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.