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Endocrine > Week 1: Chronic complications of Diabetes Mellitus > Flashcards

Week 1: Chronic complications of Diabetes Mellitus Flashcards

1
Q

Chronic complications of DM and impact

A
  • 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
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2
Q

Etiology of chronic complications of DM

A

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

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3
Q

Possible mechanisms of chronic complications of DM

A
  1. Non enzymatic glycation of proteins
  2. Increase in aldose reductase pathway
  3. Phosphokinase C activation
  4. Altered microvascular hemodynamics
  5. Increased oxidative stress
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4
Q

Mechanism for chronic complications: glycation of proteins

A
  • 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
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5
Q

Mechanism for chronic complications:aldose reductase pathway

A
  • 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
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6
Q

Mechanism for chronic complications:phosphokinase C activation

A
  • 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
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7
Q

Mechanism for chronic complications: abnormal microvascular hemodynamics

A
  • 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
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8
Q

Mechanism for chronic complications: Oxidative stress

A
  • 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
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9
Q

Diabetic nephropathy- clinical course

A
  1. Increased GFR due to increased afferent flow and pressure
    - from vasoconstriction of efferent arterioles
  2. microalbuminemia and falling GFR -due to BM thickening and mesangial expansion (proliferation and matrix production)
  3. proteinuria, low GFR, HTN -due to continued mesangial expansion
  4. end stage renal failure - glomerular sclerosis and scarring
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10
Q

Diabetic Retinopathy: biological and clinical course

A
  1. 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
  2. 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)
  3. end stage retinopathy: scarring
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11
Q

Rx of diabetic retinopathy

A
  1. tight blood glucose control
  2. laser photocoagulation to limit new vessel and zap cells that produce growth factor
  3. VEGF inhibition for diabetic macular edema
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12
Q

Clinical types of diabetic neuropathy

A

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

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13
Q

Clinical symptoms of diffuse diabetic neuropathy

A
  1. symmetric sensorimotor neuropathy
    - pain and tingling to numbers to trauma
    - lower extremities first, progresses proximally
  2. autonomic neuropathy
    - any aspect of ANS
    - posterual hypotension, impotence, gastroparesis, bladder or bowel hypofunction, abnormal sweating
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14
Q

Pathophysiology of diabetic neuropathy

A

polyol pathway

  • myoinositol depletion associated impairment of Na/K ATPase
  • impaired nerve conduction and axonal damage
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15
Q

Interventions for diabetic neuropathy

A
  • prevention=glucose control
  • symptomatic care otherwise
  • inhibition of aldose reductase can improve nerve function in diabetics with neuropathy
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16
Q

diabetes and atherosclerosis: Contributing mechanisms to CV events

A
  1. Arterial wall changes
    - lipid abnormalities
    - HTN
    - protein glycation
    - PKC activation
    - hyperinsulinemia
    - O2 radical generation
  2. Thrombus formation (pro coagulant state)
    - enhanced platelet aggregation and adherence
    - increased PAI-1
    - increased fibrinogen levels
17
Q

Typical pattern of serum lipid abnormalities in DM

A
  1. High total triglycerides
  2. low HDL cholesterol
  3. small dense LDL particles
18
Q

Mechanism for typical dyslipidemia in DM

A
  • insulin resistance results in increased HSL activity–leads to increased breakdown of TGs to FFAs
  • FFAs transported to liver and can stimulate synthesis of TG and cholesterol ester
  • these lipids can stimulate assembly and secretion of VLDL
  • Increased plasma VLDL-TG can exchange with cholesterol esters from HDL; mediated by a plasma protein called cholesterol ester transfer protein (CETP). This exchange results in lower plasma HDL-C levels and in the loss of apo A-I, the major protein on HDL
19
Q

Interventions for atherosclerosis, dyslipemia in DM

A
  • agressive control of LDL, blood pressure
  • increase HDL
  • control blood glucose levels
  • aspirin

Endocrine (33 decks)

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