Hypoglycemia and AutoImmunity?

http://www.medicalnewstoday.com/articles/133504.php

High Blood Sugar's Impact On Immune System Holds Clues To Improving Islet Cell Transplants

A biological tit for tat may hold clues to improving the success of islet cell transplants intended to cure type 1 diabetes, according to a Medical College of Georgia scientist.
In type 1, the immune system attacks insulin-producing cells causing high blood glucose levels that may temporarily reduce the attack, said Dr. Rafal Pacholczyk, an immunologist in the MCG Center for Biotechnology and Genomic Medicine.

High blood glucose, or hyperglycemia, causes all sorts of dysregulation throughout the body. "It throws off metabolism, hormonal interplay and increases the risk of severe infections," Dr. Pacholczyk said. A shot of insulin or an islet cell transplant normalizes blood glucose levels, enabling, among other things, restoration of the usual balance between effector T cells which mount an immune or autoimmune response and regulatory T cells which suppress attacks.

The suggestion here seems to be that the autoimmune attack on beta cells occurs during hypo- or normal glycemia, rather than hyperglycemia. Maybe this is the major difference between the development of diabetes type I and II. Type II diabetics usually have large amounts of free fatty acids in the blood, insulin resistance comes before the development of full-blown diabetes. Dr Harris recently wrote in a comment that type I diabetics seem to be able to maintain lower blood sugars on a ketogenic diet than people without diabetes. This might not be a good thing. Maybe type II and insulin resistance is preserved in the genome because of the obvious dangers of type I?

The idea that the beta cells are protected from autoimmune attacks during hyperglycemia --when they are most needed, and prone to attack during hypoglycemia --when they are [I]least[/I] needed, makes me wonder if autoimmune is the right word, here. Pathological re-modeling?

Dr Bernstein writes about the impossibility of maintaining perfect blood sugar levels when there is an infection.

Tumour necrosis factor is a part of the inflammatory response; tumour necrosis factor promotes insulin resistance, and mice that don't express tumour necrosis factor heal poorly. I made a bit too much of this in a recent post about TNF, wound healing, and heart disease. But that insulin resistance has a legitimate role during some part of the healing process makes sense.

So; you are wounded. The wound becomes inflamed. Your fasting blood glucose goes up. What's going on? Is the increase in blood sugar just pathological, or is it a consequence of increased lipolysis-induced physiological insulin resistance? Is extra glucose needed in the high-energy healing process? Does the increase in blood glucose have the (sometimes beneficial) effect of decreasing the immune response?

I banged up my shoulder a few years back. Fish oil worked for a while, vitamin d helps. The one fail-safe is nicotinic acid (niacin). The only way I know that the niacin is working is that when I stop taking it, the pain eventually comes back.

Niacin temporarily prevents lipolysis. But an hour or so after taking it, there is a rebound effect and lipolysis is elevated. Niacin has been shown to increase fasting blood glucose; higher free fatty acids could explain this. I prefer the idea that the thing with my shoulder improving on niacin is caused by a less interrupted flow of energy (free fatty acids, etc, not mystic stuff), less "hypoglycemia." What we call hypoglycemia isn't a lack of glucose, it's a lack of glucose and those things that spare glucose, fat, ketones.

But what if it's an immune thing, higher fasting glucose lowering the immune response? Or a remodeling thing, when energy is low, some tissue is taken apart to improve the energy status of other tissue? Unwelcome bacteria being taken apart, damaged cells being taken apart --these are similar jobs. That the immune system is involved in both of these processes is uncontroversial.

Collagenous joints are sort of at the end of the supply line, as far as blood supply goes, they could be particularly susceptible to this sort of thing.

When a wound is healing, there is a rapid local proliferation of cells. Is there an increased risk of an autoimmune response against new tissue? (Or an increase in the breakdown vs buildup portion of remodeling?)

I may be making too much from too little. That seems to be what I do.

March Madness

In March, I learned that supplementing with Creatine and Glutamine can give some people manic episodes. Careful.

I'm some people. I took the blog down for a while. While my thoughts were racing, I had a tendency to jump to conclusions way too quickly. I don't like the idea of spreading misinformation.

