"Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity"
Roger H. Unger and Philipp E. Scherer
doesn't seem to be published yet, so I'm not sure if this will actually be the abstract:
"Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.
"The wrath of God came upon them, and slew the
fattest of them. . ." 78th Psalm, Verse 31."
Great start, even I have to admit. It gets better.
I got as far as the this diagram before having to stop. Head banging is fine for rock concerts, not so good on a hard desk.
Why are Texans so fat? According to Messrs Unger and Scherer:
Woo hoo! It's gluttony and sloth. With the number of guns that there are supposed to be in Texas (I wouldn't really know) I'd be careful about throwing such generalised insults around! Though I guess insulting people in a scientific journal is a lot safer than doing the same thing in a bar in down town Dallas.
They are also, being diabetologist and/or obesity experts, utter lipophobes (see the bottom line and text of their illustration) and struggle manfully with trying to show lipids (and even, OMG, cholesterol) are directly toxic. As I say, these folks are not too bright. I doubt they would understand glucotoxicity if it kicked them in the pancreas. But then, they are probably both on a statin.
I briefly re drew their illustration for them:
I had to split the slide in two to fit in the basic cause at the top of slide 1!
The ability to confuse symptoms with causes is hysterical. They really should read Good Calories Bad Calories, but it might be a little technical (and dispiriting!) for them.
However the reason for this post is that we have, on page 3 under "Protective role of obesity", this AMAZING quote:
"Thus, we propose that adipogenesis delays, rather than causes, the metabolic syndrome induced by chronic caloric surplus."
This is ABSOLUTELY crucial. These people have finally gotten the message! And they are idiots! When a concept is so clear cut that even morons can see it, there really is hope for the world.
GOOD.
Then (thanks, Hege) there is George Bray. Bray is one of the architects of the current obesity epidemic. Probably believes in gluttony and sloth as Unger and Scherer do. Anyway, have a read at Michael Eades' post to find a little more about what Bray is like. If you haven't already got him on the list (come the revolution).
Bray is now blaming fructose for the obesity epidemic.
When dinosaurs move, well, there will be progress!
It's a good year so far!
Peter
62 comments:
Interesting. I'm from the south and as long as I don't eat fructose and grains, I don't gain weight. The fat won't let me overeat! I do have at least 30 firearms though, perhaps several hundred thousand rounds of ammmo..but not easily offended!
From George Bray's paper on fructose (abstract):
"In a meta-analysis of the relationship between soft drink consumption and cardiometabolic risk, there was a 24% overall increased risk comparing the top and bottom quantiles of consumption. Several factors might account for this increased risk, including increased carbohydrate load and increased amounts of dietary fructose."
Wow:
....factors might include increased carbohydrate load (and increased amounts of dietary fructose."
George has been thinking! Maybe he even read 'Good Calories, Bad Calories...' and he cann't get this 'carb thing' out of his mind anymore.
Paradigms ARE shifting.
What a great shift by Bray. And thanks for getting me to re-read one of my favorite Eades posts.
A day when George Bray comes out sounding like Robert Lustig is a very interesting day indeed. Wow.
Well i live in the fattest of them all so i got all y'all beat... i reside in Mississippi... and yeah i have 4 guns and i am a chick...
dont eat fructose, dont touch grains, but i dont shy away from starchy carbs like rutabagas or butternut squash occassionally either.
i base my diet around meat(buy lean and add good fat to it b/c i cant afford grassfed), add usually 2 sides of veggies(brussels, kale, spinach, turnip, etc etc)
lots of butter, coconut oil, beef fat, low O6, and i have a love affair with macadamia nuts from the fridge...and yea i dont exercise unless i have to do some work lol
fructose and wheat are consumed down here is such MASS QUANTITIES i cannot even begin to explain the dilema... it begins with parents dropping their kids off at the gas station before school to get a pack of donuts and a mt dew...then school lunch..then after school snack stops, then more or less a boxed starchy based dinner arounds pasta/rice/bread...
for the south being all about "good cooking and hospitality" this is so far from the truth... people live of premade boxed jambalaya, gumbo...rarely ANYONE cookes from scratch(besides my mama!
Oh malpaz! Your comment made me chuckle. My husband and I lived in South Carolina for about four years and one of the things we still joke about is the "breakfast" choice many people made there: honeybun (packaged of course) and a Mountain Dew...!!
Let a true Texan "weigh" in on the topic, me being born, raised and still living in Fort Worth.
We have a very large hispanic population and their diets comprise lots of corn tortillas, beans, and starchy foods. But, the diet hasn't limited itself to that community only as Mexican restaurants are literally everywhere and very popular. Just based on the number of restaurants, it is more than obvious that a whole lot of non-Hispanic Texans gobble this stuff up.
And, the meals are often huge, and to make matters worse, washed down with a Margarita or a beer or a soft drink.
