Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes

Table 1 Mechanisms of peripheral arterial disease in diabetes mellitus patients

	Disease characteristics		Mechanisms of pathology		Disease characteristics
DM	Hyperglycemia	→	Vascular inflammation	→	Atherosclerosis	PAD
	Dyslipidemia		CRP: promotes leukocyte adhesion, coagulation, and chemotaxis; inhibits eNOS; impairs fibrinolysis		(Increased plaque burden)
	Insulin resistance		TNF-α and IL-6: activate NF-κβ, leading to thrombogenesis; promote leukocyte migration and adhesion, increasing plaque instability/rupture		Atherothrombosis (Increased plaque instability/rupture)
	↑ FFA production		Endothelial cell dysfunction		Restenosis
			Decreased NO production: inhibits vasodilation		(Increased complexity)
			Increased reactive oxygen species: inhibits vasodilation
			Increased AGE production: is proinflammatory; induces leukocyte chemotaxis, adhesion, and transformation into foam cells
			Vascular smooth muscle cell derangement
			Tissue factor production: proatherogenic; procoagulation
			FGF and TGF-α: Extracellular matrix production
			Impaired synthesis of collagen: destabilizes plaque
			Apoptosis of VSMC: increases risk of plaque rupture and thrombosis
			Increased production of endothelin-1, angiotensin II, and prostanoids: leads to vasoconstriction
			Platelet dysfunction
			Enhanced uptake of glucose: increases oxidative stress; decreased NO production
			Upregulation of P-selectin, GPIb, and GPIIb/IIIa receptors: promotes platelet adhesion and aggregation
			Calcium dysregulation: increases platelet aggregation
			Hypercoagulability
			Increased tissue factor and FVII production: enhances coagulability
			Decreased antithrombin and protein C synthesis: enhances coagulability
			Rheology
			Elevated blood viscosity
			Increased fibrinogen production
			Impaired arteriogenesis
			Inhibited sensing of shear stress
			Decreased monocyte and growth factor signaling

Note that there is significant interplay between the different mechanisms: for example, impaired NO production can affect inflammation, endothelial cell function and arteriogenesis, while increased reactive oxygen species causes platelet and endothelial cell dysfunction. FFA: Free fatty acids; CRP: C-reactive protein; eNOS: Endothelial nitric oxide synthetase; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; NF-κβ: Nuclear factor-κβ; NO: Nitric oxide; AGE: Advanced glycation end products; FGF: Fibroblast growth factor; TGF-α: Transforming growth factor-α; VSMC: Vascular smooth muscle cell; GPIb: Glycoprotein Ib; GPIIb/IIIa: Glycoprotein IIb/IIIa; FVII: Factor 7; DM: Diabetes mellitus; PAD: Peripheral artery disease.