Abstract
BackgroundCVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects.Methods40 non-diabetic subjects (age = 38 ± 3 yr, BMI = 28 ± 1 kg/m2, FPG = 95 ± 1 mg/dl, HbA1c = 5.3 ± 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I).ResultsLipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 ± 10 vs. 186 ± 25 ng/ml), VCAM-1 (1066 ± 67 vs. 1204 ± 65 ng/ml) and sE-S (20 ± 1 vs. 24 ± 1 ng/ml) between 13-35% and by ≥ 2-fold plasma levels of myeloperoxidase (7.5 ± 0.9 to 15 ± 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 ± 0.6 to 22.5 ± 1.5 ng/ml), an indicator of a prothrombotic state (all p ≤ 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects.ConclusionsAn increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.
Highlights
CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state
In the Insulin Resistance Atherosclerosis Study, plasma C-reactive protein and PAI-1 levels were enhanced in insulin-resistant subjects who later developed diabetes, and PAI-1 levels predicted diabetes independently of other known risk factors [20]
Effect of a 48-hour increase low-dose lipid infusion on insulin sensitivity (Figure 1) Lipid infusion significantly decreased insulin sensitivity as shown in Figure 1 with a 27 ± 4% reduction as measured by the measured by a hyperglycemic clamp (M/I) index (p = 0.01). This observation made evident that a mild physiological increase in plasma free fatty acid (FFA) by a short-term (48-hours) low-dose lipid infusion is capable of profound metabolic effects in healthy humans, consistent with prior observations by our group [41,42]
Summary
CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. Transendothelial migration of leukocytes is regulated by soluble cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and E-selectin. Their expression is increased as ECs are activated by proinflammatory stimuli such as bacterial endotoxins, Il-1b or TNF-a, CRP, oxidized LDL or hemodynamic forces related to blood flow [3,4]. Plasminogen activator inhibitor 1 is the primary physiological inhibitor of tissue-type plasminogen activator and urokinaselike plasminogen activator and inhibits both fibrinolysis and proteolysis [17,18] Insulin resistant states such as obesity and T2DM are known prothrombotic states characterized by elevated PAI-1 levels [19]. The role of plasma FFA in thrombogenesis in humans is poorly established and no strong direct evidence is available
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