Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies

Abstract

The incidence and prevalence of diabetes mellitus is rapidly increasing worldwide at an alarming rate. Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes, accounting for approximately 90-95% of the total diabetes cases worldwide. Besides affecting the ability of body to use glucose, it is associated with micro-vascular and macro-vascular complications. Augmented atherosclerosis is documented to be the key factor leading to vascular complications in T2DM patients. The metabolic milieu of T2DM, including insulin resistance, hyperglycemia and release of excess free fatty acids, along with other metabolic abnormalities affects vascular wall by a series of events including endothelial dysfunction, platelet hyperactivity, oxidative stress and low-grade inflammation. Activation of these events further enhances vasoconstriction and promotes thrombus formation, ultimately resulting in the development of atherosclerosis. All these evidences are supported by the clinical trials reporting the importance of endothelial dysfunction and platelet hyperactivity in the pathogenesis of atherosclerotic vascular complications. In this review, an attempt has been made to comprehensively compile updated information available in context of endothelial and platelet dysfunction in T2DM.

Keywords: Hyperglycemia; Inflammation; Insulin resistance; Oxidative stress; Vascular complications.

Fig. 1

Pathophysiological events leading to vascular complications in T2DM patients

Fig. 2

Endothelial dysfunction in diabetes: Hyperglycemia leads to increase production of ROS and RNS resulting oxidative stress. Oxidative stress affects vascular homeostasis by causing increased vasoconstriction and impaired vasorelaxation and eventually leads to endothelial dysfunction. ROS reactive oxygen species, RNS reactive nitrogen species, eNOS endothelial nitric oxide synthase, NO nitric oxide, AGE advanced glycation end products, PKC protein kinase, NF-κB nuclear factor-κB

Fig. 3

Schematic representation of various biochemical factors responsible for platelet hyperactivity in T2DM

Fig. 4

Mechanisms responsible for platelet hyperreactivity in T2DM patient: Elevated cAMP levels leading to platelet inhibition via cAMP-dependent protein kinase (PKA), which disrupt signaling via receptor activation, thromboxane A2 production, MAPK pathway, activation of PKC. The transmembrane G-protein associated receptors involved are prostaglandin, P2Y, P2X, TR, and TP. Both TR and TP present novel drug targets. Antiplatelet drugs are shown in red. NO nitric oxide, AGE advanced glycation end products, RAGE AGE receptors, PKA/B/C protein kinase A/B/C, TK tyrosine kinase, PI-3 phosphoinositol-3 kinase, MAPK p38 mitogen-activated protein kinase, GC guanylate cyclase, PAR-1 protease activated receptor, TR thrombin receptor, TPα thromboxane receptor, TRA thrombin receptor antagonist, TPRA thromboxane receptor antagonist, ASA acetylsalicylic acid (aspirin) (Adapted from Kakouros et al. [16])