Vascular dysfunction in diabetes mellitus Edward P Feener, MD, George L King, MD  The Lancet  Volume 350, Pages S9-S13 (July 1997) DOI: 10.1016/S0140-6736(97)90022-2 Copyright © 1997 Elsevier Ltd Terms and Conditions

Figure 1 Biochemical changes and vascular cell abnormalities associated with hyperglycaemia Extracellular glucose can glycate proteins without enzyme action and generate oxidative by-products. Glycated proteins accumulate in the extracellular matrix and bind to AGE receptors (AGE-R) expressed on the cell surface. Glycolysis is the major pathway of glucose metabolism in the ceil. Increased concentrations of glycolytic metabolites contribute to the de-novo synthesis and increased amounts of diacylglycerol—the activating co-factor for protein kinase C (PKC). Signals generated via PKC have been implicated in various diabetic vascular abnormalities shown. The Lancet 1997 350, S9-S13DOI: (10.1016/S0140-6736(97)90022-2) Copyright © 1997 Elsevier Ltd Terms and Conditions

Figure 2 Mechanisms of insulin signalling and potential atherogenie and antiatherogenic actions of insulin in vascular cells Activation of the tyrosine kinase of the insulin receptor results in tyrosine phosphorylation of intracellular substrates such as insulin receptor substrate-1 (IRS-1), IRS2, and She. These docking proteins couple the receptor to several signalling pathways including the ras pathway that activates mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-kinase). Insulin resistance in vascular cells can impair insulin's ability to activate the latter pathway. Certain cytokines and vasoactive peptides. such as angiotensin II, can both activate the MAPK pathway and inhibit insulin's ability to activate PI-3-kinase. PKC=protein kinase C; MEK=MAP kinase-kinase The Lancet 1997 350, S9-S13DOI: (10.1016/S0140-6736(97)90022-2) Copyright © 1997 Elsevier Ltd Terms and Conditions