Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications

Abstract

Cardiovascular disease is a major complication of diabetes mellitus, and improved strategies for prevention and treatment are needed. Endothelial dysfunction contributes to the pathogenesis and clinical expression of atherosclerosis in diabetes mellitus. This article reviews the evidence linking endothelial dysfunction to human diabetes mellitus and experimental studies that investigated the responsible mechanisms. We then discuss the implications of these studies for current management and for new approaches for the prevention and treatment of cardiovascular disease in patients with diabetes mellitus.

Fig. 1

Displayed is the signaling pathway associated with insulin-mediated activation of endothelial nitric oxide synthase (eNOS). Binding of insulin to the insulin receptor leads to the phosphorylation of the insulin receptor substrate (IRS) and activation of phosphoinositide-3 kinase (PI3K) and Akt. Akt, in turn, phosphorylates eNOS. In the setting of diabetes mellitus activation of PKCβ leads to the activation of NFκB, blocks insulin signaling and reduces synthesis of nitric oxide (NO)

Fig. 2

The mitochondrial life cycle and dynamics in diabetes mellitus: 1. Mitochondrial biogenesis is reduced; 2. the balance between fission and fusion is disturbed leading to increased fission, decreased fusion, and loss of normal mitochondrial networks; 3. autophagy normally removes damaged and senescent mitochondria, but diabetes impairs autophagy leading to the accumulation of dysfunctional mitochondria. 4. The net effect is a predominance of fragmented, dysfunctional mitochondria that produce increased amounts of reactive oxygen species (ROS) and decreased amounts of adenosine triphosphate (ATP). Impaired mitochondrial energetics also leads to increased levels of diacylglycerol that may activate PKCβ and impair nitric oxide production as shown in Fig. 1