Acute Hypertriglyceridemia Induces Platelet Hyperactivity That is Not Attenuated by Insulin in Polycystic Ovary Syndrome

Abstract

BackgroundAtherothrombosis is associated with platelet hyperactivity. Hypertriglyceridemia and insulin resistance (IR) are features of polycystic ovary syndrome (PCOS). The effect of induced hypertriglyceridemia on IR and platelet function was examined in young women with PCOS.Methods and ResultsFollowing overnight fasting, 13 PCOS and 12 healthy women were infused with saline or 20% intralipid for 5 hours on separate days. Insulin sensitivity was measured using a hyperinsulinemic euglycaemic clamp in the final 2 hours of each infusion. Platelet responses to adenosine diphosphate (ADP) and prostacyclin (PGI2) were measured by flow cytometric analysis of platelet fibrinogen binding and P‐selectin expression using whole blood taken during each infusion (at 2 hours) and at the end of each clamp. Lipid infusion increased triglycerides and reduced insulin sensitivity in both controls (median, interquartile range ) (5.25 [3.3, 6.48] versus 2.60 [0.88, 3.88] mg kg−1 min−1, P<0.001) and PCOS (3.15 [2.94, 3.85] versus 1.06 [0.72, 1.43] mg kg−1 min−1, P<0.001). Platelet activation by ADP was enhanced and ability to suppress platelet activation by PGI2 diminished during lipid infusion in both groups when compared to saline. Importantly, insulin infusion decreased lipid‐induced platelet hyperactivity by decreasing their response to 1 μmol/L ADP (78.7% [67.9, 82.3] versus 62.8% [51.8, 73.3], P=0.02) and increasing sensitivity to 0.01 μmol/L PGI2 (67.6% [39.5, 83.8] versus 40.9% [23.8, 60.9], P=0.01) in controls, but not in PCOS.ConclusionAcute hypertriglyceridemia induced IR, and increased platelet activation in both groups that was not reversed by insulin in PCOS subjects compared to controls. This suggests that platelet hyperactivity induced by acute hypertriglyceridemia and IR could contribute athero‐thrombotic risk.Clinical Trial RegistrationURL: www.isrctn.org. Unique Identifier: ISRCTN42448814.

Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

“…Following overnight fasting (O/N), all the subjects underwent 5‐hour saline infusion with IS assessed by a hyperinsulinemic‐euglycaemic clamp in the final 2 hours to determine IS (M‐value). A week later, the subjects underwent 5‐hour intralipid/saline infusion (20% soybean oil, 1.2% egg yolk phospholipids and 2.2% glycerol; Kabi Fresenius Pharmacia) with a hyperinsulinemic‐euglycaemic clamp in the last 2 hours to determine IS (M‐value) . Following this procedure, all the participants underwent supervised moderate intensity (60% maximum oxygen consumption) exercise, 3 hours weekly for 8 weeks.…”

“…A week later, the subjects underwent 5-hour intralipid/saline infusion (20% soybean oil, 1.2% egg yolk phospholipids and 2.2% glycerol; Kabi Fresenius Pharmacia) with a hyperinsulinemic-euglycaemic clamp in the last 2 hours to determine IS (M-value). 18 Following this procedure, all the participants underwent supervised moderate intensity (60% maximum oxygen consumption) exercise, 3 hours weekly for 8 weeks. During the second phase of this study, the phase 1 protocol was repeated in all the subjects.…”

Pathophysiology of peripheral arterial disease in diabetes mellitus

“…77 Hypertriglyceridemia also induces platelet activation. 78 Plaque rupture promotes PAD progression in diabetes In atherothrombosis, macrophages transform into lipidladen foam cells, augmenting the expression of scavenger receptors in response to inflammatory mediators, and then break down to form fatty streaks and the lipid core of mature atherosclerotic plaques. In the later steps of atherosclerosis development, proliferation of smooth muscle cells and collagen deposition lead to the formation of a collagen-rich fibrous cap on the plaque that stabilizes the plaque and prevents vascular access to its thrombogenic core.…”

Postprandial activation of leukocyte‐endothelium interaction by fatty acids in the visceral adipose tissue microcirculation

“…Based on data demonstrating the rapid and transient nature of FA transport and accumulation in endothelial cells after fat‐meal gavage (47), we focused on the eCAM P‐selectin because P‐selectin is constitutively expressed in the vascular endothelium. Moreover, human studies demonstrate that elevations in plasma triglycerides and FFAs by lipid infusion acutely up‐regulate P‐selectin (49). Endothelia expressing P‐selectin engage circulating leukocytes by ligating the leukocyte adhesive receptor P‐selectin glycoprotein ligand‐1 (PSGL‐1) (50) to initiate a process that ultimately leads to leukocyte firm adhesion and extravasation (51).…”