Complications of Diabetes Flashcards
Diabetic Ketoacidosis is generally associated with which type of Diabetes?
Type I
Insulin resistance associated with which type of Diabetes?
Type II (they’ll have hyperinsulinemia)
What are the three organs most commonly and dramaticaly affected by diabetes?
Eyes, Nerves, Kidneys
What is the most likely cause of death for diabetic pts?
Atherosclerotic vascular disease
-Prior to age 40, the most common cause of death is renal failure. However, only 10% of diabetes pts die during this time period and after ago 40 atherosclerotic vascular disease becomes the greatest cause
Metabolic Syndrome (T2D) requires a comboination of genetic and environmental factors. The major environmental factors are:
Obesity and lack of exercise
The development of fat tissue where is a significant risk factor for metabolic syndrome?
Visceral fat tissue (in messentery and omentum)
Why is visceral fat such a risk factor?
visceral fat secretes excessive amounts of free fatty acids, leptin, TNF, Angiotensin II, PI-1.
Also reduces the secretion of adiponectin
What exactly is the mechanism by which the secretion of these substances by visceral fat leads to damage?
Various tissues take up the Free fatty acids where they are oxidized, stored as triglycerides, or converted to prostaglandins. The excessive oxidation of glucose and FFAs via the mitochondrial electron transport chain genereates the ROS “super oxide” which is a free radical that oxidizes cysteine amino acids. One of these is RAS which, when oxidized, will activate serine threonine kinases such as Protein kinase C. These free radicals can oxidize and damage many cell macromolecules
What does RAS activate once it is oxidized?
Serine threonine kinases such as protein C
What can free radicals do that is bad>
oxidize and damage many cellular macromolecules
Superoxide can be generated via what enzyme?
coenzyme Q10
How does a high glucose/ high FFA concentration cause this development of superoxide?
Excess FFA and glucose oxidation means that there is excess H+.
This excess H+ is pumped into the electron transport chain and inhibits the cytochromes from accepting an electron from CoQ10, which is what normally happens. This electron is then pushed to oxygen and SO is generated.
What do the Super Oxides then do>
activate kinases which activate nuclear factors which ctivate genes that control inflammation. These cytokines, chemokine, etc…then produce the ischemia, cellular proliferation, matrix accumulation, and dysfunction, cellular necrosis, and apoptosis
What does NO do?
vasodilator
inhibits NFKB (inflammation)
inhibits platelett aggregation
What does super oxide do to NO
Destroys it
excess glucose can generate additional super-oxide via
auto-oxidation…it is metabolized to sorbitol and advanced glycosylation end products
excess glucose will induce a deficiency of what?
myo-inositol
KNOW.. high free fatty acids also induce excessive VLDL secretion from the liver which will have adverse effects on other lipoproteins and forther accelerate microvascular disease
This is very detrimental to beta cells
Ceramide is
a particularly bad fatty acid that induces NO to cause apoptosis. Apoptosis in the islets destroys beta cells.
Arachidonate
substrate for the pro-inflammatory prostaglandins that contribute to islet destruction
What is bad about a high NADPH to NADP ratio
1) inhibits further glucose and fatty acid oxidation- The partially degraded FAs remain bound to carnitine and inhibits the transfer of more fatty acids into the mitochondria. This allows toxic organic acids to accumulate in the cytoplasm
2) Increase in the production of Glyceraldehyde 3 Phosphate, a precursor for Diacylglycerol which activates protein kinase 3
3) More lactate made…acidosis
What is super oxide a potent activator of?
Protein Kinase 3
What is aldose reductase
an enzyme present in certain cells that converts glucose to sorbitol and then to fructose
Conversion to fructose is inhibited by
high NADH concentrations
Inhibition of conversion of sorbitol to fructose leads to?
Increased levels of sorbitol in the cytoplasm….osmotic swelling of cells.
