**2. Pathophysiology of dyslipidemia and platelet abnormalities in type 2 diabetes mellitus**

Atherogenic dyslipidemia is characterized by three lipoprotein abnormalities: elevated VLDL, small LDL and decreased HDL cholesterol levels, named as atherogenic lipoprotein phenotype (Grundy, 1998). In patients with type 2 diabetes, the prothrombotic state is characterized by increased fibrinogen levels (Imperatore et al 1998), increased plasminogen activator inhibitor (PAI)-1 (Byberg et al., 1998) and abnormalities in platelet function (Trovati et al., 1988). The reason for three aforementioned phenotypes in athrogenic dyslipidemia is the increased free fatty-acid release from insulin-resistant fat cells (Taskinen, 2003; Krauss & Siri, 2004; Chahil & Ginsberg, 2006). The increased flux of free fatty acids into the liver in the presence of adequate glycogen stores promotes triglyceride production, which in turn stimulates the secretion of apolipoprotein B (ApoB) and VLDL cholesterol (Mooradian, 2008). The impaired ability of insulin to inhibit free fatty-acid release leads to enhanced hepatic VLDL cholesterol production (Frayn, 2001) which correlates with the degree of hepatic fat accumulation (Adiels et al., 2007). The increased number of plasma VLDL cholesterol and triglyceride levels decrease the level of HDL cholesterol and increase the concentration of small dense LDL cholesterol (Mooradian, 2008).

Platelet activation commenced with binding of thrombogenic substances (collagen, thrombin, components of atheromatous plaque) to receptors located on the platelet surface (Colwell & Nesto, 2003). Receptor binding triggers a series of events that include hydrolysis of membrane phospholipids, mobilization of intracellular calcium, and phosphorylation of important intracellular proteins (Colwell & Nesto, 2003). There are several platelet abnormalities seen in diabetes patients. Abnormalities of thromboxane A2 (TXA2) production were among the earliest abnormalities in platelets of diabetes patients. TXA2 is a potent activator and its synthesis is suppressed by aspirin (Natarajan et al., 2008). Platelets from patients with type 2 diabetes mellitus found to have increased expression of adhesion molecules CD31, CD36, CD49b, CD62P and CD63 (Eibl et al., 2004). Glycemic control

decreased fibrinolysis and increased procoagulation factors (Serrano Rios, 1998). Besides dyslipidemia, platelet abnormalities contributed significantly to increased risk of CVD in these patients. In patients with type 2 diabetes, the platelet abnormalities are due to increased platelet aggregability and adhesiveness (Colwell & Nesto, 2003) and enhanced platelet aggregation activity may precede development of CVD (Halushka et al. 1981, Mandal et al. 1993). It has been well known that management of dyslipidemia in diabetes mellitus includes lifestyle changes such as increased physical activity and dietary modifications. Besides, various antihyperlipidemic agents have been utilized for this purpose. In contrast, antiplatelet agents are recommended mainly for primary and secondary prevention for cardiovascular disease in T2DM. Dyslipidemia is categorized as one of the cardiovascular risk factors besides others (family history CHD, hypertension, smoking, albuminuria) (American Diabetes Association, 2011). Patients with T2DM and having dyslipidemia are eligible for primary prevention of CVD with antiplatelet agents. This chapter will discuss on different types of antiplatelet agents used as primary prevention of cardiovascular disease in patients with T2DM. It will also emphasize appropriate selection of antiplatelet agents pertaining to clinical conditions of patients with

**2. Pathophysiology of dyslipidemia and platelet abnormalities in type 2** 

the concentration of small dense LDL cholesterol (Mooradian, 2008).