On the way out, the counters often sell pralines for dessert (brown sugar laden).
Brad
Peter, thank you for the title of that study. My wife is always remarking that all I read is non-fiction and now I can show her one of the most hilarious works of fiction I've ever read. The study reads less like science and a lot more like science fiction.
I'm not a long-time reader of your blog. What is your hypothesis for the cause of obesity?
@Chris,
The most concise answer to your question, if I may intercede in Peter's behalf, is: buy, or check out from the library, Gary Taubes' "Good Calories, Bad Calories" and read it. You will then have answered your question, and will have taken a great first step in taking control of your own health.
Hi Zach, the last is nice to know. I'll still be careful.
malpaz, guns noted. Like the blog.
arnoud, matt and John yes, it seems hard to countenance, but that conclusion seems hard to avoid!
gwen, ah, the Simpsons... Though Marge does actually cook more than you might expect. Then she is skinny!
It's, why take the comment down? I agree that there are many routes to obesity other than via a diabetologist. They're just the funniest, if it was a laughing matter! I'll accept some mild racism, even if the guys were from Texas! We Europeans all just follow the USA, UK lipidologists are no different to their germanic cousins. They're all lipophobes.
Brad, a good friend/research colleage is Mexican. Nice metabolic syndrome in his thirties and a father with CVD. Nice guy, not good to see. We loaned him Lutz's book. Not a lot of help I fear.
ET, we can just delete the science from science fiction and you have pure fiction...
Hi Chis, until recently I would have just said "insulin". There is a lot of evidence that leptin controls insulin, so I may be shooting the messenger. You could also reduce it to the consumption of food in shinny plastic wrappers, especially if bar coded. But I like "Diabetologist", provided you extend that to include the AHA and other promoters of obesity....
Peter
Jim,
Tee hee, my copy of GCBC weights 974g. I was struggling to get the contents in to a one word answer (sorry Chris, not a dig, but the answer is quite long and complex. Insulin is central but possibly not the only issue)... I still like "diabetologist". GCBC is a more useful answer!
Peter
"The wrath of God came on them, and put to death the fattest of them, and put an end to the young men of Israel"
Or another translation;
"The anger of God rose against them, and he killed the strongest of them and laid low the young men of Israel"
I have no idea what the right translation would be; but in context, it doesn't sound like they were obese, it looks like they died from food poisoning.
Here's a line just before that line;
"He rained meat down on them like dust, flying birds like sand on the seashore."
So this is from when the Israelites were starving in the desert, on their way to the holy land.
Leptin is supposed to reduce the appetite for carbohydrate. When they deplete rats of fat with excess leptin therapy, hunger is reduced only while there is still body fat. Once the fat is gone, the rats go back to normal hunger but prefer to take their calories as protein rather than carbohydrate. I guess this explains in part why pure protein is so satiating, and why adding fat to it actually makes it less satiating (unless you're lean enough to be a candidate for rabbit starvation.)
It's hard for rats to self-select preferred nutrients when they're all mooshed together into food pellets.
Carb-restriction isn't just something dreamed up by Atkins, it's actually in the wiring.
http://endo.endojournals.org/cgi/content/full/endo;146/8/3652
"Leptin Modulates both Resorption and Formation while Preventing
Disuse-Induced Bone Loss in Tail-Suspended Female Rats"
Just the punch line;
"The latter could be related to the role of leptin in mediating the reciprocal differentiation between adipocytes and osteoblasts, because leptin concurrently blunted the disuse-induced increase in bone marrow adipogenesis."
Could simple fuel source determine the cell-differentiation, here? Adipocytes forming when glucose is the preferred fuel, but when glucose is discouraged and fat metabolism encouraged, we get osteoblasts?
Body leptin helps rats bones, but injections into the brain wrecks them. Not being leptin-resistant could be dangerous, some times.
"To test whether fatty acids play a messenger role between stimulation of lipolysis by norepinephrine and inhibition of leptin secretion, adipocytes were incubated with insulin (10 nM) in the presence of norepinephrine (1 µM) or palmitic acid (1 mM; Fig. 1). Because albumin strongly binds extracellular fatty acids (4), experiments were carried out at low (0.1%) and high (4%) albumin concentrations. Palmitic acid (1 mM) mimicked the inhibitory effects of norepinephrine (1 µM) on leptin secretion at low but not at high albumin concentrations (Fig. 1). This indicates that albumin, at high concentrations, effectively binds extracellular fatty acids and consequently inhibits their effects on leptin secretion. Therefore, subsequent experiments were carried out at low albumin concentrations. Concentration-response curves carried out in the presence of 0.1% albumin revealed that palmitic acid inhibited insulin (10 nM)-stimulated leptin secretion between 0.1 and 1 mM without significantly affecting basal values (Fig. 2). In fact, the palmitic acid effect critically depended on the ratio of the molar concentrations of palmitic acid over albumin with an IC50 of 4.5 (Fig. 3). This is consistent with the observation that one molecule of albumin has several low- and high-affinity binding sites for long-chain fatty acids"
That's from this study;
http://ajpendo.physiology.org/cgi/content/full/285/3/E521
It sort of works out to leptin secretion being inhibited by lipolysis within the fat cell; new fat, bound to albumin, won't suppress leptin. Does the albumin suppress the use of the newly-arrived fat for energy by the fat cell? I've gone around this idea before, but this coupled with the effect of leptin on bone cell differentiation really suggests to me that leptin is something put out by a fat-deficient cell, it's a demand for fat. Oxidizable fat, not the storing kind. So reducing body fat becomes a matter of somehow convincing fat cells to burn fat, instead of storing it.
I meant to say newly arrived free fatty acids, rather than new fat.
Okay, Peter. I get that it's all about the insulin and/or leptin. Would you advise against a diet heavy in dairy products (but with vanishing amounts of fructose and refined carbs) because they are insulinogenic? My diet is really dairy-heavy (not a big meat fan and can only eat so much), and I'm getting a bit concerned.
Well donny, I'm really very new to leptin but as I understood it leptin levels in plasma fall with weight loss, ie a fat deficient cell puts out less leptin... Oh, I see what you mean. I don't know enough about leptin to comment on it being produced by anything other than fat replete adipocytes. Can muscles produce leptin at all?
My other slight problem is with working in tissue culture with an albumin of 0.1% because physiological albumin (4%) ruins your experiment. Anyone with an albumin of 0.1% is very, very dead! Albumin of 4% (40g/l) is not high, it is normal!
So...
Hi Helen,
Casein undoubtedly spikes insulin. There are plenty of anecdotes about dairy stalling weight loss, especially cheese, but it is hard to say whether this is a pure insulin effect or a combination of total calories and large protein load irrespective of its direct effects on insulin. My personal big problem with cheese is that I generally aim for 60-70g/d of protein and a big lump of cheese does not leave a lot of spare protein grams for egg yolks and meat!
Overall I don't really worry about the insulinogenic effect per se as there are plenty of human cultures with a dairy base and associated high longevity. As we all know, being skinny is rather bad for all cause mortality... On the SAD of course.
Peter
I cut out and taped together your flow chart and pasted it to the fridge. :)
Hi Peter,
Negative comment toward Texans with guns is ill-advised. It's safer for me to pick on the Economist. Part of their report on Roger Unger and Philipp hypothesis is quoted below - the last two sentences are laughable:
"Their thesis is that lipids (the group of molecules that includes fats), which are needed in small amounts to make cell membranes, are toxic in larger quantities. Absorbing them into adipose tissue is one of the body’s ways of dealing with that toxicity. But are lipids toxic? In one sense, it is obvious that they are. The build up of fatty plaques in blood vessels, which results in atherosclerosis, is a result of the inability of the cells lining the walls of these vessels to cope with too much fat."
For Roger Unger and Philipp Scherer: no credit for stating the obvious. Just watch a Sumo wrestler in his effort to bulk up competitively. When his weight plateaus Diabetes Mellitus results.
http://www.biomedsearch.com/nih/Leptin-control-respiratory-gene-expression/14732484.html
"Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity"
I don't know if these guys have their shoes on backwards? That bit about leptin promoting fat storage...
Anyways, blocking leptin signalling in muscle cells blocks fatty acid oxidation. The cell still takes in fat, but can't use it, so it accumulates. Same thing in the liver, leptin facilitates fat burning.
Since the fat cell puts out fat when fat is accumulating, and fat accumulates when it isn't being used for energy... It seems reasonable that the purpose of leptin is to facilitate the oxidation of fat, including in the fat cell. Leptin insensitivity... If in the early development of a cell, it was kind of bad at burning fat for some reason (insufficient leptin), maybe it would learn to "thrive" on sugar? Absent leptin, the cells would be more dependent on glucose; trying to depend on fat metabolism when you're really bad at it isn't a very good survival strategy.
http://www.pnas.org/content/102/50/18011.full
Over-expressing leptin receptors in mice totally prevents "high-fat diet" induced obesity.
"In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes."
Okay so maybe leptin isn't so much the demand for the oxidation of fatty acids as it is the facilitator of fatty acid oxidation. I think people forget single cell organisms sometimes; a cell doesn't have to secrete a hormone for the benefit of some other cell, it can be for its' own benefit.
Some weird stuff... glutamine induces insulin resistance in adipose tissue, leading to depletion of fat. And this; I read an abstract where rats allowed to drink water or water spiked with MSG got hungrier. And also leaner.
Peter,
Jenny at Blood Sugar 101 believes that it is not diet but genetic factors that cause diabetes. Even with modern diet, most people do not get diabetic.
