Flashcards in Complications of Diabetes Deck (59)
Diabetic Ketoacidosis is generally associated with which type of Diabetes?
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?
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?
inhibits NFKB (inflammation)
inhibits platelett aggregation
What does super oxide do to NO
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?
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
a particularly bad fatty acid that induces NO to cause apoptosis. Apoptosis in the islets destroys beta cells.
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?
What cells are particularly susceptible to sorbitol's inhibitance of the PI pathway via its blocking of myo-inosital active transport?