Pathophysiology
Summary
Diabetes mellitus is a chronic endocrine disorder that has widespread pathological effects, particularly through the formation of advanced glycation end products (AGEs) due to chronic hyperglycemia. AGEs crosslink proteins, weakening arterial walls and accelerating atherosclerosis. When AGEs bind to their specific receptors, known as RAGE, they initiate pro-inflammatory cascades and reactive oxygen species production, damaging vascular endothelial cells. One microscopic manifestation is microangiopathy, characterized by thickening of the basement membrane in small vessels due to excess type IV collagen production.
Diabetic nephropathy is a key contributor to chronic kidney disease. It is marked by glomerular basement membrane thickening and nodular glomerulosclerosis, identifiable by Kimmelstiel-Wilson nodules. These damaged glomeruli allow albumin to leak into the urine, a precursor to further renal impairment.
Diabetic retinopathy, a leading cause of blindness, comes in two forms: nonproliferative and proliferative. Nonproliferative diabetic retinopathy involves microaneurysms, retinal blood vessel ruptures leading to flame hemorrhages, and ‘cotton wool spots’ which are fluffy-white appearing areas caused by micro-infarctions of the nerve fiber layer. Proliferative diabetic retinopathy involves neovascularization of the retina due to an increase in VEGF, which often leads to hemorrhage and cloudy vision, blockage of aqueous humor drainage leading to glaucoma, and retinal detachment. Diabetes increases the incidence of retinopathy due to factors such as damage from AGEs, osmotic damage, and inflammation.
Diabetes also impacts the cardiovascular system. Chronic hyperglycemia initiates AGE-induced endothelial damage, facilitating atherosclerotic plaque formation and increasing the risk for coronary artery disease (CAD). This cascade can lead to myocardial infarctions and heart failure, making cardiovascular disease the leading cause of death among diabetics. The risk of cerebrovascular disease, including strokes, is also elevated in these individuals.
Many types of cells trap glucose intracellularly by converting it to sorbitol via aldose reductase. However, some tissues like the retina, lens, and Schwann cells lack sorbitol dehydrogenase and are unable to metabolize sorbitol further to fructose. os sorbitol is osmotically active, accumulation causes cellular edema in tissues lacking sorbitol dehydrogenase, resulting in osmotic damage. This leads to cellular edema, protein precipitation in the lens causing cataracts, and demyelination of Schwann cells, culminating in peripheral neuropathy.
Diabetic neuropathy typically presents with a ’stocking glove’ and has far-reaching implications. It can cause diabetic foot ulcers due to a combination of arterial disease and immune dysfunction. These ulcers may devolve into gangrene, sometimes requiring amputation. Charcot joints may occur due to neuropathic arthropathy. Gastrointestinal problems like gastroparesis arise from vagal neuropathy, while autonomic neuropathy can cause conditions ranging from impotence to orthostatic hypotension.
The integumentary system is also affected, as seen in conditions like acanthosis nigricans, which cause velvety pigmented skin plaques, especially in the neck, back, & axillae and necrobiosis lipoidica. Diabetics are also more susceptible to recurrent fungal infections and bacterial infections because of factors like impaired wound healing, urinary retention, and elevated blood glucose levels, which create a favorable environment for their proliferation.
Lesson Outline
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FAQs
Advanced glycation end products (AGEs) form through non-enzymatic glycation, where glucose bonds covalently with free amino groups on proteins. AGEs cause damage or dysfunction by crosslinking proteins, especially in collagen. These alterations can reduce arterial intimal integrity, allowing LDL to enter vessel walls and speed up atherosclerosis. Additionally, AGEs can bind to receptors of AGE (RAGE) throughout the body, triggering the release of growth factors and inflammatory cytokines. This cascade of events leads to tissue damage, particularly to vascular endothelial cells, by generating reactive oxygen species.
Diabetic microangiopathy involves histological changes such as diffuse basement membrane thickening in capillaries and small arterioles due to overproduction of type IV collagen by vascular fibroblasts. Concentric layers of eosinophilic hyaline around the basement membranes of capillaries another histological feature. The diffuse basement membrane thickening reduces the integrity of capillaries, leading to leakage of plasma proteins.
Diabetic nephropathy, a leading cause of chronic kidney disease, is characterized by diffuse glomerular basement membrane thickening and glomerulosclerosis, which are changes seen on histology. Glomerulosclerosis involves hyaline deposition in leaky glomerular capillaries. Leaky capillaries spill albumin into urine, and microscopic albuminuria is an early marker of diabetic kidney disease. Severe manifestations of diabetic nephropathy include significant albuminuria along with reduced glomerular filtration rate (GFR).
Diabetic retinopathy, one of the main causes of blindness in the US, comes in two forms: nonproliferative and proliferative. Nonproliferative diabetic retinopathy involves microaneurysms, retinal blood vessel ruptures leading to flame hemorrhages, and "cotton wool spots" which are fluffy-white appearing areas caused by micro-infarctions of the nerve fiber layer. Proliferative diabetic retinopathy involves neovascularization of the retina due to an increase in VEGF, which often leads to hemorrhage and cloudy vision, blockage of aqueous humor drainage leading to glaucoma, and retinal detachment. Diabetes increases the incidence of retinopathy due to factors such as damage from AGEs, osmotic damage, and inflammation.
Diabetic neuropathy is a common complication of diabetes. Many types of cells trap glucose intracellularly by converting it to sorbitol via aldose reductase. However, some tissues like the retina, lens, and Schwann cells lack sorbitol dehydrogenase and are unable to convert sorbitol further to fructose. As sorbitol is osmotically active, accumulation causes cellular edema in tissues lacking sorbitol dehydrogenase, resulting in osmotic damage. Damage to Schwann cells causes demyelination, leading to a "stocking glove" peripheral neuropathy, which involves a loss of proprioception and vibration. Other possible consequences include cranial nerve palsies, gastroparesis due to vagus nerve damage, and autonomic neuropathy leading to a host of complications, including impotence, neurogenic bladder, and orthostatic hypotension.
