Gregory Cartee (UW) - Effects of CR on insulin signaling in skeletal muscles
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Focusing on skeletal muscle since 80% of insulin effect is driving glucose
into skeletal muscles.

In diabetics, decline in glucose uptake most pronounced in skeletal muscles
relative to other organs (e.g. brain pretty constant).

Insulin transports glucose into cell, but does many other thing - protein
synthesis, lipid metabolism.

Glucose transport is rate limiting step in glucose metabolism in skeletal
muscles.

Most of data presented today is from rats.

Method: CR animal, then take out leg muscle and experiment with it in vitro
(while muscle fibers are still alive).

Rats studied were 25-40% CR. Relatively short term CR prior to test - 20 days,
since change in insulin sensitivity is pretty rapid (see below).

Effects of CR on insulin signaling

Aging decreases rats insulin sensitivity with age. Long term CR prevents, and
even reverses insulin sensitivity in isolated rate muscles - glucose cleared
more quickly when bathed in a fixed amount of insulin.  Old CR muscles were
*more* sensitive to insulin than young AL animals.

Insulin sensitization via exercise is an acute effect, not much long term
change in insulin sensitivity with exercise.  Appears to be a different
mechanism than increased sensitivity via CR. Total GLUT4 abundance in cell
is increased with exercise,  whereas CR doesnt increase total (just amount
bound to cell surface) - see below.

How long (on CR) does it take to get insulin sensitization?

After 5 days of CR, rats insulin sensitivity is enhanced - pretty darn quick.
Dont know yet how long it takes to "tail off" yet - at least 2 days, and he
suspects fairly quickly.

Took longer (20days) to get increased sensitivity in old rats subject to
late onset CR.

Similarly rapid (e.g. 7 days) in obese humans subject to severe CR.  After
3 months, there is a further increase in humans - once body composition has 
changed, normalized for body surface area.

CR doesnt alter total GLUT4 abundance, in rats or monkeys - a transporter
protein that helps with glucose disposal. Reason, when insulin binds to cell,
it encourages GLUT4 to bind to cell surface, where it can help transport
glucose into cell. In CR animals, GLUT4 moves to cell surface more readily
than in AL when exposed to the same level of insulin, to facilitate glucose
clearance in the presence of low insulin. So CR animals can have low basal
insulin, and low insulin response, without impairing glucose clearance.

IRS-1 and IRS-2, and PI3Kinase are critical along insulin signaling path for
glucose transport. CR doesnt seem to impact these much. Perhaps CR acts
downstream of PI3-kinase.

Cell membrane very involved in the process of glucose processing - lots of
these molecules become impeded in cell membrane and help with moving glucose
from bloodstream to interior of cell. The impact of CR on cell membrane
properties (e.g. increased fluidity) may be significant - but he doesnt know.

Summary: CR impacts some aspects of the insulin signaling path, but not others,
leading to increased insulin sensitivity.

Question: How does a muscle "know" that it is in a CRed situation, in order
to trigger these effects?

Extra glucose being processed through non-standard (spare) glucose metabolism
pathway can result in insulin sensitivity. Could be triggered by extra glucose
(food). Perhaps the opposite is occurring in CR - decrease in food leads to
decreased activity in this extra pathway which could lead to increased insulin
sensitivity. Some supporting evidence for this in his rat model.

Glycogen storage in CR is actually not much different, even maybe a little
higher, than AL animals - somewhat surprising.  If animals eat once a day
(instead of 3) - insulin sensitivity not much different. Glycogen stores
(on average) arent significantly difference between limited daily feeding
and EOD fed animals.

His results seem to contradict Mattsons data. He thinks that it may have
to do with time of measurement relative to meals.

Glucose levels in free living animals only about 10% lower than AL animals
throughout the day. Insulin is *much* lower.