Week 1: Chronic complications of Diabetes Mellitus Flashcards
Chronic complications of DM and impact
- Diabetic nephropathy -most common cause of chronic renal failure in adults
- diabetic retinopathy - leading cause of new blindness in adults
- Neuropathy and Atherosclerosis- DM is most common cause of amputations
Etiology of chronic complications of DM
METABOLIC ABNORMALITIES
-complications occur in Type 1 and 2
-studies shown that complications can be reduced by careful blood glucose control
GENETIC
-25-50% patients don’t develop serious complications despite uncontrolled DM
less than 10% still get it with controlled DM
CONCLUSIONS: varied susceptibility to glycemia
Possible mechanisms of chronic complications of DM
- Non enzymatic glycation of proteins
- Increase in aldose reductase pathway
- Phosphokinase C activation
- Altered microvascular hemodynamics
- Increased oxidative stress
Mechanism for chronic complications: glycation of proteins
- glucose attaches to AA residues on proteins (glucose+protein=ketoamine) and crosslink to form advanced glycation end product (AGE)
- cross linking of protein molecules at glycation moieties occurs over time
- extent of glycation depends on glucose exposure, e.g. Hb in RBCs and proteins in capillary BM are most prone to glycation
- AGE formation may alter function of protein molecules, e.g. leaky BM in retina and renal glomerulus
- AGE can stimulate matrix production by vascular SM, and renal glomerular mesangial cells
Mechanism for chronic complications:aldose reductase pathway
- excess glucose enters cell, some is metabolized to sorbitol via alternative pathway by aldose reductase. Sorbitol converted to fructose
- excess sorbitol pulls water into cells–> swelling, cell damage. Causes diabetic cataracts, possibly neuropathy
- depletes myoinositol, a precursor to molecules involved in cell signaling: reduced PKC activation and Na/K ATPase activity
Mechanism for chronic complications:phosphokinase C activation
- in endothelial cells, vascular SM, renal mesangial cells, that don’t have high aldose reductase
- glucose directly activates diacylglycerol and PKC
- stimulates synthesis of collagen and fibronectin in BM and matrix production by vascular SM and renal mesangial cells
- contributes to nephropathy, atherosclerosis
Mechanism for chronic complications: abnormal microvascular hemodynamics
- early in diabetes: increased blood flow in capillary beds in renal glomerulus and retina
- pressure can damage capillaries
- early flow changes can be reversed by: improved glucose control, ACE inhibitors, ARBs
Mechanism for chronic complications: Oxidative stress
- metabolism of excess glucose makes more free O2 radicals:
- proliferation of vascular SM cells (atherosclerosis)
- inhibition of endothelial cell growth (atherosclerosis)
- inhibit endothelial NO production (atherosclerosis and HTN)
- promotion of AGE products
Diabetic nephropathy- clinical course
- Increased GFR due to increased afferent flow and pressure
- from vasoconstriction of efferent arterioles - microalbuminemia and falling GFR -due to BM thickening and mesangial expansion (proliferation and matrix production)
- proteinuria, low GFR, HTN -due to continued mesangial expansion
- end stage renal failure - glomerular sclerosis and scarring
Diabetic Retinopathy: biological and clinical course
- background retinopathy: pericyte and capillary damage-> retinal ischemia (asymptomatic or blurred vision)
- microaneurysms from capillary dilatations
- dot and blot hemorrhages: intra retinal bleeding
- hard exudates: lipid deposits from bleeding
- capillary loss leading to ischemia - proliferative: neovascularization to vitreous bleeding, retinal detachment (vision loss)
- VEGF responds to ischemia, causes growth of abnormal blood vessels and fibrous tissue
- fibrovascular growth leads to vessel bleeding and fibrous tissue contracting and pulling retina off its blood supply (detachment) - end stage retinopathy: scarring
Rx of diabetic retinopathy
- tight blood glucose control
- laser photocoagulation to limit new vessel and zap cells that produce growth factor
- VEGF inhibition for diabetic macular edema
Clinical types of diabetic neuropathy
FOCAL
-mononeuritis simplex (nerve infarct)-typically CN 3/4. goes away 3-4 months
-entrapment syndromes (e.g. carpal tunnel)
DIFFUSE- more common
-symmmetric sensorimotor neuropathy: longest nerves affected fist
-autonomic neuropathy
-proximal neuropathy
Clinical symptoms of diffuse diabetic neuropathy
- symmetric sensorimotor neuropathy
- pain and tingling to numbers to trauma
- lower extremities first, progresses proximally - autonomic neuropathy
- any aspect of ANS
- posterual hypotension, impotence, gastroparesis, bladder or bowel hypofunction, abnormal sweating
Pathophysiology of diabetic neuropathy
polyol pathway
- myoinositol depletion associated impairment of Na/K ATPase
- impaired nerve conduction and axonal damage
Interventions for diabetic neuropathy
- prevention=glucose control
- symptomatic care otherwise
- inhibition of aldose reductase can improve nerve function in diabetics with neuropathy