What do you say?
Donny, this is why people keep telling me to get in to leptin reading. Leptin comes from fat, it says we've got lots of fat, let's burn it. It says it everywhere. It is the balance to insulin????
Glutamate and adipocytes, fascinating. Of course insulin resistance in fat cells stops them hoarding fat. That's the usual flip from obesity to diabetes... But depleting adipocytes and staying slim, interesting. Do you think glutamate might be a sympathomimetic and be acting like noradrenaline to stimulate lipolysis with insulin resistance freeing up the hormone sensitive lipase as the method? Are the slim but hypercaloric rats hyperglycaemic?
JohnN, sigh. Obviously these people are not too clever (OMG I hope they don't carry guns!) and they have no concept of how to control adipose accumulation, but I still feel that there is a glimmer of hope here in amongst the utter garbage!
Good on you Togo!
Gyan, EVERYTHING is genetic. I would just go back to my parallel with smoking. If everyone, everywhere, smoked exactly 10 cigarettes per day, life long, not all of them would get lung cancer. We could then look for the genes which controlled the "genetic" disease of lung cancer.
There are a number of people who's genes cause them to break more easily on the Food Pyramid than others. If we all ate exactly to the food pyramid only some folks would get diabetes, we could look for the genes which cause the genetic disease of diabetes. They are there.
There are two explanations for rising diabetes incidence. The first is that diabetic people only have sex with diabetic people, plus contraception is banned if blood glucose is above 12mmol/l and abstinance is enforced if BG is below 10mmol/l. We would then see an explosion of the genes for diabetes, facilitated by viagra of course.
Or, we could have a pre existing spread of genes in the population which are diabetes neutral in the absence of eating to the food pyramid. Bring in the food pyramid and the "bad" genes show. Some people cope with more carbs than others. Some people break. At any body weight.
Oops, three expalnations! I guess you could have the third explanation as hyperglycaemia (or any other toxin you care to think about) being genotoxic and that new genes for diabetes have been developed in the last 30 years. Easier to think about than the diabetic orgies... But about as convincing.
Peter
Okay, the msg fed rats;
-------------------------------
Monosodium l-glutamate (MSG), an umami taste substance, may be a key molecule coupled to a food intake signaling pathway, possibly mediated through a specific l-glutamate (GLU) sensing mechanism in the gastrointestinal tract. Here we investigated the effect of the spontaneous ingestion of a 1% MSG solution and water on food intake and body weight in male Sprague-Dawley rats fed diets of varying caloric density, fat and carbohydrate contents. Fat mass and lean mass in the abdomen, blood pressure, and several blood metabolic markers were also measured. Rats given free access to MSG and water showed a high preference (93-97%) for the MSG solution, regardless of the diet they consumed.
Rats ingesting MSG had a significantly smaller weight gain, reduced abdominal fat mass, and lower plasma leptin levels, compared to rats ingesting water alone. Naso-anal length, lean mass, food and energy intakes, blood pressure, blood glucose, and plasma levels of insulin, triglyceride, total cholesterol, albumin, and GLU were not influenced by the ingestion of the MSG solution.
These same effects were observed in a study of adult rats. Together, these results suggest that MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels. Moreover, these changes are likely to be mediated by increased energy expenditure, not reduced energy intake or delayed development. Conceivably, these effects of MSG might be mediated via gut GLU receptors functionally linked to afferent branches of the vagus nerve in the gut, or the afferent sensory nerves in the oral cavity.
---------------------------
So it looks like the rats are not hyperglycemic.
Brain cancer-- there's two types, right? Glucose vs Glutamine dependence for growth? But the two basic fuels aren't glucose and glutamine, they're glucose and fat. I'm not really sure how it works... but it's interesting that glutamine and glycine both can improve lipid profile, which would suggest an improvement in fatty acid oxidation, and that the two are also necessary for uric acid synthesis. Uric acid is an antioxidant that has been accused of causing oxidant stress and proliferation of endothelial cells, which to me sounds like uric acid has an important role in the healing process, perhaps by encouraging the oxidation of fat. There are no villains here, you taught me that.
I was wondering if you would mind taking a look at this? It's a little out there, but I think the guy may have a point. ;)
http://naivenutrition.blogspot.com/2010/03/your-sialic-acid-is-trying-to-kill-you.html
Whoops, forgot the link.
Hi Peter,
I think there are other environmental toxins involved with potentiating diabetes and other diseases, as well as your second explanation. A diet of fructose and PUFAs helps, too.
