Flashcards in B2.050 Prework 1 Chronic Complications of Diabetes Deck (49)
what is the difference between micro and macrovascular disease?
macro includes damage induced in large and medium sized muscular arteries
micro includes damage in small vessels
what is responsible for the long term complications of diabetes?
how is glycemic control primarily assessed?
percentage of glycated hemoglobin
what is the recommended HbA1c level in diabetic patients?
maintenance below 7%
what are AGEs?
advanced glycation end products
formed as a result of noenzymatic reactions between intracellular glucose derived dicarbonyl precursors with amino groups of proteins
what is the AGE-RAGE signaling axis?
AGEs bind to RAGE receptors expressed on inflammatory cells, endothelium, and vascular smooth muscle
what are the 4 primary negative effects of the AGE-RAGE signaling axis?
1. release of cytokines and growth factors
TGFB- leads to deposition of excess basement membrane material
VEGF- implicated in retinopathy
2. generation of ROS in endothelial cells
3. increased procoagulant activity
4. enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
what other effect can AGEs have outside of receptor mediated effects?
can cross link extracellular matrix proteins
what are some of the negative effects of AGE mediated cross linking?
collagen type 1-decreases elasticity, predisposing vessels to injury
collagen type 4- decreases endothelial cell adhesion and increases extravasation of fluid
protein- resists digestion
what is protein kinase C?
intracellular protein activated by calcium and DAG
what are effects of excessive PKC activation by hyperglycemia?
VEGF, TGFB, and procoagulant protein plasminogen activator inhibitor-1
how does hyperglycemia disturb the polyol pathway?
excess glucose is metabolized by aldolase reductase to sorbitol
sorbitol metabolized to fructose using NADPH
decrease of NADPH availability for reduction of glutathione
less GSH for antioxidant mechanisms
what is an effect of sorbitol accumulation?
what is the effects of hyperglycemia induced flux through the hexosamine pathway?
increased intracellular levels of fructose-6-phosphate (substrate for glycosylation)
generation of excess proteoglycans
what pancreas alterations are commonly found in type 1 diabetes?
reduction in number and size of islets
leukocytic infiltrates in islets
what pancreas alterations are commonly found in type 2 diabetes?
subtle reduction in islet cell mass
amyloid deposition within islets
what is the hallmark of diabetic macrovascular disease?
what is the most common cause of death in diabetes?
MI caused by atherosclerosis of the coronary arteries
what is 100x more common in diabetics than in the general population?
gangrene of the lower extremities
what is hyaline arteriolosclerosis?
hyaline thickening of the wall of the arterioles which causes the narrowing of the lumen
what is one of the most consistent morphologic features of diabetes?
diffuse thickening of the basement membrane
what is the result of thickening of the basement membranes?
diabetic capillaries are more leaky than normal to plasma proteins
underlies development of diabetic nephropathy, retinopathy, and some neuropathy forms
what is the second leading cause of death in diabetics?
what are 3 renal lesions encountered in diabetic nephropathy?
1. glomerular lesions
2. renal vascular lesions (arteriolosclerosis)
what are the most important glomerular lesions?
capillary basement membrane thickening
diffuse mesangial sclerosis
what percentage of cases of diabetic nephropathy show widespread thickening of the glomerular capillary basement membrane?
virtually all of them
when does GBM thickening begin?
2 years after onset of diabetes
amounts to 30% by 5 years
what is mesangial increase typically associated with?
overall thickening of the GBM
what does the progressive expansion of the mesangium correlate with?
measures of deteriorating renal function such as increasing proteinuria