Given the obtained data from the flow cytometry, it can be concluded that platelets express higher CD62P levels in patients with type 2 diabetes mellitus, and are pre-active at the baseline stage without the hexogen agonist treatment since the beginning as this state of platelets is related to the existing metabolic environment in patient with type 2 diabetes mellitus. Platelets are quite sensitive and responsive to environmental changes. The rate of glucose concentration in platelets indicates the rate of extracellular glucose concentration because glucose is not dependent on insulin in order to enter platelet [
22‐
24]. Chronic and long-term hyperglycemia is particularly recognized as a major factor for the activation of platelets and formation of pre-active platelets in patients with type 2 diabetes mellitus [
25‐
27]. In the present study, the treatment of PRPs with mild agonist ADP stimulation led to the lower induction of CD62P expression and reduced reactivity in both diabetic and control platelets probably due to the desensitization phenomenon. The extent of CD62P expression was lower in a tube, which first had a mild agonist stimulation, and it was then treated with a high dosage of ADP than a tube which was solely treated with a high dosage of ADP, and thus it can be concluded that platelets decreased the response to agonist under the effect of desensitization phenomenon that could help platelets that were constantly exposed to agonist in a diabetes metabolic environment [
28]. This reduced response is higher among diabetic platelets and leads to the higher reduction of expression for CD62P. In the diabetes metabolic environment, platelets are constantly exposed to the produced ADP by platelets that are activated in such an environment and under hyperglycemia. Based on findings of the present research, this phenomenon is effective for reducing the activation of platelets in response to ADP. Platelets are pre-active in the patients with type 2 diabetes mellitus and display the lower irritability to ADP either in low or high dosages. This reduction of sensitivity and irritability of diabetic platelets might be due to the desensitization of diabetic platelets in diabetic vessels and in constant stimulation by ADP, thereby leading to the reduced response of platelets to ADP. However, the sensitivity and irritability of platelets of non-diabetic individuals to ADP are always higher and express more rates of CD62P throughout the agonist treatment. The mild agonist stimulation of platelets (for both groups) led to reduced irritability of platelets to ADP. According to platelet micro-particles, findings indicated that if platelets, which were already exposed to the mild agonist stimulation and desensitized under diabetic vascular conditions, were exposed to high dosage of ADP, for instance, to a thrombotic clot, they would produce more amounts of micro-particles. High rate and systematic production of platelet micro-particles was considered as a pro-inflammatory mediator and pathological factor [
29]. Chronic hyperglycemia and pre-active platelets with high expression rates of CD62P among patients with type 2 diabetes mellitus predisposed the patients to atherosclerosis as an important complication among such patients. There is the evidence for roles of platelets in the atherosclerosis, which is intermediated by production of platelet micro-particles, that can be considered as a prognostic marker for atherosclerotic cardiovascular diseases such as diabetes [
30,
31]. Study limitations included small sample sizes and time limit. It is recommended that this study should be done with a larger sample size in several clinics. Furthermore, responses of platelets to natural anti-aggregation material such as PGI2 and NO are reduced among these patients; and all items of pathogenesis of atherosclerosis are also involved in this disease [
32]. Based on the derived data from this research, the response of platelets and their irritability to ADP indicated a reduction among patients; and such reduced sensitivity to ADP along with reduced response to
PGI2 and
NO might be according to the occurrence of atherosclerosis in the patients. Considering structural characteristics and sizes of platelet micro-particles, their local production made them strong tools in platelet-cellular communications for transfer of bioactive molecules with platelet origin such as growth factors and other signaling molecules and miRNAs [
33]. It occurs if they act as pro-inflammatory mediators and pathological factors in different pathological situations when they are systematically and abundantly produced, thereby leading to the progress of atherosclerosis and thrombotic complications [
34,
35]. According to the research data, the platelets, which had the lower reactivity, produced more micro-particles. Such micro-particles in a systematic production brought thrombotic complications; and the phenomenon might be involved in diabetic complications as well. Diabetic ulcers are the most common and serious complications of diabetes. Ulcer healing is a complex biological and dynamic process consisting of four stages, namely hemostasis, inflammation, proliferation and remodeling. This process includes various types of cells, extracellular compounds, growth factors and cytokines all of which are affected by diabetes type 2 diseases and lead to delayed healing of ulcers [
36,
37]. Since the mild platelet stimulation, which causes developing desensitization, leads to the reduced reactivity of platelets, it may be a factor for facilitating such a late healing of diabetic ulcers.