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

Farsad Afshinnia, Viji Nair, Jiahe Lin, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Kumar Sharma, Patrice E. Fort, Thomas W. Gardner, Helen C. Looker, Robert G. Nelson, Frank C. Brosius, Eva L. Feldman, George Michailidis, Matthias Kretzler, Subramaniam Pennathur

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65 Scopus citations


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. DKD 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-C20 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 (ACACA) 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 mitochondrial B-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.

Original languageEnglish (US)
Article numbere130317
JournalJCI Insight
Issue number21
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • General Medicine


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