That oleic acid, lp(a) thing, this is suggestive;
---------------------------------
Oleic acid is a monounsaturated fatty acid and is one of the major components of membrane phospholipids. Oleic acid contributes about 17% of the total fatty acids esterified to phosphatidylcholine, the major phospholipid class in porcine platelets.1
Oleic acid inhibits collagen-stimulated platelet aggregation by approximately 90% when used at a concentration of 10 µg/ml.1 fMLF-induced neutrophil aggregation and degranulation is inhibited by 55% and 68%, respectively, using 5 µM oleic acid. This inhibition is comparable to that observed using arachidonic acid under the same conditions.2 Oleic acid, whether applied extracellularly (EC50 = ~60 µM) to human platelets or released from membrane phospholipids, causes an increase in intracellular calcium levels.3
-------------------------------
Of course, I have no idea what normal concentrations of oleic acid in the the pig would be.
Um, no platelets, no serotonin? I'll try to be good.
Hey Peter, your illustration gave me a good laugh the other morning. Thanks :)
Hey Peter--
I think maybe we were wrong about the leptin. It might be secreted in the cell, but it seems likely that it encourages glutamine metabolism. Fat metabolism just goes along for the ride. Leptin in the brain interferes with Serotonin signalling, decreasing appetite for glucose. Increasing appetite for protein. Umami. Leptin is insulin for glutamic acid.
The apparent effect of encouraging fat for energy probably comes from the fact that glutamine metabolism is permissive of fat metabolism, where glucose metabolism is inhibitory.
Glutamine has the effect it does in fat cells precisely because it is the true foil of glucose. Glutamic acid is the one protein that stimulates leptin in the absence of glucose or insulin. I said something about glutamine dependent brain cancer, saying that fat would be the true fuel, I guess maybe I shouldn't have said that.
Glutamine itself has no effect on leptin secretion--there's an obvious advantage there, a built-in safety against uncontrolled glutamine metabolism.
They should have discovered leptin in the 20's. No way those guys would have wandered around in the dark for so long. And they didn't even have the internet.
The Warburg effect-- if they ever figure out how to use it properly, maybe the mirror image would work for glutamine-dependent cancers.
Something we have to remember here. Yeast put out insulin as a demand for glucose. Similarly, fat cells put out leptin as an indirect demand for glutamine. Hyperleptinism is basically a simple glutamine deficiency. At least at a functional level. This idea has me pretty much cornered.
I have followed this blog of yours, Peter, for some time and find it fascinating.
Just now Dr.Mercola has come out with a recommendation that fructose consumption be limited to less than 25g per day. That brought me back here to try to get a handle on the issue.
Since you guys relish a debate ad have to admit you are in the minority, despite the apparent swing you cover in this post, I pray that you would be happy to dissect the errors in the following dissection of Taubes: http://reason.com/archives/2003/03/01/big-fat-fake/3
I can't pretend to a fraction of your Endocrinological knowledge but I must admit that the article seemed quite convincing, albeit overly genuflecting to the hallowed peer-review process, the "weight of evidence" i.e.papers published and other canards.
Any help factualising (I made that word up just for you!) me and mine would be most appreciated. Cheers, guys!
Hi Cloud Tiger,
The article is a ripost to "What if it's all been a big fat lie?", which is superseded by GCBC.
But, ah, it was Reaven! Taubes said some researchers were unhappy with how he quoted or "used" them...
I'm a bit shocked by it being Reaven, who should know better.
"One can lose weight on a low-calorie diet if it is primarily composed of fat calories or carbohydrate calories or protein calories. It makes no difference!"
Absolutely, ignoring the Colpo-Eades non event, which is irrelevant to the real world.
What matters to me it is the calorie unrestricted LC vs extreme Weight Watchers (both give the same weight loss, usually more in the ketosis group, but then they usually eat less voluntarily!) which is telling. Reaven either doesn't understand or is guarding some sort of funding base! Unrestricted calories and satiation on ketosis. Or Weight Watchers. Take your pick!
As for Fumento, he is beyond hope and has blood on his hands. It is, after all, just an opinion piece. No references other than higher authorities. The more people it convinces the more damage he has done.
I'm not a debater or an opinion leader, I'm far too selfish with my time. I'm happy to provide information on or off the blog but even this takes more time than I have, I'm not here to save the world from individual crooks or idiots. I'm fascinated with how the world works. If people want my insights they are very welcome to them. If, alternatively, they want to follow the "gluttony and sloth makes you fat" route, that is perfectly fine too. Make the choice, pay the price!
But there is a price.
Justin, you're welcome...
donny, where does the glutamine deficiency come from?
Peter
Peter
"When dinosaurs move, well, there will be progress!"
Lovely. :)
I saw a study yesterday on the effects of hyperinsulin on muscle cells. They take in glucose, and make glutamine.
I think maybe we've been holding the Krebs cycle the wrong way up all these years. Where glutamine feeds into it, that should maybe be at the top.
In the same way that glutamine is permissive of fat metabolism in the fat cell where glucose is "prohibitive", glutamine is permissive of fat metabolism in the muscle cell. I was thinking of glutamine as the control rod, and fat as the fuel, but that's backwards.
