Albuminuria, the HDL Proteome, and Coronary Artery Calcification in Type 1 Diabetes: the DCCT/EDIC Study

Abstract

Objective –

Albuminuria is an important risk factor for cardiovascular disease in diabetes. We determined whether albuminuria associates with alterations in the proteome of HDL of subjects with type 1 diabetes mellitus (T1DM), and whether those alterations associated with coronary artery calcification (CAC).

Approach and Results –

In a cross-sectional study of 191 subjects enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), we used isotope dilution tandem-mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that eight proteins associated with albuminuria. Two of those proteins, α−1-microglobulin/bikunin precursor (AMBP) and prostaglandin-H2 D-isomerase (PTGDS), strongly and positively associated with the albumin excretion rate ( P<10 ⁻⁶). Furthermore, paraoxonase 1 (PON1) and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (0.43–0.92, 95% CI, P=0.018) for PON1 and 0.59 (0.40–0.87, 95% CI, P=0.0079) for PON3. Only one protein, PON1, associated with both albumin excretion rate and CAC.

Conclusions –

Our observations indicate that the HDL proteome is remodeled in T1DM subjects with albuminuria. Moreover, low concentrations of the anti-atherosclerotic protein PON1 in HDL associated with both albuminuria and CAC, raising the possibility that alterations in HDL’s protein cargo mediate in part the known association of albuminuria with cardiovascular risk in T1DM.

Graphical Abstract