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14 Cards in this Set

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2 metabolic abnormalities of diabetes
hyperglycemia (impaired glucose metabolism)
insulin resistance
surrogate of ir
post-load hyperinsulinemia
surrogate of glucose metabolism
impaired glucose tolerance (IGT), impaired fasting glucose (IFG)
1997 impaired glucose value
110mg/dl+
2003 impaired glucose value
100mg/dl+
cutpoint for high insulin
11.0 UI/L
cutpoint for high homocysteine
18.6 micromol/L
how hyperglycemia may damage brain
1) increased oxygen free radical generation in AD 2) increased formation of advanced glycation endproducts in AD 3)atherosclerosis of small and large cerebral vessels
how insulin resistance impairs brain
1)associated with impairef ucntion of frontal cortex, a brain region very sensitive to metabolic regulation 2)short-time insulin infusion enhances cognitive performance ==> abnormalities of the insulin signaling in the neurons can lead to a defective glucose supply with negative effects on brain energy production 3) insulin modulates b-amyloid protein levels through enhancing its production and or inhibiting its breakdown
hcy mechanism for vascular damage
impair endothelial function, enhance LDL oxidation and deposition in ther arterial wall, activate coagulation cascade.
role of ide
One leading theory is that both insulin and beta amyloid 42 are competing for the attention of IDE, or insulin-degrading enzyme. This is one of the main enzymes that clear both beta amyloid and insulin. If IDE is showing a preference for insulin when both substances are present, then the beta amyloid will lose out, the theory goes.
significance of beta amyloid
early onset: important
but late onset: One of the nagging questions is what does this have to do with late-life Alzheimer's disease, which really accounts for 95 percent or more of everybody we will see with Alzheimer's?" Galasko says. "We don't have clear evidence from anywhere that beta amyloid is overproduced in late-onset Alzheimer's."

If it's not overproduction that's the culprit, then it might be something else, possibly decreased breakdown or "clearance" of the protein, Craft and Galasko say.

Beta amyloid is created and broken down in healthy people all the time, although scientists aren't sure what its role is in the body. It's possible that the longer forms of the protein, such as amyloid 42, have no real function at all.
study of insulin and beta amyloid
Craft and her colleagues focused specifically on the clearance -- the breaking down and purging -- of beta amyloid 42 from the brain to the spinal fluid in 16 healthy, older adults.

Ten women and six men each underwent, at separate times, two infusions either of a placebo or insulin plus dextrose, a sugar. Then they had their blood, spinal fluid and cognitive abilities measured.

Not surprisingly, the insulin infusion produced an increase in insulin concentration in the spinal fluid sample. More notably, it also led to an increase in amyloid 42, especially in older participants.

Interestingly, insulin infusion improved memory performance in the younger participants. But older participants who had an increase in beta amyloid 42 levels in their spinal fluid showed a decline in memory skills.

"It's possible that higher amyloid in their spinal fluid reflected a problem with clearing insulin in the brain," Craft suggests.

Galasko says it's unclear why the protein was found in the spinal fluid. One leading theory is that both insulin and beta amyloid 42 are competing for the attention of IDE, or insulin-degrading enzyme. This is one of the main enzymes that clear both beta amyloid and insulin. If IDE is showing a preference for insulin when both substances are present, then the beta amyloid will lose out, the theory goes.

Still, the new study is potentially significant, researchers agree. "It is the first demonstration in humans that levels of this protein can be affected by an acute challenge of any sort," Craft says.
what the Craft study implies for insulin and disease
Adds Galasko: "[Another] part of the study which is of interest is the general concept that we can do something, give some kind of substance [for example, insulin] that alters levels of beta amyloid in the spinal fluid and this has not been an easy thing to prove. At present, we don't have any available treatment for Alzheimer's disease that alters beta amyloid, so it's encouraging."

The findings could eventually open up a new class of therapies for Alzheimer's, experts say.

"What's happening is a bit of a paradigm shift within the field," Craft says. "Different areas within Alzheimer's disease that are now coming to the forefront have to do more with metabolic processes, with inflammation. We're looking at agents that reduce insulin levels. Insulin sensitizers that have been brought to use for diabetes in the past three to four years may actually benefit patients with Alzheimer's."