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JCI Insight. 2019 Oct 1. pii: 130317. doi: 10.1172/jci.insight.130317. [Epub ahead of print]

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

Abstract

BACKGROUND:

In this study, we aimed to identify the lipidomic predictors of early type-2 diabetic kidney disease (DKD) progression which are currently undefined DKD progression.

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 glomerular filtration rate (GFR) was ≥90 mL/min. Affymetrix GeneChip Array was used to measure renal transcript expression. DKD Progression was defined as ≥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 to 144). The 32 progressors had significantly higher relative abundance of polyunsaturated triacylglycerols (TAG)s and a lower abundance of C16-20 acylcarnitines (AC)s (p<0.001). In a Cox regression model the main effect terms of unsaturated free fatty acids and phosphatidylethanolamines and the interaction terms of C16-20 ACs and short, low-double-bond TAGs by categories of albuminuria independently predicted progression of DKD. Renal expression of acetyl-CoA carboxylase encoding gene (ACACA) correlated with serum diacylglycerols in the glomerular compartment (r=0.36, p=0.006), and with low-double-bond TAGs in the tubulointerstitial compartment (r=0.52, p<0.001).

CONCLUSION:

Collectively, the findings reveal a previously unrecognized link between lipid markers of impaired mitochondrial β-oxidation and enhanced lipogenesis, with 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.

FUNDING:

R24DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572.

KEYWORDS:

Chronic kidney disease; Diabetes; Fatty acid oxidation; Metabolism; Nephrology

PMID:
31573977
DOI:
10.1172/jci.insight.130317
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