*5.4.1 Insulin treatment*

Platelet hyperactivity, which largely occurs together with hyperglycemia and hyperinsulinemia, is well known in T2DM [103]. Notably, despite the absolute or relative deficiency of insulin in T1DM, platelet hyperactivity also occurs in T1DM. This phenomenon has elicited debate on the role of insulin in platelet functions. The data available on platelet functions in T1DM are usually at the beginning of insulin treatment or follow-up, which have reported mixed results: no change [86, 104, 105], reduced functions [38], or enhanced activity [24]. These discrepancies in study results can be accounted for by the differences in insulin dosages that produce hypoglycemia, duration of disease, individual peculiarities such as obesity, hyperlipidemia, and plasma calcium and magnesium balances.

Low dose or physiological levels of insulin inhibit platelet aggregation through several mechanisms [38, 106]. These include: decreasing intracellular cAMP levels [38], decreasing calcium mobilization [107] but increasing magnesium influx [108], nitric-oxide-mediated increase in cGMP [38], stimulation of prostacyclin synthesis [109]. Low-dose Insulin prevents second wave aggregation in diabetics, an effect augmented by calcium channel blockers [110]. It is therefore apparent that physiological levels of insulin suppress platelet function, effects that are reversed in its absence during diabetes mellitus type1.

The studies that showed increased platelet hyperactivity concurrent with hyperinsulinemia induced hypoglycemia [94], with attendant increase in counter-regulatory hormones such as adrenaline [111, 112] and increase in vWF-platelet adhesiveness [24], results which were similar to findings in T2DM [113].

Experimental *in vitro*, insulin has antagonistic effects on PRP activation in healthy humans. While at low levels, it decreases platelet aggregation to ADP, at supraphysiological levels, aggregation to ADP is increased [114]. *In vitro,* in healthy controls, supraphysiological insulin enhances ADP-induced whole blood platelet expression of
