Week 10 Flashcards
How do we classify chronic complications of diabetes?
2 big categories: macrovascular complications and microvascular complications
Macrovascular problems with diabetes
• Atherosclerosis • Hyaline Arteriosclerosis
How does diabetes cause atherosclerosis - what causes it? - How? - collagen - effects - sites
- Advanced glycation end products (AGEs): “proteins with glucose attached” - Cause inflammation and initiation of wound healing when they lodge somewhere; They can cause direct damage to tissue by crosslinking collagen. - Type 1 collagen is in the wall of the arterioles and type 4 collagen is in the basement membrane. Issues with the basement membrane have microvascular and macrovascular effects - Crosslinking of type 4 collagen causes alterations in binding of the endothelium to the basement membrane. A looser binding causes leakiness on fluid and proteins. - Crosslinking of type 1 collagen causes stiffening of arteries or arterioles. When proteins get trapped, it is harder for them to get broken down. In the microvasculature, LDL can get trapped in the wall and intima. - Normally, vessels are able to expand in response to the pressure but when they become thickened/stiffened, they can’t withstand the pressure as well and there is endothelial damage/dysfunction - Sites affected: Heart disease, ischemia in hands and feet, peripheral vascular disease
Hyaline Arteriosclerosis - what happens - effects
○ Hyalinosis-usually from leaky vessels/proteins leaking. It can be all types of proteins (small proteins like albumin, etc). As the proteins cause damage (hyalinosis), you could eventually end up with sclerosis. - Can eventually lead to thickening of the vessel and narrowing of the lumen - Compromised blood supply to heart, kidneys, etc
Microvascular problems with diabetes
- Vascular proliferation - Prothrombotic state
Vascular proliferation - how does this occur? - where is this a problem - what can this cause?
○ is a response to injury and start of wound healing response-release of cytokines, growth factors, VEGF (new vessels) ○ This poses the biggest problem in the eyes –> Vascular retinopathy: Angiogenesis can be good but when it involves the retina, it can cause a lot of problems ○ You can also end up with fragile vessels which can cause hemorrhages in patients who also have hypertension
Prothrombotic state - what happens? - where is it located? - what causes it? - clots - growth factors - what can you leak
- AGE binds to RAGE which causes increased production of cytokines and changes properties of endothelium in a similar way to how direct damage causes a change in endothelial properties - RAGE receptors are in endothelial cells, in macrophages, on vascular smooth muscles - Endothelium is normally antithrombotic but when damage occurs, you get a more prothrombotic state - In addition, plasminogen activator inhibitor causes a “decrease in breaks on the coagulation system”. You can’t inhibit clot formation as well - Binding causes cytokine and growth factor release (especially VEGF and TGFB) - Part of the problem is that this is a vicious cycle and everything adds up to cause exponential problems - In diabetic nephropathy, when you are leaking proteins, you can get a loss of antithrombin 3
Diabetes chronic complications - brain - eyes - arteries - heart - pancreas - kidneys - bladder - extremities
- microangiopathy -> cerebral vascular infarcts - retinopathy, cataracts, glaucoma - hypertension - MI - islet cell loss - nephrosclerosis, glomerulosclerosism arteriosclerosis, and pyelonephritis - autonomic neuropathy - peripheral neuropathy, peripheral vascular atherosclerosis, gangrene, infections
Protein Kinase C - How does it get activated? - effect
- G-coupled protein receptor (IP3/DAG pathway): gets activated by DM, ends in protein transcription/production, - increased glucose leads to spontaneous development of DAG, increased DAG leads to increased production of protein kinase C (independent of the signaling, just amplifies signaling further) - results in increased transcription in a lot of these factors (TGFB, VEGF, & PAI1), this is happening on top of the AGERAGE binding (exacerbates effect)
Oxidative Stress - what binds - produces - how does it cause that? - why is this so bad?
- AGERAGE binding - produces ROS - increased intracellular glucose results in decreased NADPH since it gets used up as a cofactor for aldose reductase (glucose –> sorbitol via aldose reductase + NADPH), NADPH is a critical component for reducing glutathione & reduced glutathione (GSH) is important in clearing up ROS specifically hydrogen peroxide - there are other mechanisms to deal with superoxide & hydroxyl radicals, increased hydrogen peroxide will results in increased damage in cells throughout the body
Pathology of Diabetic Nephropathy - Microvascular - Macrovascular - long term effects
- Microvascular injury contributes more to renal disease than macrovascular injury; hyaline arteriosclerosis decreases GFR via reduced hydrostatic pressure so less blood entering tubule, this narrowing of afferent and efferent arterioles will cause ischemia further down the road, ischemia downstream effects are necrosis or damage to the tubules, - Macrovascular disease: endothelial dysfunction of the larger renal arteries supplying the kidney, can result in accelerated atherosclerosis or stenosis which causes decreased blood supply to the kidneys or globally, - overtime the tubular damage leads to repair & scarring which contributes to the long-term diabetes effects on kidneys, eventually will have sclerosis of the tubules (lose nephron = decreases functional renal mass) which leads to increased intraglomerular pressure in the remaining nephrons
What is this? - which is more affected?
- hyaline arteriosclerosis - Top artery = more affected = thicker & more pink material (due to sclerosis over time) & more narrow lumen –> necrosis & epithelial cells sloughing off , Bottom artery = less affected
What is this? - where is it? - initial steps - end stages
- nodular sclerosis caused by deposition of glycated end products or activation of AGERAGE or signaling pathway - mesangium - Proliferation of mesangial cells then mesangial cells respond to injury by producing collagen, mesangial matrix is made by mesangial cells (mesangial cells make their own matrix), overtime this causes sclerosis (very focal within mesangium then eventually becomes diffuse), this will have an impact on filtration and scarring will lead to a dysfunctional nephron
What is this?
- sclerosis & hyalinosis
What is diffuse mesangial sclerosis
hyalinosis caused by deposition of collagen & leaky vessels, leaking out proteins like albumin or antithrombin (mentioned earlier)
What is this? - caused by? - effects
- thickening of basement membrane in glomeruli - deposition via signaling and by type IV collagen cross-linking - traps proteins like albumin in the basement membrane; ross-linking of basement membranes causes them to be leaky and also causes problems with absorption & secretion of ions within the tubules as well, all of this adds to the dysfunction,
