The anti-inflammatory function of HDL is impaired in type 2 diabetes: role of hyperglycemia, paraoxonase-1 and low grade inflammation

Abstract

BackgroundFunctional properties of high density lipoproteins (HDL) are increasingly recognized to play a physiological role in atheroprotection. Type 2 diabetes mellitus (T2DM) is characterized by low HDL cholesterol, but the effect of chronic hyperglycemia on the anti-inflammatory capacity of HDL, a metric of HDL function, is unclear. Therefore, the aim of the present study was to establish the impact of T2DM on the HDL anti-inflammatory capacity, taking paraoxonase-1 (PON-1) activity and low grade inflammation into account.MethodsThe HDL anti-inflammatory capacity, determined as the ability to suppress tumor necrosis factor-α (TNF-α) induced vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in endothelial cells in vitro (higher values indicate lower anti-inflammatory capacity), PON-1 (arylesterase) activity, hs-C-reactive protein (hs-CRP), serum amyloid A (SAA) and TNF-α were compared in 40 subjects with T2DM (no insulin or statin treatment) and 36 non-diabetic subjects.ResultsT2DM was associated with impaired HDL anti-inflammatory capacity (3.18 vs 1.05 fold increase in VCAM-1 mRNA expression; P < 0.001), coinciding with decreased HDL cholesterol (P = 0.001), apolipoprotein A-I (P = 0.038) and PON-1 activity (P = 0.023), as well as increased hs-CRP (P = 0.043) and TNF-α (P = 0.005). In all subjects combined, age- and sex-adjusted multivariable linear regression analysis demonstrated that impaired HDL anti-inflammatory capacity was associated with hyperglycemia (β = 0.499, P < 0.001), lower PON-1 activity (β = − 0.192, P = 0.030) and higher hs-CRP (β = 0.220, P = 0.016).ConclusionsThe HDL anti-inflammatory capacity is substantially impaired in T2DM, at least partly attributable to the degree of hyperglycemia, decreased PON-1 activity and enhanced low grade chronic inflammation. Decreased anti-inflammatory protection capacity of HDL conceivably contributes to the increased atherosclerosis risk associated with T2DM.

The HDL anti‐inflammatory function is impaired in the context of low‐normal free thyroxine in diabetic and nondiabetic individuals

“…HDL cholesterol was decreased, and triglycerides were elevated in T2DM. The HDL anti-inflammatory capacity was strongly impaired in T2DM as expected 6 (Table 1) (Table 1). Notably, however, multivariable linear regression analysis demonstrated that the HDL anti-inflammatory capacity was inversely associated with FT4 (P = .048) when taking account of age, sex and the presence of diabetes (Table S1, model 1).…”

“…7 Further studies are warranted to confirm these observations and to delineate the underlying molecular mechanisms, which could include pro-inflammatory processes affecting HDL function as reflected by the association of impaired HDL antiinflammatory capacity with high sensitivity C-reactive protein. 6 In summary, we show here for the first time an inverse association of FT4 in the euthyroid range with the anti-inflammatory capacity of HDL, an important metric of HDL function predictive of coronary events.…”

“…Details of inclusion criteria and routine clinical and laboratory procedures have been reported elsewhere. 6 Thyroid function parameters of 2 participants from that study were not available. The medical ethics committee of the University Medical Center Groningen had approved the study.…”

“…Our current findings thus extend earlier reports regarding an impaired HDL anti-oxidative function in the context of lower FT4 levels and add to accumulating evidence that low-normal thyroid function is not only associated with unfavourable changes in circulating lipoprotein levels as such, but also affects pathways involved in lipid transport and endothelial function, critical events in the development of atherosclerosis. 3,6 Given that the relationship of thyroid hormone status with proatherogenic biomarkers may be altered in the context of hyperglycaemia, 3 we included diabetic subjects in this study. We did not measure free triiodothyronine (FT3), reasoning that changes in FT4 in relation to variations in TSH are more outspoken than changes in FT3.…”

High-Density Lipoprotein Particles and Their Relationship to Posttransplantation Diabetes Mellitus in Renal Transplant Recipients

“…Using J774 macrophages, CEC to apoB-depleted plasma was found to be positively correlated with large-and medium-sized HDL, HDL size, as well as HDL particle concentration [56,57], while in another report, CEC was also correlated with HDL particle concentration though not with HDL particle size [51]. Of further importance, β-cell function is likely to be related to HDL anti-oxidative function as well [54], which is in part determined by paraoxonase-1 (PON-1), an anti-oxidative enzyme which predominantly resides on large HDL particles [46,58,59]. However, serum PON-1 activity did not predict incident T2DM in the general population [60].…”