Research Article: Type 2 diabetes is associated with loss of HDL endothelium protective functions

Date Published: March 15, 2018

Publisher: Public Library of Science

Author(s): Tomáš Vaisar, Erica Couzens, Arnold Hwang, Michael Russell, Carolyn E. Barlow, Laura F. DeFina, Andrew N. Hoofnagle, Francis Kim, Christina A. Bursill.


One of the hallmarks of diabetes is impaired endothelial function. Previous studies showed that HDL can exert protective effects on endothelium stimulating NO production and protecting from inflammation and suggested that HDL in obese people with diabetes and dyslipidemia may have lower endothelial protective function. We aimed to investigate whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile.

In a case-control study (n = 41 per group) nested in the Cooper Center Longitudinal Study we tested the ability of HDL to protect endothelium by stimulating endothelial nitric oxide synthase activity and suppressing NFκB-mediated inflammatory response in endothelial cells. In parallel we measured HDL protein composition, sphinogosine-1-phosphate and P-selectin.

Despite similar levels of plasma HDL-C the HDL in individuals with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress TNFα-dependent NFκB-mediated inflammatory response in endothelial cells (P<0.001) compared to non-T2D controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG). Significantly, 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 diabetic plasma (P = 0.017) and correlated with HDL-mediated eNOS activation. 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.

Partial Text

Although dyslipidemia characterized by high triglycerides and low levels of HDL-cholesterol (HDL-C) is a hallmark of diabetes, mounting evidence supports the idea that HDL function rather than HDL-C concentration is the relevant measure of HDL protective properties. Three studies have demonstrated that HDL cholesterol efflux capacity (CEC), the ability to accept cholesterol from lipid-loaded macrophages, is impaired in people with cardiovascular disease and is inversely related to risk of CVD.[1–3] In addition to the reverse cholesterol transport from peripheral tissues, several other biological functions of HDL have been identified by which HDL exerts protective effects on endothelial function: namely its ability to reduce inflammation, apoptosis, and thrombosis.[4–6] In healthy individuals, HDL is anti-inflammatory; however, in chronic illnesses characterized by systemic inflammation, such as diabetes, HDL may become “dysfunctional” and actually promote inflammatory responses.[7, 8]

All subjects in the present study were moderately overweight (BMI>25, mean BMI 29.3±4.6 kg/m2). Consistent with their diabetes diagnosis, the subjects in the diabetic group had modest but significantly higher blood glucose and glycated hemoglobin A1c levels (Table 1). There were no differences between control and diabetic groups in any of the plasma lipids measures including HDL-C, LDL-C and triglycerides, as well as in blood pressure, or systemic measure of inflammation (hsCRP). Clinical and demographic characteristics of the study population are presented in the Table 1.

In the present study of community dwelling patients with T2D and normal lipid profiles, we found that diabetes significantly impaired HDL endothelial protective functions, as measured by ability of HDL to stimulate eNOS and attenuate NF-κB activation in response to TNFα, despite lack of differences, compared to non-diabetic subjects, in traditional clinical measures associated with metabolic syndrome and cardiovascular risk (HDL-C, TG, LDL-C, BMI, hypertension or CRP). Moreover, our results strongly suggest that in vivo endothelial dysfunction may be associated with the observed HDL dysfunction and that this HDL dysfunction is not associated with level of glycemic control. Collectively, our data indicate that the ability of HDL to maintain endothelial health is impaired in T2D and may contribute the endothelial dysfunction associated with T2D.

In summary, our study provided strong evidence suggesting that type 2 diabetes impairs HDL-mediated eNOS activation and HDL-mediated attenuation of NFκB signaling in endothelial cells and that this HDL dysfunction may be associated with in vivo endothelial dysfunction. This HDL dysfunction appears to be independent of plasma lipids (HDL-C, TG, LDL-C) or other risk factors associated with endothelial dysfunction (i.e. BMI or central obesity). These findings suggest that loss of HDL endothelial protective functions may contribute to increased risk of CVD in diabetes. Our findings also suggest that these HDL functions might be target for development new therapeutics for CVD.




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