I plan to go through some of my March posts, and try to weed out some of the noise, but for now, I'm going to just put it back out there. I'm having a little trouble telling the baby from the bathwater, now that I'm back at normal speed.

Does potassium control testosterone secretion?

To recap; we have five senses of taste. Sweet, sour, bitter, salty and umami.

Insulin associates with the sense of sweet and regulates glutamine.

Leptin associates with the sense of umami and regulates glutamate.

Amylin associates with the sense of sour and regulates lactate.


So we're down to salty and bitter. Let's do salty next.

The obvious choice for a nutrient that the salty receptors are particularly attuned to is sodium, but I believe this is a modern distortion, and that potassium is the nutrient involved here.

L. Frassetto, R. Curtis Morris, Jr. and A. Sebastian did a study where they supplemented the diets of postmenopausal women with potassium bicarbonate.

http://jcem.endojournals.org/cgi/content/abstract/82/1/254


The theory is that the acid/base balance of the body determines protein wasting; when the system is less acidic, less nitrogen is lost in the urine. I've been doubtful about this study's results, more nitrogen might have been lost in the stool, but I now find myself less skeptical.

What causes an increase in muscle mass? Ask a bodybuilder, he'll know. Testosterone.


http://sciencelinks.jp/j-east/article/200707/000020070707A0256523.php

We report for the first time that supraphysiological concentrations of
testosterone induces relaxation in RA. This response may occur in part via
ATP-sensitive K'+' channel opening action

Now, there is nothing new about the idea that testosterone activates potassium channels. So what does that mean? Testosterone regulates potassium.

Here's another, don't believe me, believe this;

http://www.jstage.jst.go.jp/article/jphs/103/3/103_309/_article

We report for the first time that supraphysiological concentrations of
testosterone induces relaxation in RA. This response may occur in part via
ATP-sensitive K+ channel opening action.

If potassium is regulated by testosterone, doesn't it then make sense that rising levels of potassium will increase testosterone levels?


I have to warn here about the dangers of potassium-loading. Testosterone regulates potassium for a reason; in excess, this stuff is extremely dangerous.

Here's a little proof. I saw better proof a few years ago, in a study where rat pups were rendered potassium deficient. They failed to produce potassium.


http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03c

Amelia Sánchez-Capeloa,
Asunción Cremadesb,
Francisco Tejadab,
Teodomiro Fuentesb
and Rafael Peñafiel, a
aDepartments of Biochemistry and Molecular Biology, University of
Murcia, 30100 Murcia, Spain
bDepartments of Pharmacology,
Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
Received 2
August 1993;
revised 8 September 1993.
Available online 14
November 2001.

Abstract
Potassium deficiency produced different effects in the kidney of male or female mice. While in female, potassium deficiency caused a marked renal hypertrophy with no significant changes in testosterone-regulated enzymes, such as ornithine decarboxylase and β-glucuronidase, in the male the same treatment provoked a marked fall of these enzymes owing to a dramatic decrease in plasma testosterone. Potassium replenishment restored plasma testosterone and renal enzymatic activities. These results show for the first time, that potassium modulates circulating
testosterone and suggest that this cation could exert an important regulatory
role in controlling androgen actions

Again, potassium deficiency causing testosterone secretion to decrease in male animals. Female animals proper hormonal balance involves less testosterone secretion than males does; the lower potassium intake in this study was more within their homeostatic range, so that the effect on testosterone in the female mice was lessened.

Again, anybody reading this do not I repeat do not potassium-load. Include foods that are not potassium depleted (that is, non-refined foods) in your diet. If your testosterone levels are low, it seems to me that you may be potassium-deficient.

Salty, potassium, testosterone. Looks like we're down to bitter.

This is getting a little silly

http://www.jbc.org/content/279/14/13393.abstract

This response to amino acids was decreased by 60% when glutamine was omitted. Insulin release by SUR1–/– islets was also stimulated by a ramp of glutamine alone.

In normal islets, methionine sulfoximine, a glutamine synthetase inhibitor,
suppressed insulin release in response to a glucose ramp.

High glucose doubled glutamine levels of islets.

Glutamine has been found to induce "insulin resistance" in fat cells.

Muscle cell glutamine production is increased by insulin.

