1. Formation of advanced glycation end products (AGEs). AGEs are formed as a result of nonenzymatic reactions between intracellular glucose-derived precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) and the amino groups of proteins. The rate of AGE formation is greatly accelerated by hyperglycemia. AGEs bind to a specific receptor (RAGE), which is expressed on inflammatory cells (macrophages and T cells), endothelium and vascular smooth muscle. The detrimental effects of AGE-RAGE signaling within the vascular compartment include the following:
Release of cytokines and growth factors, including transforming growth factor β (TGFβ), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy (discussed later)
Generation of reactive oxygen species (ROS) in endothelial cells
Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins. These cross-linked proteins can trap other plasma or interstitial proteins; for example, low-density lipoprotein (LDL) gets trapped within AGE-modified large-vessel walls, accelerating atherosclerosis (Chapter 10), while albumin can be trapped within capillary walls, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy (discussed later).
2. Activation of protein kinase C. Activation of intracellular protein kinase C (PKC) by calcium ions and the second messenger diacylglycerol (DAG) is an important http://ebooksmedicine.net
Fig. 20.25 Long-term complications of diabetes.
signal transduction pathway in many cellular systems. Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause activation of PKC. The downstream effects of PKC activation are numerous and include production of proangiogenic molecules such as vascular endothelial growth factor (VEGF), implicated in the neovascularization seen in diabetic retinopathy, and profibrogenic molecules such as transforming growth factor β, leading to increased deposition of extracellular matrix and basement membrane material.
3. Disturbances in polyol pathways. In some tissues that do not require insulin for glucose transport (e.g., nerves, lens, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor. NADPH also is required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH). As described in Chapter 2, GSH is one of the important anti-oxidant mechanisms in the cell, and reductions in GSH increase cellular susceptibility to oxidative stress. In neurons, persistent hyperglycemia appears to be the major underlying cause of diabetic neuropathy (glucose neurotoxicity).
The most important morphologic changes are related to the many late systemic complications of diabetes. These changes are seen in both type 1 and type 2 diabetes (see
Fig. 20.25
Pancreas. Lesions in the pancreas are inconstant. One or more of the following alterations may be present: