Today’s is the LAST of the SfN Neuroblogging for this year. It was a great time, with so much awesome science! This one was a little more complicated than the others and needed some more time. Also, this talk made me ABSOLUTELY paranoid that I needed to eat a Clif bar. You’ll see, you’ll want one too by the end.
McNay et al. “Impact of recurrent hypoglycemia on cognitive and brain function.” 4.03 Symposium
PEARSON-LEARY, et al “The role of insulin-regulated glucose transporter 4 in memory and insulin-mediated glucose uptake in the hippocampus” 715.09, VV96.
Now most people with a little bit of science knowledge know that glucose is VERY important for your brain, and insulin is very important for your brain and body. All your cells need glucose to function, and your brain needs a constant, steady supply. No other food will do. If someone suffers from acute hypoglycemia (and we’re not talking just being hungry, we’re talking much more severe), they suffer cognitive impairments. This highlights the importance of metabolic control, how well your body controls its blood glucose, particularly in responses to things like acute hypoglycemia (low glucose) or after a bolus of food that would otherwise cause hyperglycemia (high glucose).
And as with the humans, so with rats. McNay et al have shown that in a 4-arm maze spatial working memory task where an animal has to select recently unexplored arms, acute hypoglycemia makes them make mistakes. The answer to why this happens may be in measures that the authors have taken of glucose in the hippocampus while the rats are performing in the arm maze task. In a normal rat performing the task, glucose dips lower in the hippocampus while they are working, as it gets utilized for performance. This could certainly explain why acute hypoglycemia, when there is no glucose available, makes the rats poor performers. If the rats get a shot of glucose prior to the task, their performance is better – and their hippocmpal glucose isn’t drained while they’re on the maze.
But what about repeated hypoglycemia? When a rat is given repeated hypoglycemic episodes, but has a NORMAL glycemic level (we call that euglycemic) at the time of testing, instead of having their glucose levels fall in the maze like a normal rat, their glucose levels stay normal, in fact they look like rats who have received a BOLUS of glucose beforehand. And along with this, you get…improved cognitive function. So acute hypoglycemia? Always bad for your cognitive function, but repeated hypoglycemia? Maybe not so much.
But that’s only as long as your glucose levels remain high. Rats with repeated hypoglycemia who are hypoglycemic when they are tested actually show WORSE cognitive performance than any of the other groups. And this effect is seen in humans as well. Type I diabetics, for example, often have repeated hypoglycemia, due to overshooting their dose when taking insulin. But then, when they suffer hypoglycemia again…they have decreased cognitive performance, resulting, for instance, in both impaired memory and poor decision-making (such as “oh, my blood glucose is 40 and I’m about to pass out? Ok, I’ll just drive home and get a Clif bar”).
So what is mediating these changes in cognitive performance? McNay et al think it has to do, at least in part, with glucose transporters. In the brain, we usually think of GluTs 1 and 3, which are NOT regulated by insulin (you’ll see why this is relevant in a second) and always present, allowing the brain to get a steady supply of glucose. Their data show that after previous hypoglycemic episodes, both mRNA and protein levels of these GluTs are increased and hence the brain really is as if it’s getting extra shots of glucose. [There are other changes – in synaptic function, for instance – that parallel the interaction between acute glucose level and history of hypoglycemia in modulating cognitive function, but this is complex enough just thinking about glucose!]
Now, in addition to GluTs 1 and 3, some parts of the brain – including the hippocampus – also express GluT4: a transporter that’s regulated by insulin. Most people think of GLUT4 as being present in the body, where insulin signaling moves it to the cell membrane and allows your cells to take up glucose. But the presence of GluT4 in the brain suggested that insulin itself could be modulating how glucose is utilized in the brain, independent of cognitive activity or other signals: that turns out to be exactly the case, and – moreover – insulin signalling is a key part of hippocampal memory processes; if it’s blocked, the rats can’t do memory tasks at all. Conversely, give the rat extra insulin – like you might have when you need to remember the location of those tasty berries you just ate – and hippocampal function is enhanced. But that enhancement is prevented if GluT4 is blocked. All of this is yet one more reason to go to the gym: both rats and humans with impaired insulin sensitivity – the condition underlying type II diabetes – show cognitive impairments that McNay and others have shown are likely directly caused by that insulin resistance.
And here we get even more complicated. Here we get into beta amyloids. I’m sure you’ve all heard of those. They are associated with the development of Alzheimer’s. And now, it looks like they are also associated with glucose utilization. Previous studies have shown that beta amyloid precursor levels might increase after chronic hypoglycemia, and glucose use in the brain decreases during Alzheimer’s. So does beta amyloid have anything to do with this system? With cognitive performance and with brain glucose levels? It looks like that’s the case. McNay et al. showed data that repeated hypoglycemia modelled after that experienced by Type I diabetic patients led to marked brain amyloid accumulation; and separately, they showed that after delivery of oligomeric amyloid to the hippocampus, glucose utilization actually went down – accompanied by memory impairment – and there was ALSO a decrease in hippocampal GluT4 movement to the cell membrane.
Based on these data, McNay et al propose an interaction. Under normal conditions, insulin helps regulate cognitive function by increasing GluT4 translocation in the brain, allowing for more glucose transport during times of cognitive challenge. But when there’s amyloid around, the amyloid decreases GluT4 movement (likely via direct blockade of insulin receptiors)and stops the insulin effect, impairing cognitive function. Of course, this is all preliminary, and we’ll have to find it in humans, but understanding the interactions between metabolism, cognitive function, and markers of cognitive decline can help us learn more about both about normal cognitive function and about problems like diabetes and Alzheimer’s.
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