Thomas A Ciulla, MD
Most cells can reduce the transport of glucose inside the cell when exposed to hyperglycemia, but the retinal capillary endothelial cells, renal glomerular mesangial cells, and the neurons and Schwann cells in the peripheral nerves are unable to do this efficiently. This explains why hyperglycemia has a greater effect on these particular cell types. Diabetic tissue damage in the retina is a result of genetic susceptibility and comorbidities such as hypertension and hyperlipidemia interacting with repeated acute changes in cellular metabolism and cumulative long-term changes to stable macromolecules. Four pathways have been implicated in the development of retinal pathology as a consequence of hyperglycemia: the polyol (aldose reductase) pathway, the advanced glycation end-products (AGEs) pathway, the hexosamine pathway, and the diacylglycerol (DAG) pathway. Aldose reductase is an enzyme which converts glucose to sorbitol; excess sorbitol is associated with diabetic abnormalities. AGEs are proteins that have become irreversibly modified by nonenzymatic glycation, causing intracellular and extracellular structural damage. AGE receptor binding triggers a cascade of celluslar signaling events, such as activation of mitogen-activated protein (MAP) kinase or protein kinase C (PKC). Most intracellular glucose is metabolized through glycolysis, but some is diverted into a signaling pathway to produce uridine disphosphate (UDP) N-acetyl glucosamine. Glucosamine interacts with transcription factors, ultimately altering gene expression. Hyperglycemia induces increased DAG activity, leading to increased vascular endothelial growth factor production (VEGF), and increased activation of PKC. PKC β inhibition prevents VEGF from increasing PKC β activation, theoretically preventing the endothelial cell proliferation and increased blood-retinal barrier permeability that contribute to proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). VEGF plays a role in normal physiology, but also plays a significant role in pathophysiology. VEGF stimulates angiogenesis and is a potent inducer of vascular permeability. Less well known is that VEGF is proinflammatory; VEGF receptors are present and active on all inflammatory cell types. VEGF levels are elevated in patients with DME and those with PDR. VEGF levels are elevated in the aqueous as well as in the vitreous. These 4 pathways induce cellular dysfunction and damage through the production of glucotoxins (eg, reactive metabolites), activation of cell signaling molecules, or both. Hyperglycemia-induced mitochondrial superoxide production activates these 4 damaging pathways by inhibiting glyceraldehyde-3 phosphase dehydrogenase (GAPDH).
|
