.
Euglycemic-hyperglycemic clamp studies with [U-13C] glucose were conducted in matched healthy control (HC), and in T1D individuals with established early DKD, and without clinical microvascular complications. All groups had similar estimated glomerular filtration rates (eGFR, CKD-EPI equation). Urine and plasma were collected throughout the course of the clamp study. Blood glucose levels were maintained at 100 mg/dl (±20) for the euglycemic clamp and 300 mg/dl (±20) for the hyperglycemic clamp arms of the study. Urine was analyzed with LC-MS for labeled urinary metabolites which reflect kidney metabolism.
Urinary metabolites in the glycolytic and TCA cycle (mitochondrial) were detected in all three groups. Analysis of the TCA cycle metabolite isotopologues (malate, fumarate and α-ketoglutarate) under hyperglycemic clamp demonstrated significantly increased labeled glucose incorporation into the HC urine in comparison to T1D individuals with and without DKD. Incorporation into citrate and cis-aconitate were significantly elevated in the HC group only versus T1D DKD group.
These metabolic flux labeling studies suggest that T1D results in diminished kidney mitochondrial metabolism, compared to HC under hyperglycemic conditions. This difference was even more pronounced between HC and T1D with DKD. Our data strongly suggests that metabolic changes occur in T1D that results in reduced glucose mitochondrial metabolism, even prior to clinical DKD.
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