Glutamine is the limiting factor to cell growth and proliferation. That's why insulin makes muscles make glutamine. I'm afraid we're back to running the machine too fast causing accelerated aging. Everything seems to be running very fast when you block glucose metabolism in nematode worms. But the fat doesn't count when it comes to cellular proliferation; it's the "glutamine clock" that matters. This may be why dumping antioxidants on the worms cancels the life-extension, it may interfere with the ability of fat to slow down this clock.
Vitamin c and carotid artery thickening? Does ldl cholesterol deliver fat to the artery wall to keep the cells from dividing too fast? An excess of antioxidants would cause uncontrolled proliferation and the depletion of glutamine. Gosh.
An excess need of proliferation, such as in a gut under constant attack, might also deplete glutamine, causing among other things some pretty crappy ldl that isn't up to the job of modulating proliferation of smooth muscle cells in the artery wall.
I meant to say that in the muscle cell, when palmitic acid and glucose and insulin are all present, the muscle makes a little glutamine, burns a little fat. Glucose is taken into the cell at a slower rate essentially because the cell is living at a slower rate.
The beta cells in the pancreas must be very bad at making insulin.
Peter, I *loved* the slides you came up with. So much so that I pretty much built a whole post around them on my blog here:
http://weightmaven.org/2010/03/14/obesity-cause-or-symptom/
As I mention there, I tweaked your diagrams to work for the general case rather than this paper; I marked both with credits to you and linked to the originals.
I hope this use is okay with you. Please let me know if it isn't!
From Dr Bernstein;
The autoimmune attack upon beta cells, the presumed cause of type 1 diabetes is focused upon several proteins. One is insulin, and another is present on the special vesicles or bubbles that are formed at the outer membrane of the beta cell. These vesicles contain insulin. Normally, they burst at the surface of the cell, releasing insulin granules into the bloodstream. The more vesicles created when more insulin is manufactured, the greater the autoimmune attack upon the beta cell. If less insulin is released, less of this protein is exposed to attack.
--------------------------------
http://www.medicalnewstoday.com/articles/133504.php
------------------------------
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.
Researchers at Canada's University of Alberta were the ones to find high blood glucose causes a short-lived suppression of the attack mode of the immune system followed by a slow return of homeostasis. The result: Islet cell transplants done in mice immediately after a blood glucose spike were dramatically more successful than those done days later, according to the research published in 2007 in the Scandinavian Journal of Immunology. In fact, the early recipients did not require immunosuppression, which transplants patients receive to reduce the risk that their new insulin-producing cells also will become targets for their immune system. However, this generalized immune suppression puts patients at increased risk for infections, cancer and other diseases. "Basically, your guard is down," Dr. Pacholczyk said.
Alternative scenario; beta cells put out insulin for the same reason that yeast cells put out insulin, to get food. The more food, the more insulin, yeast are indiscriminate. The beta cells are not so careless. They put out lots of amylin, which affects the use of glucose for energy, the growth is modulated by the pathway that involves the pepck enzyme, rather than fat.
In times of excessive hyperglycemia, a certain amount of proliferation takes place, using up precious precursor cells in the process.
Hypoglycemia hits. There is a localized energy shortage. "Immune" cells show up to either take apart starvation-damaged beta cells. What would some well-placed glucose do to this process?
Dr Harris recently commented that type one diabetics seem to be able to achieve lower blood sugar levels on the ketogenic diet than non diabetics. Is this a coincidence?
In type 2 diabetes, amyloid plaque buildup is common. This should decrease the Pepck pathway, increasing production of glutamine. Palmitic acid would rescue the pancreas cells from excessive proliferation for a while, increasing their lifespan. Maybe the buildup of amyloid plaque is sufficient in itself to eventually take the cell out?
Jenny also claims that Type-2 diabetics produce less insulin than non-diabetics.
Is that true?
Hi Gyan,
Yes, probably so. There are several ways of looking at this, first is that if they make enough insulin to force fat in to adipocytes they will stay fairly normoglycaemic. As the pancreas finally cannot force any more fat in to adipocytes they will stop gaining weight and start to spill NEFA from their adipocytes and develop hyperglycaemia (mostly from muscle acyl moiety accumulation) plus elevated FFAs (ie they lose their adipose derived protection from diabetes). Their liver was cooked years ago. Once they are hyperglycaemic they will induce apoptosis in their beta cells at an increased rate and insulin production will plummet. It is the failure of the pancreas which precipitates type 2 diabetes when obesity cannot buffer any longer.
Second is there may be specific genetic defects which impair the first phase insulin response. There is a break away of glucose which it is then up to the second phase to try and control. It struggles. Again, irrelevant if you live in an environment without refined carbohydrate. Unless you are back in to breeding only people with poor glucose response curves.... That OGGT before sex again!