Atherogenic dyslipidemia is characterized by three lipoprotein abnormalities: elevated VLDL, small LDL and decreased HDL cholesterol levels, named as atherogenic lipoprotein phenotype (Grundy, 1998). In patients with type 2 diabetes, the prothrombotic state is characterized by increased fibrinogen levels (Imperatore et al 1998), increased plasminogen activator inhibitor (PAI)-1 (Byberg et al., 1998) and abnormalities in platelet function (Trovati et al., 1988). The reason for three aforementioned phenotypes in athrogenic dyslipidemia is the increased free fatty-acid release from insulin-resistant fat cells (Taskinen, 2003; Krauss & Siri, 2004; Chahil & Ginsberg, 2006). The increased flux of free fatty acids into the liver in the presence of adequate glycogen stores promotes triglyceride production, which in turn stimulates the secretion of apolipoprotein B (ApoB) and VLDL cholesterol (Mooradian, 2008). The impaired ability of insulin to inhibit free fatty-acid release leads to enhanced hepatic VLDL cholesterol production (Frayn, 2001) which correlates with the degree of hepatic fat accumulation (Adiels et al., 2007). The increased number of plasma VLDL cholesterol and triglyceride levels decrease the level of HDL cholesterol and increase

Platelet activation commenced with binding of thrombogenic substances (collagen, thrombin, components of atheromatous plaque) to receptors located on the platelet surface (Colwell & Nesto, 2003). Receptor binding triggers a series of events that include hydrolysis of membrane phospholipids, mobilization of intracellular calcium, and phosphorylation of important intracellular proteins (Colwell & Nesto, 2003). There are several platelet abnormalities seen in diabetes patients. Abnormalities of thromboxane A2 (TXA2) production were among the earliest abnormalities in platelets of diabetes patients. TXA2 is a potent activator and its synthesis is suppressed by aspirin (Natarajan et al., 2008). Platelets from patients with type 2 diabetes mellitus found to have increased expression of adhesion molecules CD31, CD36, CD49b, CD62P and CD63 (Eibl et al., 2004). Glycemic control

T2DM and dyslipidemia.

**diabetes mellitus** 

improvement led to a significant decline in their expression (Eibl et al., 2004). In type 2 diabetes patients, platelets increased surface expressionof GP Ib and GP IIb/IIIa (Vinik et al., 2001). GP Ib mediates binding to von Willebrand factor (vWf) which is important in plateletdependent thrombogenesis (Natarajan et al., 2008). Increased expression of GP IIb/IIIa on platelet surfaces leads to enhanced fibrinogen binding, platelet cross-linking and thrombogenesis (Colwell & Nesto, 2003). In patients with type 2 diabetes, decreased platelet insulin receptor number and affinity responsible for platelet hyperactivity (Vinik et al., 2001). Platelets have been shown to be targets of insulin action as they act as functional insulin receptor for insulin binding and autophosphorylation (Vinik et al., 2001). Insulin reduces platelet responses to the agonists' adenosine diphosphate (ADP), collagen, thrombin, arachidonate and platelet-activating factor. (Natarajan et al., 2008). In patients with type 2 diabetes also, platelets show disordered calcium homeostasis (Li et al., 2001). This may cause hyperactivity including platelet shape change, secretion, aggregation and thromboxane formation (Beckman et al., 2002). Furthermore, the deficiency of magnesium in diabetes has been associated with platelet hyperaggregability and adhesiveness (Gawaz et al., 1994). In type 2 diabetes patients, the reduced vascular synthesis of the anti-aggregants prostacyclin and nitric oxide by endothelium, shift the balance towards aggregation and vasoconstriction (Vinik et al., 2001; Ferroni et al., 2004). In type 2 diabetes patients with acute hyperglycaemia, shear stress-induced platelet activation and P-selection expression (Natarajan et al., 2008). Hyperglycaemia also causes non-enzymatic glycation of platelet membrane proteins resulting in changes in protein structure and conformation, as well as alterations of membrane lipid dynamics (Brownlee et al., 1988; Winocour et al., 1992). This could result in enhanced expression of certain crucial platelet receptors, for instance, P-selectin and GP IIb/IIIa, thus altering platelet activity (Ferroni et al., 2004). Glycated LDL causes an increase in intracellular calcium concentration and platelet nitric oxide (NO) production, as well as inhibition of the platelet membrane Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) activity (Ferroni et al., 2004).
