Page 327 first aid 2014: Two main ways: nonenzymatic glycosylation and osmotic damage due to sorbitol
Nonenzymatic glycosylation:
Small vessel disease and large vessel disease
Large vessel disease: You have too much sugar in your blood because insulin isn't moving it into cells. This sugar will start attaching to the blood vessels by nonenzymatic glycosylation which means that you're adding sugars onto a functional group without the help of an enzyme. Have you ever spilled something sugary on the floor? It gets all sticky, doesn't it? So will the endothelial cells that make up your blood vessels. So things will start sticking to them, like LDL and blood cells that eat them and turn into foam cells. If things fill up the blood vessel, then you get crappy blood flow, low oxygen delivery and damage to cells. This is why diabetics start losing toes and are at an increased risk for getting a stroke or an MI.
Small vessel disease: If you have too much stuff in your blood, LDL and sugar, that will bring in more water into your blood vessels as well. More water means higher blood pressure. Higher blood pressure leads to a thickened basement membrane. What does a basement membrane do? It blocks most things from going through like cells and proteins while letting things that you need to for cells to grow like water and sugar and O2. If your basement membrane is thick, then you will have low O2 going to the cells in the retina as well as the nerves. You get ischemic damage from this low O2 and the cells will give off signals like vegf to tell the body that they need more O2 so make more blood vessels for us. This leads to increased blood vessel proliferation as well as retinal hemorrhage because even though the basement membrane is thicker, it is also more permeable.
Page 107 first aid
How do you keep glucose in cells? First way: phosphorylate it with glucokinase or hexokinase and you get glucose-6-phosphate. Another way is to turn glucose into sorbitol using aldose reductase. Then you have sorbitol dehydrogenase to turn sorbitol into fructose. But what if some of your cells don't have sorbitol dehydrogenase? Then you would get stuck with a lot of sorbitol in your cells. Schwann cells, retina, kidney only have aldose reductase and the lens has mostly aldose reductase. So you have a lot of sorbitol which exerts a certain osmotic pressure, bringing in water. Having a lot of water damages cells (remember that the hallmark of reversible damage to cells is cell swelling when you don't have enough O2 to make atp to run the Na/K pump). Schwann cells myelinate axons but if they're swelling and putting pressure on the nerves they're supposed to protect, you would have pressure atrophy. Which nerves do schwann cells myelinate? Peripheral nerves so you get degeneration of motor, sensory and autonomic nerves. Increased water in the lens leads to cataracts (this is also the mechanism for infantile cataracts in galactosemia).
Hope this is right and hope this helps.
