Insulin resistance: a proinflammatory state mediated by lipid-induced signaling dysfunction and involved in atherosclerotic plaque instability

Abstract

The dysregulation of the insulin-glucose axis represents the crucial event in insulin resistance syndrome. Insulin resistance increases atherogenesis and atherosclerotic plaque instability by inducing proinflammatory activities on vascular and immune cells. This condition characterizes several diseases, such as type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), obesity, hypertension, dyslipidemia, and other endocrinopathies, but also cancer. Recent studies suggest that the pathophysiology of insulin resistance is closely related to interferences with insulin-mediated intracellular signaling on skeletal muscle cells, hepatocytes, and adipocytes. Strong evidence supports the role of free fatty acids (FFAs) in promoting insulin resistance. The FFA-induced activation of protein kinase C (PKC) delta, inhibitor kappaB kinase (IKK), or c-Jun N-terminal kinase (JNK) modulates insulin-triggered intracellular pathway (classically known as PI3-K-dependent). Therefore, reduction of FFA levels represents a selective target for modulating insulin resistance.

Figure 1

Lipid signaling interference generates insulin resistance. (a) Signaling through phosphatidylinositol 3-kinase (PI3-K) is crucial for insulin-mediated glucose transport in hepatocytes and skeletal muscle cells and for inflammatory protein and hormone secretion in adipocytes and pancreatic β cells. Free fatty acids (FFAs) induce a defective insulin-mediated signaling mainly through the activation of protein kinase C (PKC θ), inhibitor κB kinase (IKK) and c-Jun N-terminal kinase (JNK). (b) Main cell types involved in the development of insulin resistance. (c) Main inflammatory cell populations involved in hyperinsulinemia-induced inflammatory states.