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DEMS: Unit II > Diabetes Complications > Flashcards

Flashcards in Diabetes Complications Deck (19):
1

Mechanisms of hyperglycemia ==> micro-vascular diabetic complications

  • polyol pathway
  • non-enzyme glycosylation ==> pro-inflammatory pathway
  • elevation of protein kinase C (PKC)
  • oxidative carbonyl stress
  • Bownlee unifying hypothesis

2

Characteristics of polyol pathway in DM

  • Glucose → sorbitol / fructose → osmotic + oxidative stress → abnormal cellular function
  • Aldose reductase is the therapeutic target

3

Characteristics of non-enzymatic glycosylation pathway in DM

  • hyperglycemia ==> more glucose bind to amines and nucleic acids ==> irreversible rxns ==> advanced glycosylation end products (AGE)
  • AGEs ==> diabetic complications: nephropathy, vasculopathy, retinopathy
    • interfere with basement membrane function + NO in vasculature leading to abnormal vasculature and collagen production
    • interferes DNA function and repair

4

Characteristics of elevation of protein kinase C in DM

  • @ renal and vascular cells ==> production of ECM proteins collagen and fibronectin ==> basement membrane thickening
  • @ endothelial cells PKC elevations ==>
    • increased expression of ICAMs
    • increased expression of plasminogen inhibitor activator-1 (PAI-1)
    • increased expression of vascular endothelial growth factor (VEGF)
    • defective production of vasodilating factor NO.

5

Characteristics of elevation of oxidative carbonyl stress in DM

  • Diabetes is associated with increased extracellular and intracellular oxidative burden.
  • ↑ intracellular reactive oxygen species → 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.

6

Brownlee unifying hypothesis

  • glucose usually goes to mitochondria
  • If excess glucose, mitochondria becomes uncoupled, leads to reactive O2 species → retinopathy

7

Microvascular complications in DM

  • Retinopathy
  • Neuropathy
  • Nephropathy
  • Amputation

8

Characteristics of diabetic retinopathy

  • Periocyte → autoregulation cell of blood flow in retina.
    • Periocytes = neurons and thus love glucose
    • too high or too low causes them to die → rerouting of vascular architecture.
  • Capillary dropout, basement membrane thickening, leakage of intravascular fluids leading to soft and hard exudates → hypoxic state → VEGF → Neovascularization and proliferative retinopathy → blindness

9

Diabetic retinopathy tx/prevention

  • Do annual ophthalmologic examinations, keep tight glycemic control to prevent this
  • May need to intervene with laser therapy, photocoagulation, inject steroids or anti-VEGF (can prevent 80-90% of retinopathy/blindness w/early intervention)

10

Characteristics of diabetic 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)

11

Characteristics of diabetic nephropathy

  • 35% of people with diabetes will get this
  • Long preclinical phase with normal or supranormal GFR
  • Proteinuria is a critical marker
  • Measure microalbumin to assess early changes & treat.
  • Once there is gross proteinuria, rapid degeneration and renal failure ensue
  • Slow progression with ACE-I, tight glycemic control

12

Macrovascular complications of DM

  • CV disease
  • HTN contributes to all microvascular and macrovascular complications of DM

13

Vascular wall response to DM

1. Abnormal endothelial cell function:

2. Abnormal vascular smooth muscle cell function

 3. Inflammation and decreased fibrinolysis

 

14

Abnormal endothelial cell fxn in DM

a. Abnormal clotting factor production- decreased tPA and increased PAI-1

b. Inflammation due to expression of adhesion molecules (aggregation of platelets and leukocytes)

c. Decreased endothelium dependent vasomotion

d. Increased cytokine and chemokine production

         

15

Abnormal vascular smooth muscle cell fxn in DM

a. Enhanced vascular smooth muscle (VSM) proliferation and migration

b. Increased production of matrix proteins, cytokines and growth factors

c. Altered contractile function

16

Abnormal vascular inflammation and decreased fibrinolysis in DM

]a.Platelet adhesion and activation

b.Monocyte adhesion and macrophage activation and invasion into sub-intimal space, expression of cytokines and chemokines

c.Foam cell formation and activation of metalloproteinases

17

Tx/prevention of macrovascular complications in DM

  • Interventions to decrease cardiovascular risk are even more effective in people w/ DM due to their increased CV burden
  • treatment with b blockers, antihypertensives and lipid lowering agents, have great outcome benefits in this population
  • Aspirin has less of an impact in diabetes, but should be used in high risk subjects and people with diabetes and established CVD.
  • early intensive glycemic control (first 3-10 years of diabetes) in people with diabetes decreases macrovascular events years later. 

18

Normal Presentation of hypoglycemia 

  • Adrenergic sx (mediated by epinephrine/glucagon)
    • Sweating
    • Tremor
    • Tachycardia
    • Anxiety
    • Hunger
  • Neuroglycopenic sx
    • Dizziness
    • Headache
    • Decreased mental activity
    • Clouding of vision
    • Confusion
    • Convulsions
    • Loss of consciousness

 

19

Characteristics of hypoglycemia unawareness

  • loss of adrenergic response to hypoglycemia 
  • progress directly to altered mental status
  • often occurs in context of frequent episodes of hypoglycemia