Article published by the Endocrine Society Article published by the Endocrine Society

(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.

Objective—: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). Approach and Results—: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides ( P <0.01) and 15% poorer in sphingosine-1-phosphate ( P <0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[ ³ H]arginine to L-[ ³ H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls ( P <0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% ( P <0.001) and 39% ( P <0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity ( P <0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 ( P <0.05) and in Akt phosphorylation at Ser473 ( P =0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity ( P =0.90) and phosphorylation at Ser1177 ( P =0.87). Conclusions—: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.

Alterations affecting high-density lipoproteins (HDLs) are one of the various abnormalities observed in dyslipidemia in type 2 diabetes mellitus (T2DM) and obesity. Kinetic studies have demonstrated that the catabolism of HDL particles is accelerated. Both the size and the lipidome and proteome of HDL particles are significantly modified, which likely contributes to some of the functional defects of HDLs. Studies on cholesterol efflux capacity have yielded heterogeneous results, ranging from a defect to an improvement. Several studies indicate that HDLs are less able to inhibit the nuclear factor kappa-B (NF-κB) proinflammatory pathway, and subsequently, the adhesion of monocytes on endothelium and their recruitment into the subendothelial space. In addition, the antioxidative function of HDL particles is diminished, thus facilitating the deleterious effects of oxidized low-density lipoproteins on vasculature. Lastly, the HDL-induced activation of endothelial nitric oxide synthase is less effective in T2DM and metabolic syndrome, contributing to several HDL functional defects, such as an impaired capacity to promote vasodilatation and endothelium repair, and difficulty counteracting the production of reactive oxygen species and inflammation.