There is also the fascinating issue of haemochromatosis. Iron overload allows a reasonable first phase insulin response but blunts second phase. Initially people are exquisitely insulin SENSITIVE, probably because their peripheral tissues are never exposed to hyperinsulinaemia and they can cope many years with some hyperglycaemia, especially if they accidentally eat LC-ish. As soon as they develop any insulin resistance they cannot make the sustained second phase insulin response needed to cope and type two diabetes (of a type) occurs. These people are never hyperinsulinaemic.
There are probably other scenarios, but ultimately, hypoinsulinaemia can often be (possibly always relative hypoinsulinaemia?) a feature of type 2, certainly advanced cases where the pancreas has been completely flogged to death. These folks are then functionally type 1 without the possibility of a honeymoon period...
Peter
donny, you are way ahead of me. But the glutamate amylin is interesting. There is some evidence that amyoid is a protective response in the brain Alzheimers patients. Can you fit this in to glutamate/glucose scenario?
Peter
Beth, absolutely, feel free...
Peter
Gluttony, sloth and the metabolic
syndrome: a roadmap to lipotoxicity Link to free full text.
Thanks Ted, if anyone wants to bang their heads....
Peter
I'm trying to figure out just when the manic episode actually started. I took some vitamin d yesterday for the first time in two weeks, and it just stopped, dead flat. Maybe that's a coincidence. So now I have to sort through some of this mess, and see what still makes sense. The idea that a free glutamic acid deficiency or excess would be as serious as hypoglycemia or hyperglycemia seems obviously true.
For alzheimers... well, MSG, monosodium glutamate. We have a hormone that specifically controls sodium, aldosterone. This is a taste. One that controls glutamic acid, leptin. Glutamic acid and its metabolites also seem to be integral to calcium metabolism, in multiple ways all over the body. That's two hormones, two tastes, umami and salty. Insulin associates with glucose, which is another taste. And potassium uptake is regulated by insulin. Three tastes, three hormones. Is there a krebs cycle metabolite that also is affected by aldosterone? And, we're down to two tastes that aren't associated with specific hormones, to my knowledge. If these hormones exist, are they also associated with particular minerals? Calcium and magnesium seem like likely candidates. Since glutamic acid associates with leptin and calcium both, I'm tempted.
MSG causes lesions in rodents, unless they are given free access to water. One study suggested a change in osmolarity as the cause. Hyperinsulinism should obviously have an effect on potassium, which may disregulate electrolyte balance, which should also have an effect on nutrient availability and fate in the brain.
And this;
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L-glutamic acid is oxidized by the brain to alphaketoglutaric acid, NH3 and later CO2 and H2O and is the only amino acid that on its own can maintain brain slice respiration (Weil-Malherbe, 1936)
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This glutamate as a neuro-exciter thing, it's almost like the single cells sense of "taste" was reworked into the ability to think.
And this is me not manic. Sigh.
The effect of glutamic acid metabolites on calcium metabolism might make the association of calcium leptin and glutamic acid difficult. And of course there's the obvious vitamin d thing--but doesn't vitamin d control calcium through phosphorus metabolism? Is there a flavour and Krebs cycle metabolite to go with vitamin d?
Again, not manic. Just interested.
Lactic acid. It's sour. Amylin is put out in the brain and the pancreas, it increases the production of lactic acid from glucose. So we have hormone, taste and Krebs cycle metabolite.
Leptin causes bone precursor cells to differentiate into solid bone type cells rather than adipose. Energy status and nature determines differentiation. Obvious implications to homeostasis.
Germ-free mice are lean and live longer, you give them gut bacteria from normal non-obese mice, they get fat. There's an interface here; the mice are put together in such a way as to select a diet on which they can thrive, as long as they can self-select nutrients (taste and smell.)
If you destroy this ability by providing only chow, the mice can adjust the hormonal balance in such a way as to stay lean and healthy. Adding normal gut bacteria to a germ-free mouse "blinds" the mouse's metabolism.
If you give the germ free mouse bacteria from a lean mouse, you are giving them a metabolic problem that is relatively easy to solve. From a fat mouse, the opposite.
People sure do seem to like sour milk products. Whenever I buy sugar-free gum, I can't stop eating it. It generally contains citric acid.
This might explain Kitiva. Generation after generation of choosing from the same types of food, the fact that they still eat what they ate hundreds of years ago suggests no disruption of food type or supply. Also, Mexican Pima Indians vs. Arizona.
Move aside, insulin. I think we're up to at least three "master" hormones.
I think the problem here lies in that amylin is mostly researched as a lucrative product.
I don't want to be too crazy here; pasteurized milk, gut bacteria, lactic acid? What effect is there on the signal to the pancreas, compared to raw milk?