Where does this conversion to sorbitol and the osmotic swelling generally take place
In the lens, contributes to blurring of vision
What is Myo-isositol?
It is a molecule involved in the Phosphatidylinositol (PI) pathway. PI is found on the outside of plasma membranes and has a rapid turnover. Must have intracellular myo-inositol for this pathway. Myo-inositol is generally concentrated inside the cell by an active transport system.
What blocks myo-inosital active transport?
sorbitol
What cells are particularly susceptible to sorbitol’s inhibitance of the PI pathway via its blocking of myo-inosital active transport?
Neurons
It is apparent from several studies that in order for Na/K ATPase to be functional, both arms of the PI pathway must function correctly (DAG and IP3 arms).
Na/K ATPase is reduced in a number of diabetic issues, particularly nerves where it is vital for nerve conduction.
What is the basic concept behind non-enzymatic glycosylation?
Whenever glucose comes in contact with protein or DNA molecules, it can become covalently linked via the aldehyder group on glucose and the terminal amino acid groups on arginine, lysine, and nucleic acids.
The initial step in NEG is what?
formation of a schiff base…very labile, easily reversible, reaches equilibrium within hours
What occurs after Schiff base formation
Amadori product formation (less labile)
Reversal of the Amadori product takes about how long?
Four weeks….this is the product that is used to measure hemoglobin A1C which monitors pts glucose control over the previous 4-8 weeks
What determines the extent of NEG
the concentration of glucose and the period of time that DNA or protein is exposed to it?
- If these glucose molecules happen to block an important binding or enzymatic site, they can disrupt normal function. Glycosylation can also create novel binding sites so that the protein binds to things that it normally would not.
Glycosylated proteins can undergo a series of oxidation-dehydration reactions and rearrangements to form:
complex advanced glycosylation end products (AGE-products)
What is the most important result of this reaction?
the formation of cross-links between proteins and/or strands of DNA via these AGE-products.
Are AGE reactions reversible?
No…prevent normal degradation of these proteins
Macrophages and endothelial cells have a receptor for AGE proteins. When these cells bind an AGE protein, they activate Protein Kinase C which leads to ischemia and inflammation
ok
What proteins make up the extracellular matrix?
collagen, elastin, fibronectin
What proteoglycans make up the extracellular matrix?
heparan sulfate
Collagen and Elastin are mainly:
structural proteins (like the steel beams of a building)
Fibronectin is:
adhesive protein
Collagen synthesis is stimulated by
TGF-beta (elevated in diabetes by protein kinase C)
What inhibits collagen synthesis?
Nitric Oxide
Proteoglycans act as:
fillers (like mortar)
Proteoglycan synthesis is inhibited by?
Protein Kinase C
Heparan sulfate is the most important proteoglycan because it does what?
determines size and charge sieving property of basement membrane
Heparan sulfate is held in place byu binding to:
collagen
Heparan binding to collagen is disrupted by?
glycosylation
Basement membranes in diabetic patients:
feature increased collagen (b/c TGF-beta stimulates collagen synthesis and TGF-beta is eloevated by protein kinase c) and a reduction in heparan sulfate (due to reduced production and reduced binding to collagen). see the ecm section oif handout
Diabetes is a disease of the body’s filters, meaning
diabetes negatively impacts basement membranes
Glomerular filtration is determined by three factors
1) perfusion pressure
2) glomerular capillary surface
3) Integrity of the basement membrane
Within days of development of diabetes, what happens to perfusion pressure in the glomerulus?
It goes up because of dilation of the afferent and constrictin of the efferent arterioles
Kidneys enlarge in diabetes?
yes
GFR Is increased?
yes
TIght regulation of blood glucose will arrest the progression of nephropathy at what stage?
micro-albuminuric….variable effect at later stages
Read section on diabetic nephropathy
really only makes sense when you see it all connecting
The fundamental pathophysiology of a neuropathic ulcer is:
pressure—> ischemia—> inflammation
