Diabetes Complications Flashcards
Mechanisms underlying the excess macrovascular complications in diabetes
Vascular wall response to diabetes:
- Abnormal endothelial cell function
- Abnormal clotting factor production
- Inflammation due to expression of adhesion molecules
- Decreased endothelium dependent vasomotion
- Increased cytokine and chemokine production
Abnormal vascular smooth muscle cell function:
- Enhanced vascular smooth muscle (VSM) proliferation and migration
- Increased production of matrix proteins, cytokines and growth factors
- Altered contractile function
Inflammation and decreased fibrinolysis
- Platelet adhesion and activation
- Monocyte adhesion and macrophage activation and invasion into sub-intimal space, expression of cytokines and chemokines
- Foam cell formation and activation of metalloproteinases
Therapeutics interventions for macrovascular complications in diabetes
Lipid lowering significantly decreases mortality and cardiovascular events in people with diabetes
Trials demonstrate decreased CV mortality with intensive blood pressure control (Also hypertension contributes to all microvascular and macrovascular complications of diabetes.)
Treatment with β blockers, antihypertensives and lipid lowering agents, have great outcome benefits. Aspirin has less of an impact in diabetes, and should be used in high risk subjects and people with diabetes and established CVD.
Intensive glycemic control (first 3-10 years of diabetes) in people with diabetes decreases macrovascular events years later.
Mechanisms by which hyperglycemia causes the development of microvascular diabetic complications
Polyol pathway
Non-enzymatic glycosylation
Elevation of Protein Kinase C
Oxidative/Corbonyl Stress
What are the microvascular complication of diabetes
Retinopathy
Nephropathy
Neuropathy
Small vessels cannot defend themselves against high glucose
PKC activation causes damage to vasculature, retina, kidney, heart.
What are the macrovascular complications of diabetes?
CVD: 77% percent of all hospitalizations and 80% of all mortality in diabetes are secondary to cardiovascular disease.
What is the legacy effect?
Tight blood glucose control for 4-5 years early in the disease process leads to decreased CV events 10-20 years later
How does the polyol pathway contribute to the microvascular damage in diabetes?
Hyperglycemia leads to an influx of glucose into cells, which can be metabolized by aldose reductase to sorbitol and fructose.
These molecules can cause osmotic and oxidative stress leading to abnormal cellular function. Inhibitors of aldose reductase can block this pathway.
How does non-enzymatic glycosylation contribute to the microvascular damage in diabetes?
Pro-inflammatory pathway
Result of hyperglycemia, glucose is more likely to bind to amines and nucleic acids and then undergo irreversible rxns producing advanced glycosylation end products (AGE)
AGEs have well established role in diabetic complications including nephropathy, vasculopathy, retinopathy.
AGEs interfere with basement membrane function + NO in vasculature leading to abnormal vasculature and collagen production; interferes DNA function and repair too.
How does elevation of protein kinase C contribute to the microvascular damage in diabetes?
Pro-inflammatory pathway
In renal and vascular cells protein kinase c leads to the production of the extracellular matrix proteins collagen and fibronectin which creates basement membrane thickening
In endothelial cells PKC elevations promotes increased expression of ICAMs - adhesion molecules which promote monocyte and platelet aggregation at the vessel wall, increased expression of plasminogen inhibitor activator-1 (PAI-1), increased expression of vascular endothelial growth factor (VEGF), and defective production of vasodilating factor NO.
How does oxidative/carbonyl stress contribute to the microvascular damage in diabetes?
Diabetes is associated with increased extracellular and intracellular oxidative burden.
Increased intracellular reactive oxygen species lead to short term cellular dysfunction + long-term tissue damage.
Oxidant injury leads to enzymatic blockade of normal glycolysis leading to shunting of glucose metabolites into the deleterious pathways outlined above.
Circulating and intracellular antioxidant levels are decreased in diabetes.
Retinopathy
Diabetes is the leading cause of blindness in the U.S.
Periocytes: autoregulation cell of blood flow in retina.
Periocytes are neurons and thus love glucose, too high or too low causes them to die which causes rerouting of vascular architecture.
Capillary dropout, basement membrane thickening, leakage of intravascular fluids leading to soft and hard exudates leads to hypoxic state causing more VEGF which causes neovascularization and proliferative retinopathy and eventually blindness
Do annual ophthalmologic examinations, keep tight glycemic control to prevent this
Retinopathy progression is largely preventable with early intervention with panretinal photocoagulation, laser therapy, photocoagulation, inject steroids or anti-VEGF
Neuropathy
Mononeuritis multiplex is unique to diabetes, is an infarction of nerves. Usually sensory only, unless a CN in which case it can be motor and sensory.
Most common is distal symmetric polyneuropathy (think fingers and toes). Starts as pain and prickling, progresses to numbness. Causes serious troubles in feet including ulcers.
Autonomic neuropathy is most dangerous; leads to hypoglycemia unawareness; causes ED, constipation. Strong predictor of premature death.
Diabetic amyotrophy (amyotrophy = progressive wasting of muscle tissues)
Nephropathy
Diabetes is the leading cause of renal failure/dialysis and transplant nationwide.
Aggressive control of hyperglycemia (with intensive therapy) and blood pressure (with ACE inhibitors or β blockers) has been shown to retard the progression of nephropathy in DM patients.
What is is the most frequent cause of non-traumatic lower limb amputations?
diabetes
What is the stage in retinopathy where intervention should be started?
severe proliferative
