Endothelial dysfunction, inflammation, and insulin resistance: A focus on subjects at risk for type 2 diabetes

Abstract

Subjects with obesity, family history of type 2 diabetes, polycystic ovary syndrome, previous gestational diabetes, dyslipidemia, hypertension, impaired glucose tolerance or impaired fasting glucose, and those with metabolic syndrome are at risk for the development of type 2 diabetes. Some of them are also at risk for cardiovascular disease. Some underlying abnormalities such as insulin resistance, endothelial dysfunction, and low-grade chronic inflammation are frequently present and closely associated in all these groups. The flow of substrates, hormones, and cytokines from visceral fat to skeletal muscle and to the endothelial cells, along with some genetic abnormalities that lead to impaired insulin action in the peripheral tissues and to impaired insulin-stimulated nitric oxide production in endothelial cells, may play a role in establishing these shared metabolic and vascular derangements. Weight loss, thiazolidinediones, and metformin improve vascular function in subjects at risk for type 2 diabetes and may prove to reduce cardiovascular events in these individuals.

The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health

“…19,20 It is known that elevations in FFA also lead to endothelial dysfunction. 1 The study by Kim et al suggests that IKK␤ is mediating insulin resistance in endothelium in response to FFA resulting in endothelial dysfunction using a mechanism similar to that in metabolic targets of insulin. Thus IKK␤ may play an important role in both metabolic insulin resistance and vascular endothelial dysfunction.…”

“…1 Insulin resistance and endothelial dysfunction are also prominent features of important cardiovascular disorders including hypertension, coronary artery disease, and atherosclerosis. 2 Indeed, insulin resistance is thought to be the tie that binds metabolic and cardiovascular disorders together in an unhappy union called the metabolic syndrome (aka the insulin resistance syndrome).…”

“…Interestingly, inflammation mediated by innate immune signaling pathways has been implicated in both metabolic insulin resistance and vascular endothelial dysfunction. 1,5,6 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kim et al demonstrate that treatment of vascular endothelial cells with the free fatty acid (FFA) palmitate activates IKK␤ (a proinflammatory signaling molecule), impairs insulin signaling, and decreases insulin-stimulated production of nitric oxide (NO). 7 Importantly, inhibitory effects of FFA treatment on insulin signaling and NO production are blocked by overexpression of a dominant inhibitory mutant of IKK␤.…”

Development of multiple complications in type 2 diabetes is associated with the increase of multiple markers of chronic inflammation

“…Chronic systemic inflammation is now being recognized as the major causative factor for the pathogenesis of type 2 diabetes (T2DM) (1,2). It was also realized recently that the development and the propagation of several severe diseases could be found in T2DM patients, including macro-and microvascular disease (3,4) renal failure (5), and cancer (6) associated with chronic inflammation.…”

“…In addition, to be the causative factor for the pathogenesis in T2DM (13,14) chronic systemic inflammation has also been found to be associated with the pathogenesis of CVD and diabetic nephropathy. Since nephropathy and macro-and microvascular disease are frequently developed in patients with T2DM, we have made an effort to investigate the relationship between chronic inflammation and T2DM, and also their clinical complications (15)(16)(17).…”