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    Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians

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    Name:
    130317.2-20191030092222-covere ...
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    Author
    Afshinnia, Farsad
    Nair, Viji
    Lin, Jiahe
    Rajendiran, Thekkelnaycke M
    Soni, Tanu
    Byun, Jaeman
    Sharma, Kumar
    Fort, Patrice E
    Gardner, Thomas W
    Looker, Helen C
    Nelson, Robert G
    Brosius, Frank C
    Feldman, Eva L
    Michailidis, George
    Kretzler, Matthias
    Pennathur, Subramaniam
    Show allShow less
    Affiliation
    Univ Arizona, Dept Med, Div Nephrol, Coll Med
    Issue Date
    2019-11-01
    Keywords
    Chronic kidney disease
    Diabetes
    Fatty acid oxidation
    Metabolism
    Nephrology
    
    Metadata
    Show full item record
    Publisher
    AMER SOC CLINICAL INVESTIGATION INC
    Citation
    JCI Insight. 2019; 4(21): e130317. https://doi.org/10.1172/jci.insight.130317.
    Journal
    JCI INSIGHT
    Rights
    Copyright © 2019, American Society for Clinical Investigation.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    BACKGROUND. In this study, we identified the lipidomic predictors of early type 2 diabetic kidney disease (DKD) progression, which are currently undefined. METHODS. This longitudinal study included 92 American Indians with type 2 diabetes. Serum lipids (406 from 18 classes) were quantified using mass spectrometry from baseline samples when iothalamate-based glomerular filtration rate (GFR) was at least 90 mL/min. Affymetrix GeneChip Array was used to measure renal transcript expression. DIM progression was defined as at least 40% decline in GFR during follow-up. RESULTS. Participants had a mean age of 45 +/- 9 years and median urine albumin/creatinine ratio of 43 (interquartile range 11-144). The 32 progressors had significantly higher relative abundance of polyunsaturated triacylglycerols (TAGs) and a lower abundance of C16-C 2 0 acylcarnitines (ACs) ( P< 0.001). In a Cox regression model, the main effect terms of unsaturated free fatty acids and phosphatidylethanolamines and the interaction terms of C16-C20 ACs and short-low-double-bond TAGs by categories of albuminuria independently predicted DKD progression. Renal expression of acetyl-CoA carboxylase-encoding gene (ACACIA) correlated with serum diacylglycerols in the glomerular compartment (r = 0.36, and P = 0.006) and with low-double-bond TAGs in the tubulointerstitial compartment (r = 0.52. and P < 0.001). CONCLUSION. Collectively, the findings reveal a previously unrecognized link between lipid markers of impaired mitochondria beta-oxidation and enhanced lipogenesis and DKD progression in individuals with preserved GFR. Renal acetyl-CoA carboxylase activation accompanies these lipidomic changes and suggests that it may be the underlying mechanism linking lipid abnormalities to DKD progression.
    ISSN
    2379-3708
    PubMed ID
    31573977
    DOI
    10.1172/jci.insight.130317
    Version
    Final published version
    Sponsors
    United States Department of Health & Human Services - National Institutes of Health (NIH) - USA [R24DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572]; Program for Neurology Research and Discovery at Michigan Medicine; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases - United States Department of Health & Human Services - National Institutes of Health (NIH) - National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
    ae974a485f413a2113503eed53cd6c53
    10.1172/jci.insight.130317
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