Suppressing glutamine synthesis suppresses insulin release in response to glucose.

Insulin regulates glucose indirectly. Glutamine production decreases availability of glutamate, which reduces availability of glutamate-derived metabolites necessary to mitochondrial respiration. Less fat is fed into the kreb's cycle, increasing the cell's dependence on fermentation of glucose for energy, which increases the demand for glucose. Remember how exercise can increase glucose uptake without increased insulin? This is apparently why. And they did the study in 2004.

For proper symmetry, I guess it will be necessary that leptin increases the production of glutamate.

No wonder insulin is anabolic. It spares proteins from mitochondrial respiration (krebs cycle)

Methionine sulfoximine inhibition of glucose stimulated insulin secretion was
associated with accumulation of glutamate and aspartate.

I should say that insulin is expressed by the beta cells in reaction to glutamine to facilitate its uptake. Insulin will increase the demand for glutamine in any cell. If pre-made glutamine is not present, the demand for glutamine will be served by the synthesis of glutamine from glutamate. Sometimes I talk right around my main point.

Add on;


I went back and reread that glutamine inducing insulin secretion study, and they mentioned this;


http://content.nejm.org/cgi/content/full/338/19/1352?ijkey=523a998947f513e19c80d3216f3446ce60d9eb4f


"Hyperinsulinism and Hyperammonemia in Infants with Regulatory Mutations of the Glutamate Dehydrogenase Gene"


Glutamate dehydrogenase is an enzyme needed to convert glutamate to alpha-keto glutarate, which feeds into the kreb's cycle, and is thus needed to burn fat.


Lets see. Glutamine induces insulin secretion (And insulin induces glutamine production). Excess of an enzyme that breaks glutamate down into alpha keto-glutaric acid induces insulin secretion.
It almost looks like the lack of glutamate induces insulin secretion.

The control of GDH through ADP-ribosylation is particularly important in insulin-producing β cells. Beta cells secrete insulin in response to an increase in the ATP:ADP ratio, and, as amino acids are broken down by GDH into α-ketoglutarate, this ratio rises and more insulin is secreted. SIRT4 is necessary to regulate the metabolism of amino acids as a method of controlling insulin secretion and regulating blood glucose
levels.

So what would glutamine do? Spare glutamate, so that it can be made into alpha-keto glutarate?

More alpha keto glutarate. Does the Kreb's cycle use more alpha keto glutarate when glucose is providing acetyl coa? Like, the clock runs faster?

'Tis a slippery beast. Insulin appears to regulate glucose. But not really. Appears to regulate glutamine. But that might just be because glutamine spares glutamate so it can be broken down to alpha keto glutarate.

So it actually appears to create a demand for alpha keto glutarate, and glucose and glutamine merely facilitate this; except that muscle cells produce glutamine in reaction to insulin....

Okay. Muscle cells are pretty heavy on protein. Insulin might stimulate glutamate production from glutamic acid, at the same time providing substrate for both alpha keto glutaric acid and glutamine.

I'm sort of tied in knots.

But I think the proper way of looking at this is probably that insulin doesn't actually try to "regulate" anything. It's probably all about equilibrium, anyways.

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.

http://people.csail.mit.edu/seneff/alzheimers_statins.html

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.

The case for leptin as a regulator of glutamic acid metabolism

http://ajpregu.physiology.org/cgi/content/full/293/4/R1468

My first clue that leptin might be a regulator of glutamate metabolism came from this study;

Protein appetite is increased after central leptin-induced fat
depletion

Leptin reduces body fat selectively, sparing body protein. Accordingly, during chronic leptin administration, food intake is suppressed, and body weight is reduced until body fat is depleted. Body weight then stabilizes at this fat-depleted nadir, while food intake returns to normal caloric levels, presumably in defense of energy and nutritional homeostasis. This model of leptin treatment offers the opportunity to examine controls of food intake that are independent of leptin's actions, and provides a window for examining the nature of feeding controls in a "fatless" animal. Here we evaluate macronutrient selection during this fat-depleted phase of leptin treatment. Adult, male Sprague-Dawley rats were maintained on standard pelleted rodent chow and given daily lateral ventricular injections of leptin or vehicle solution until body weight reached the nadir point and food intake returned to normal levels. Injections were then continued for 8 days, during which rats self-selected their daily diet from separate sources of carbohydrate, protein, and fat. Macronutrient choice differed profoundly in leptin and control rats. Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test.

