Figure: Insulin signaling pathways in the endothelium for the production of nitric oxide (NO) and endothelin-1 (ET-1).
Image created for and published in the doctoral thesis of my colleague Dr. Yvo H.A.M. Kusters titled "Unraveling obesity’s road to diabetes and cardiovascular disease: contributors to insulin resistance, beta-cell dysfunction and vascular dysfunction".
Created with Adobe Illustrator and Photoshop.
Description:
Insulin signaling pathways in the endothelium for the production of nitric oxide (NO) and endothelin-1 (ET-1). In healthy individuals, hyperinsulinemia results in a net vasodilation, whereas in obesity, this response is either blunted or paradoxical vasoconstriction may occur. Several circulating and paracrine factors are involved: angiotensin II (AngII), tumor necrosis factor (TNF), and free fatty acid (FFA) inhibit the phosphatidylinositol 3-kinase (PI3K) pathway and stimulate the mitogen-activated protein kinase (MAPK) pathway via a crosstalk at multiple levels. TNF and AngII can inhibit IRS-1 through c-Jun N-terminal kinase (JNK). AngII can bind to the angiotensin type 1 receptor (AT1R) and inhibit IRS-1 and lead to the production of reactive oxygen species (ROS), which reduces NO bioavailability. FFA can activate protein kinase C theta (PKC-theta), which results in activation of the mitogen-activated protein kinase (MAPK) signaling pathway as well as in inhibition of PI3K. Adiponectin can stimulate 5'-adenosine monophosphate-activated protein kinase (AMPK), which stimulates eNOS and inhibits the MAPK pathway; in obesity, adiponectin levels are decreased.