"In order to investigate the effect of leucine residues on the taste of peptides, some oligo peptides containing leucine residues were synthesized and their taste was evaluated. The hydrophobicity of leucine residues markedly caused the bitterness of peptides and stronger bitterness was always found when a leucine residue was located at the C-terminus of peptides. The possibility of 2 binding sites between the bitter peptides and the bitter taste receptors of the gustation cells was postulated."
Mice fed a leptin-deficient diet depleted their fat mass within a few weeks (I put this under do not try at home). Pouring leucine on rat's chow increased liver fat-- were the rats thrown out of their homeostatic range? Men get more visceral fat than women, when women go through menopause, they start developing more visceral fat. Leucine is way anabolic, according to Dr Eades, it can by itself block marathon nitrogen loss. If I had to pick a hormone, I guess it would be the entire sex hormone family.
And leucine provides nitrogen for the production of alanine to keep the alanine/glucose cycle going.
You did ask about the Alzheimer's and amyloid, and now I have a perspective on it, since I think I might have the amyloid and the lactic acid pointed in the right direction.
When the sun's shining, you make hay. I think amylin is the demand for pyruvic acid, as well as the facilitator of its metabolism, and that what increases the demand for pyruvic acid is the presence of pyruvic acid. Pyruvic acid diabetes of the brain?
http://people.csail.mit.edu/seneff/alzheimers_statins.html
The brain is not being carefully, steadily nourished in this picture. Anyways, however it happens, pyruvic acid swings too high, there's too much amylin released in anticipation that this will go on forever, the cell becomes nutrient depleted. And Hyperamylin-ic. Poor management of nutrients is a very bad idea in the brain. Which is really only a slight modification of what Stephanie Seneff says. She explains how this pathway would allow the synthesis of fats that might be deficient in the ApoE4 brain. So misregulation of this protective pathway would of course really suck.
They should have listened to Pennington.
Whoops. Pyruvic acid is sour, too.
Hey Peter, great slides. If I may: Donny, this is Peter's site, and I, as I'm sure he likes folks to comment, but dude, really, you've taken over HIS blog (that's what your own blog is for). Besides, most of you're comments are way off topic, hence making it a total cluster f*^k to read.
Peter, thanks, had to vent a little. Cheers, Calvin
I have great respect for Peter, and if HE feels that way, than I apologize.
yeah donny, whoa there! my eyes are bleeding.
Hi All,
I'm not unhappy about donny's posts. There have been a number which I have found very useful espec the GAG paper, some absolutely intriguing (platelets, serotonin, vascular wall receptors, arteriosclerosis, and some confusing. I get minor discomfort when I cannot perceive the direction of the thought train and do not have the time to settle down and try to understand what the relevance might be. This latter is my main problem. Life is settling down again after the last few hectic days but there is such a backlog of reading and posting that stuff gets left and there are limits to what anyone can read and think about.
The comments are pretty obviously "donny comments" and skipping over them is a small price to pay if there are useful ideas there, so I'm comfortable on that front.
donny,
My problem is getting a logical sense of where you are going. Some of the ideas are too far out for intuition by me and you will need to spoon feed me more digestible size pieces. Sorry if that disappoints! The current arteriosclerosis posts are so drawn out and pedantic because I'm feeling my way and want to be as sure as I can be that I have the correct ideas and to then get those across. There has been a long hiatus off of CVD posting while I've been thinking.
Peter
Okay Peter. I getcha. Just to show that I'm not just a madman, my basic idea is this;
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?
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. And should improve the steady supply of the energy needed to make proper repairs.
But I realize that your comment section isn't really the place to work this idea through, so don't worry, I won't. Thanks for understanding.
donny, OK. I have your blog bookmarked
Peter
Hi Petro, great post. So would you say that adipose becomes insulin resistant relatively late in the game?
Probably.....
I liked your diagrams so much, I re-posted them on my blog, with attribution.
@donny
Nothing new on your blog since April 2, 2010???
Start streaming some of the stuff your thinking out loud here onto your blog and let some of the chemo/neuro/bio freaks pound on it.
You'll move things along a lot faster if you use that incredible resource called 'other people's brains'. ;-)
Peter's only one guy, and a very busy one at that. The dimensions you're exploring are deep and broad. Gonna need more help out in those depths! You need a full on dive team and support ship!!
Be well,
Ben
I suffer metabolic syndrome, I spent most of my life fighting and hating my fat, which to some degree still do just not as much, I even hae a blog called metabolic syndrome in blogger, you can read and read the link I give there. anyway fat cells job is to deal with metabolic dysfunction, I have come to learn, the worse your metabolic profile the more fat cells you need to survive the chronic nutrtional defincies.
and yes reducing your carbs really helps, my a1c is coming down.
I am feeling better adn have more energy sleeping better etc by eating lower carb (but I don't restrict fruit tho if I am hungry for it) and sugar regulation supplements, and digestive enzymes, wow what a different it is making after 38 years of dealing with this problem. read my blog for more information.
rose
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