Increased transvascular retention of atherogenic lipoproteins in type 2 diabetes relates to their enhanced proteoglycan-binding

Subendothelial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins drives atherosclerotic arterial disease. In peripheral interstitial fluid from patients with type 2 diabetes (T2D), levels of such particles have been shown to be paradoxically reduced relative to those in serum, presumably reflecting their increased retention within the arterial wall. To identify possible mechanisms involved in lipoprotein retention in T2D, we obtained serum and skin blister fluid from such patients and matched controls, together with skin biopsies in a subset of individuals. In T2D, smaller LDL and VLDL remnant particles were more prominent in serum, but not in interstitial fluid, reflecting their enhanced vascular entrapment. The interstitial-fluid-to-serum ratio of apolipoprotein-B was 58% lower in T2D than in controls (0.14 vs 0.33), concomitant with increased susceptibility for LDL binding to proteoglycans. The most marked differences were seen in patients with clinically evident cardiovascular disease. The degree of transvascular retention was positively related to the propensity of isolated serum LDL to bind aortic proteoglycans, both in T2D and in controls. Skin unesterified cholesterol levels were higher in T2D patients relative to healthy controls. With aging, both proteoglycan binding and apparent vascular retention of LDL increased in controls, but not in T2D, indicating that these mechanisms may also be relevant for atherogenesis in non-diabetic individuals.