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 β-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.