Mechanisms of Action of Drugs for Treating Endothelial Dysfunction in Diabetes Mellitus

Abstract

Endothelium is the thin cellular layer lining all the blood vessels, and responsible for regulation of vascular tone, clotting, tissue perfusion, healing and repair. Being in direct contact with blood, it is the primary target of any abnormality, such as hyperglycemia-induced endothelial dysfunction in case of diabetes mellitus. Hyperglycemia and insulin resistance in diabetes cause endothelial injury through diverse mechanisms such as oxidative stress, inflammation and impairment of nitric oxide bioavailability, all of which lead to compromised endothelium-mediated vas-cular reactivity. Therapeutic management of endothelial dysfunction in diabetes is necessary in order to prevent and treat the resulting microvascular and macrovascu-lar complications such as neuropathy, nephropathy, retinopathy, cardiomyopathy and atherosclerosis. Drug classes used to prevent or treat endothelial dysfunction in diabetes include glucose-lowering drugs, insulin-sensitizers, lipid-lowering drugs, renin angiotensin system-blockers, nitric oxide synthesis modulators, antioxidants, anti-inflammatory drugs and ion channel modulators (discussed in detail). Therapies that show promise as future interventions include vitamin D or its analogues, TRP channel modulators, ivabradine and others. Also, nutritional therapies such as pro-biotics are being speculated as promising future therapies for diabetes-linked endo-thelial dysfunction. Though the presence of multiple pathogenic mechanisms in diabetes ensures a large number of drug targets, it also introduces redundancy in signalling pathways and hence the need for poly-pharmacy. Drugs with multiple targets or mechanisms of action hold promise as future therapies of endothelial dysfunction in diabetes.