Thursday, March 18, 2010

Amylin; the pyruvic acid regulator

My work on leptin raised an obvious possibility. There are five tastes, umami, sweet, bitter, sour and salty. Leptin goes with glutamate, umami. Insulin with sweet, obviously. Are there other hormones corresponding to flavours? That might give a clue to their importance to whole-body homeostasis.

After a while it occurred to me that Amylin, which is the peptide that accumulates in amyloid plaque in the pancreas of people with type 2 diabetes, and in the brain of people with alzheimers, appears to sensitize people to leptin. Dr Bernstein gives amylin to some of his patients in order to decrease appetite for glucose. Now, does that sound familiar? So although amylin isn't technically a hormone, it seemed a likely candidate for a third taste related hormone-like substance. This Stephanie Steneff article gave me the information that I needed.

However, amyloid-beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate (the product of anaerobic glucose metabolism) into lactate, through an anaerobic fermentation process, with the further production of a substantial amount of ATP.

I thought lactic acid was the significance of sour because of this. But then I realized that since amylin facilitates pyruvic acid breakdown into lactate, it must be secreted instead in response to the presence of pyruvic acid.

Once you look at it that way, something becomes obvious. The beta cell secretes insulin in response to glucose. It does this for the same reason that a yeast cell does; to get and use glucose. Beta cells are so bad at this that they provide enough insulin to service the needs of the entire human body.

Following this line of reasoning, it makes sense that excessive amounts of amylin would be produced or secreted when large amounts of pyruvic acid are present. The amylin facilitates the use of pyruvic acid for energy. (The actual amount of pyruvic acid needed to cause this amyloid production overshoot would depend on the level of resistance in the alpha cell, where amylin and glucagon are both produced.)

So the amyloid plaque in type 2 diabetes and alzheimer's starts to look like the signature of a bloom effect. Large amounts of glucose must have been broken down to pyruvic acid, spurring excess amylin production. The cells aren't intelligent; just like yeast cells, they have no idea that the high levels of pyruvic acid aren't forever, so they overproduce in anticipation.

Now, this is important; why would large amounts of pyruvic acid form? One possibility is that a local energy crisis has occurred, forcing cells to turn to the fermentation of glucose for a quick source of energy. This would lead to large amounts of pyruvic acid in the area. After which large amounts of amylin production overshoot would make sense.

What would cause the cells to turn to glucose fermentation? In cancer cells, it has been suggested that a local lack of oxygen might cause this. This makes obvious sense, fermentation is anaerobic.

Another possibility occurred to me, again thanks to Stephanie Stennef's article. You can't ferment fat; a local lack of free fatty acids might cause the excess fermentation of glucose that leads to pyruvic acid formation and high-gear amylin release. Animals that burn more fat for energy vs sugar live longer, this crosses many animal species.

Niacin, vitamin D, and a low carb diet done properly can raise adiponectin levels. Adiponectin lowers glucose production in the liver. What lowers glucose production? Our old friend physiological insulin resistance. When free fatty acids (particularly palmitic acid) enter the cell and feed into the Kreb's cycle, cellular energy needs are met and the need for glucose is reduced.

Increased fatty acids should make the fermentation of glucose to pyruvic acid less necessary and therefore no amylin overshoot should occur.

It seems likely that when blood levels of free fatty acids are high, the probability of cells needing to turn to glucose fermentation to meet their energy needs becomes much lower. This has obvious implications to the development of cancer.

That leads to thinking about what happens besides cancer when levels of free fatty acids are low. If a yeast-like bloom can occur when free fatty acids are not present, (fat acting as a control-rod of glucose and glutamate metabolism is another way to look at physiological insulin resistance), then tissues that are in greater than usual need of energy should be more susceptible to damage.

Tissues that are healing, for instance.

Adiponectin decreases the risk of heart disease and atherosclerosis. Most of the nutrients that Dr Davis at HeartScan Blog advocates to reverse plaque increase adiponectin levels.

More free fatty acids, lessened likelihood of a disrupted energy supply. A problem in this is that Type II diabetics often have higher than usual levels of free fatty acids in their blood. But they also often have compromised, undersized mitochondria; this could force them to turn to glucose when energy needs are high. I think this free fatty-acid "paradox" has thrown conventional science way off-track.

Once you're thinking lack of energy, compromised repair you think; cavities, bone loss, sarcopenia or muscle loss. All of the western diseases showed up together. It makes sense that they might have a common cause. Are we falling apart because we're not putting ourselves together?

Notice that Amylin, by helping to break down pyruvic acid to lactate, which can itself be metabolized, also may decrease glucose metabolism. When this is happening just a little bit more, not pathologically localized like in type II diabetes or in Alzheimers, insulin levels should be reduced, triglyceride synthesis should be lowered, and as a consequence more free fatty acids should be available to be oxidized.