Leptin seems to decrease appetite in rats only until fat mass is depleted. After that, appetite returns, and is similar in calories to non-leptin treated animals, but food preference changes to protein from carbohydrate in comparison to control rats. This suggests that rather than regulating calories, it regulates appetite for protein. In a similar way, insulin infusions will increase the appetite for glucose.

Now, glucose tastes sweet, so I wondered if there was a particular taste associated with leptin. I was looking for a protein taste, so umami seemed like a likely possibility. And umami is specific to glutamate.

So I needed a study showing the secretion of leptin in reaction to proteins. And I found it in this;

Regulation of leptin secretion from white adipocytes by insulin, glycolytic
substrates, and amino acids

The aim of the present study was to determine the respective roles of energy substrates and insulin on leptin secretion from white adipocytes. Cells secreted leptin in the absence of glucose or other substrates, and addition of glucose (5 mM) increased this secretion. Insulin doubled leptin secretion in the presence of glucose (5 mM), but not in its absence. High concentrations of glucose (up to 25 mM) did not significantly enhance leptin secretion over that elicited by 5 mM glucose. Similar results were obtained when glucose was replaced by pyruvate or fructose (both 5 mM). L-Glycine or L-alanine mimicked the effect of glucose on basal leptin secretion but completely prevented stimulation by insulin. On the other hand, insulin stimulated leptin secretion when glucose was replaced by L-aspartate, L-valine, L-methionine, or L-phenylalanine, but not by L-leucine (all 5 mM). Interestingly, these five amino acids potently increased basal and insulin-stimulated leptin secretion in
the presence of glucose.

Unexpectedly, L-glutamate acutely stimulated leptin secretion in the absence of glucose or insulin.

Finally, nonmetabolizable analogs of glucose or amino acids were without effects on leptin secretion. These results suggest that 1) energy substrates are necessary to maintain basal leptin secretion constant, 2) high availability of glycolysis substrates is not sufficient to enhance leptin secretion but is necessary for its stimulation by insulin, 3) amino acid precursors of tricarboxylic acid cycle intermediates potently stimulate basal leptin secretion per se, with insulin having an additive effect, and 4) substrates need to be metabolized to increase leptin secretion.

Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.

Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true.


Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.

Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true. Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.

Notice that fat consumption was no different in the leptin-treated rats than in the control mice in that first study. This is because leptin does not directly regulate fat.

Also notice that although the two sets of rats were in drastically divergent hormonal states, they still took in the same number of calories. My guess would be that this has more to do with the amount of work being done in the body than anything else. Matt Stone may have a point; if the body expresses hunger, something, somewhere needs doing. I would disagree with him that calories matter in this; appetite, and the senses, should be trusted. We've forgotten how to trust all of our senses. That's why nobody seems to notice anymore when they make a major nutritional scientific breakthrough.

We really need to live in the real world.

Roaming Brownouts

http://journal.shouxi.net/qikan/article.php?id=412025

Snell Dwarf mice burn more fat, less sugar when at rest.

Do the modern diseases of civilization have a common cause? Is this cause a series of roaming brownouts, energy shortages throughout the body? Wear exceeds repair, and the repair that is done is shoddy.

This could show up in a number of areas, including;

1 tissue that receives relatively little blood flow.

2 tissue in higher than usual need of energy for repair. Such as the arteries, especially at main branching points.

3 tissue with very high energy needs at the best of times, such as the brain.

There is strong evidence that increased energy from fatty acids vs. glucose use during fasting increases the lifespan, this crosses a wide number of species. I see longevity as the fight against entropy. Things last longer if kept in better repair. Interventions that increase HDL and lower triglycerides in humans also raise free fatty acids, which induces physiological insulin resistance.

Which should also have the obvious effect of lessened disruption of the delivery of the energy needed for proper maintenance and repair to high-need tissues with less disruption. I see the possibility of a condition similar to a bloom in yeast, depleting blood of nutrients in a very localized hypoglycemia. Measuring blood sugar doesn't tell you what is happening in a very acute area.