Discussion

Studies have shown that insulin-treated diabetic patients have increased platelet aggregation.20-22Postprandial P-selectin increased by 23% with the activation of platelet activator, and postprandial P-selectin expression increased to 57%, but if 0.1 U/kg insulin was given before a meal, postprandial platelet activation was significantly related to the higher insulin level in postprandial blood.23 Further studies have found that this increase in postprandial platelet activation was activated by the thromboxane pathway after high postprandial insulin levels.24 In our study, it was found that the effects of glimepiride, metformin, or acarbose on MAADP tested by TEG were not statistically significant in diabetic patients with acute ischemic vascular events, and insulin therapy may increase the level of MAADPtested by TEG and even promote the risk of platelet aggregation. This conclusion may partly explain the increased cardiovascular risk in diabetic patients treated with insulin.2-6, 8
In healthy people, insulin at physiological concentrations plays a role in the inhibition of platelet aggregation: insulin promotes NO synthesis25, and NO induces an increase in cGMP while promoting the upregulation of cGMP and cAMP-dependent pathways.26 NO also increases the effect of prostacyclin, which synergistically reduces platelet aggregation25. In addition, insulin itself reduces platelet aggregation by inhibiting ADP- or thrombin-induced calcium mobilization and platelet-collagen interactions.27
Compared with the effect of physiological concentration, the effect of exogenous insulin under pathogenic conditions on platelets is opposite. The antiplatelet aggregation effect of insulin by increasing the cGMP concentration of platelets is impaired in obese diabetic patients.9 Similarly, for diabetic patients with insulin resistance, the inhibitory effect of insulin on platelet aggregation is weakened or even disappears.13 First, insulin-resistant diabetic patients have reduced platelet surface insulin receptors and decreased sensitivity, which makes platelets overactivated.28 Second, calcium levels in platelets are elevated by insulin stimulation, leading to further activation and aggregation of platelets.26 Third, hyperinsulinemia induces an increase in tissue factor levels and promotes thrombus formation.29 Platelet tissue factor synthesis in T2DM patients is resistant to inhibition by insulin.30Angiolillo et al proved that the P2Y12-dependent and P2Y12-independent pathways of platelet reactivity were altered in T2DM patients compared with nondiabetic patients, and insulin-treated DM patients had greater ADP-induced platelet aggregation compared with non-insulin-treated DM patients.20 Therefore, the loss of responsiveness to insulin together with increased signaling through P2Y12 may explain the hyperactivity of platelets in patients with T2DM.31
In addition, for healthy people, insulin can inhibit the collagen pathway of platelet aggregation and increase the cGMP concentration in platelets; however, for insulin-resistant patients, insulin cannot inhibit the interaction between platelets and collagen at all, and it cannot increase the cGMP concentration in the platelets of obese subjects.13
Several limitations should be considered in this study. Firstly, we conducted a retrospective analysis in the study, it is difficult to distinguish whether the patients included were suffering from insulin resistance. This is also the focus of our prospective research in the future. Secondly, we only included partly oral hypoglycemic agents to analyze.