Diabetic Cellular Damage Flashcards
In the fasting state blood glucose concentration is determined by the balance between endogenous glucose production is through…
Hepatic glycogenolysis and gluconeogenesis and use insulin dependent tissues
What is different about diabetes insipidus when compared the diabetes mellitus?
The symptoms of both are similar (inc urination and thirst)
Different b/c urine not concentrated normally, frequent, pale in color, low concentration of solutes
What is type 1 diabetes mellitus?
The inability to produce insulin and usually diagnosed in childhood
What is type 2 diabetes mellitus?
Combination of insulin resistance and dysfunctional pancreatic beta cells
What types of food and hormones stimulate insulin release?
Sugars, amino acids, free fatty acids
Glucagon, GLP-1, GIP and secretin
What is the key feature of diabetes?
increase in Insulin resistance
Uncontrolled liver glucose production
Do beta cells still function in type 2 diabetes?
Yes but there is not enough insulin being made
What are the macrovascular complications of diabetes?
Cardiovascular disease (dyslipipdemia)
Ischemic heart disease
Stroke
Peripheral vascular disease
What are the microvascular complications of diabetes?
Retinopathy
Nephropathy
Peipheral neuropathy
<p>Which tissues are damaged in long-term hyperglycemia?</p>
<p>Capillary endothelia in retina</p>
Renal mesangial glomerulus cells</p>
Schwann cells in the peripheral nerves</p>
Diabetic complication are indicated to occur…
Intracellularly
What does aldose redutase do?
Reduces toxic aldehydes to sugar alcohol
ex. reducing galactose to galacticol using electrons from NADPH
If glucose levels are too high in the eye what forms?
Sorbitol using NADPH
Why would oxidative stress occur if there is excess glucose?
NADPH is wasted converted glucose to sorbitol so there is less to re-reduce glutathione, a critical antioxidant. The build up of sorbitol causes osmotic swelling (in the eye for example) because it is trapped in cells.
What does the gene AKR1B1 do?
Encodes aldose reductase
Eliminates some toxic lipid aldehydes
May reduce inflammatory responses
What happens to sorbitol of AKR1B1 (aldose reductase) is inhibited?
The sorbitol level is reduced and NADPH is not wasted
The process of aldose reductase reducing aldehydes incorrectly in a diabetic state is called…
Increased flux through polyol pathway
What are Advanced Glycation Endproducts (AGEs)?
Low molecular weight products that diffuse out of cells
Large molecules derivatives that have been damaged (or crosslinked)
What are the step in intracellular AGE precursor damage?
- Intracellular proteins damaged (gene regulators)
- Modification of extracellular matrix molecules - affects signalling
- Modification of circulating proteins in blood (albumin)
What is a protein that is irreversibly modified or crosslinked by AGEs?
Hemoglobin A modified to Hemoglobin A1c
What can A1c be used for in term of diabetic testing?
Long term glucose damage
What do Receptors for AGEs react to in the blood?
Activates inflammatory cytokines and growth factors
What causes protein kinase C (PKC) activation in hyperglycemia?
Lipid second messenger diacylglycerol (DAG)
What happens in the hexosamine pathway?
Excess glucose is shunted to the pathway which may cause N-acetyl glucosamine to be added to Ser/Thr instead of phosphorylation
What does the hexosamine pathway affect?
Endothelial cells and kidney cells
In the four types of damage pathways, how did inhibitors hold up?
They were ineffective
What is the common factor in the four types of damage pathways?
Increased production of reactive oxygen species by mitochondrial electron transport
If there is too much glucose, too much ____ is made and the ___ gets backed up.
NADH, ETC
What is the diabetes pathway model of all four pathway damage together?
Hyperglycemia to superoxide to ultimately damages glycolytic enzyme glyveraldehyde-3-P-dehydrogenase (GAPDH)
What is a possible treatment for the pathway damage model?
Transketolase activators
