Diabetes mellitus in peripheral artery disease: Beyond a risk factor

Abstract

Peripheral artery disease (PAD) is one of the major cardiovascular diseases that afflicts a large population worldwide. PAD results from occlusion of the peripheral arteries of the lower extremities. Although diabetes is a major risk factor for developing PAD, coexistence of PAD and diabetes poses significantly greater risk of developing critical limb threatening ischemia (CLTI) with poor prognosis for limb amputation and high mortality. Despite the prevalence of PAD, there are no effective therapeutic interventions as the molecular mechanism of how diabetes worsens PAD is not understood. With increasing cases of diabetes worldwide, the risk of complications in PAD have greatly increased. PAD and diabetes affect a complex web of multiple cellular, biochemical and molecular pathways. Therefore, it is important to understand the molecular components that can be targeted for therapeutic purposes. In this review, we describe some major developments in enhancing the understanding of the interactions of PAD and diabetes. We also provide results from our laboratory in this context.

Peripheral Artery Disease: Molecular Mechanisms and Novel Therapies

“…These processes lead to endothelial dysfunction, vasoconstriction, smooth muscle cell remodeling, macrophage phenotypic transformation, inflammation, and ultimately, the development of atherosclerosis. [3][4][5] Oxidative stress results from the overproduction of advanced glycation end products and their receptors in diabetes mellitus (DM), increased nicotinamide adenine dinucleotide phosphate hydrogen oxidase expression and renin-angiotensin system activation in hypertension, via xanthine oxidase and nicotinamide adenine dinucleotide phosphate hydrogen oxidase in hypercholesterolemia, and cigarette smoke extracts in smokers. [3][4][5][6] However, these 3 risk factors also promote PAD via independent mechanisms.…”

“…[3][4][5][6] However, these 3 risk factors also promote PAD via independent mechanisms. [3][4][5] Besides direct endothelial dysfunction, the impaired metabolic state of DM appears to contribute to abnormal platelet and coagulation activation, thus promoting atherothrombosis. 7 In animal models, DM also impedes the development of collateral blood flow through vascular regeneration, while insulin resistance and hyperglycemia-related metabolic changes impair the ability of the skeletal muscle to recover from injury.…”

Impact of Nutraceuticals on Type 1 and Type 2 Diabetes Mellitus-Induced Micro- and Macrovasculopathies

“…Similarly, peripheral artery disease development is intertwined with atherosclerotic plaques, which may either totally or partially occlude the peripheral vasculature [50].…”

“…Known risk factors for macrovascular complications seem to be similar across the subclasses (cerebrovascular diseases, coronary artery diseases, and peripheral artery diseases) and include aging, hypertension, dyslipidemia, diabetes and its extended duration, and obesity [49,50]. However, for peripheral artery diseases, smoking and diabetes account for a large part of risk factors.…”

Targeting the Histone Methyltransferase SETD7 Rescues Diabetes-induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin 3G

“…1 Among the constellation of cardiovascular comorbidities, DM shows the highest association with peripheral artery disease (PAD), a condition characterized by atherosclerotic lesions, reduced blood supply and chronic ischemia of the lower extremities. 2 DM is highly prevalent in patients with PAD and has been co-diagnosed in nearly 40% of all PAD patients. 3 Despite advances in revascularization strategies, the rate of limb amputation due to chronic limb ischemia remains high and associates with cardiovascular morbidity in DM patients.…”