Aim:
One of the hallmarks of diabetes is impaired endothelial function. High density lipoproteins (HDL) can exert protective effects on endothelium stimulating NO production and protecting from inflammation. Previous study suggested that HDL in obese people with diabetes and metabolic syndrome and markedly low HDL-C lost endothelial protective function. We aimed to test whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile.
Methods:
In a case-control study (n=40 per group) nested in the Cooper Center Longitudinal Study, we isolated HDL and measured its ability to stimulate activity of endothelial nitric oxide synthase (eNOS; phosphorylation of Ser1177) in endothelial cells and the ability of HDL to suppress inflammatory response of endothelial cells (NFkB activation). Additionally, we also measured by LCMS levels of sphingosine-1-phosphate (S1P) and plasma P-selectin by ELISA.
Results:
The HDL in people with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress inflammation in endothelial cells (
P
<0.001) compared to non-diabetic controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG).The ability of HDL to stimulate eNOS activity was negatively associated with plasma levels of P-selectin, an established marker of endothelial dysfunction (r=–0.32,
P
<0.001). Furthermore, sphingosine-1-phosphate (S1P) levels were decreased in plasma of people with diabetes (
P
=0.017) and correlated strongly with HDL-mediated eNOS activation.
Conclusions:
Collectively, our data suggest that HDL in individuals with type 2 diabetes loses its ability to maintain proper endothelial function independent of HDL-C, perhaps due to loss of S1P, and may contribute to development of diabetic complications.
Possible role of protein phosphorylation in the mitogenic effect of high density lipoproteins on cultured vascular endothelial cells.
