Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c

Abstract

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.

Structure-function relationships of HDL in diabetes and coronary heart disease

“…Multivariate analysis based on PLS regression also unraveled the association of T2DM with the loss of very large HDL, but the association with a gain of small HDL was even stronger (Figure 3). These changes are probably caused by increased CETP activity (9)(10)(11). Opposite to T2DM, CHD is associated with the loss of small and medium-sized HDL and the gain of large HDL (Figure 3).…”

Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit

“…In contrast, HDL ability to protect LDL oxidation correlates positively with sphingosine-1-phosphate [42] and phosphatidylserine [124] levels. Interestingly, earlier studies have shown an inverse association between phosphatidylcholine-based readily-oxidizable polyunsaturated fatty acid content [125] and antioxidative activity of HDL [126] . Furthermore, such activity is negatively associated with the content of proinflammatory PLs commonly present in these particles, such as phosphatidic acid [127] , [128] , ceramide [124] , [126] and lysophosphatidylcholine [128] .…”

“…Interestingly, earlier studies have shown an inverse association between phosphatidylcholine-based readily-oxidizable polyunsaturated fatty acid content [125] and antioxidative activity of HDL [126] . Furthermore, such activity is negatively associated with the content of proinflammatory PLs commonly present in these particles, such as phosphatidic acid [127] , [128] , ceramide [124] , [126] and lysophosphatidylcholine [128] . Finally, both cholesteryl ester and triglyceride content have previously shown negative correlations with antioxidative activity of HDL [124] .…”

Diabetes and dyslipidemia: characterizing lipoprotein metabolism

“… 131 Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small dense HDL3. 132 Gomez Rosso et al 132 showed that defective functionality of small dense HDL particles was present in patients with type 2 diabetes mellitus with poor glycemic control. The HDL had also diminished its antioxidant ability.…”