Sunday, September 20, 2009

Palmitic Acid+ CARBS = Mouse Skeletal Muscle IR

Peter at Hyperlipid and Stephan at Whole Health have dispelled yet again myths regarding the indictment of the 16:0 long-chained saturated fatty acid Palmitic Acid as the prime instigator of insulin resistance (IR). Researchers are always wrong -- it's... HIGH CARBS PLUS Palmitic acid.

Their brilliant posts discuss below:
--Sportzaid (FRUCTOSE) + Palmitate = IR RETARDNESS
--High Carb Lab Chow + Palmitate = IR in the brain

Yes. Such inferences applied to low carbers (LCers) is pure ridiculousness. Non-applicable.

Low/no carb + Palmitic Acid = GOOD THING. All the low-carb/high saturated fat (palmitic acid) and ketosis trials by Hays JH, Volek JS, and Krauss RM have shown reductions in blood insulin, blood glucoses (BG) and peripheral tissue insulin resistance (IR). Directly contrary to the high carb animal or human studies.

Palmitic Acid (16:0 SFA)

Palmitic acid has a special evolutionary, adaptive role in mammalian metabolism. Stephan showed that it likely 'fills in' when blood glucose starts to decline.

G E N I U S ! !

Our mammalian *sses are full of palmitic acid. We release palmitic acid into our blood streams during b*tt-burning long low-intensity cardio, physical exercise, ketosis, starvation, and intermittent fasting.

What is the most important organ in the body? (Some males may argue otherwise. Hey, get your mind outta the gutter for a second -- and I apologize gentlereader if the last post had anything to do with it.) The organ of the most vital importance is understandably controversial but in reading Stephan's post and given that he is a neurobiologist, let's say for a moment... it's the B R A I N. The brain like other vital organs (nerves, retina, kidneys) have unregulated glucose access because glucose is the valued currency of energy. Few GLUT transporters (or none) exist in these tissues. Whatever is in the bloodstream, is in the tissue. These also are the first organs to be damaged by high, unremitting, toxic blood glucose concentrations. We tell individuals with diabetes on hypoglycemic medications, if the BG goes below 60 g/dl, they are in a lot of trouble. Consciousness, rational thoughts, driving (yes, DUIs can be cited), physical movements SHUT DOWN. Comas occur at below BG 40 g/dl, including fatal ones. Of course this rarely happens to those not taking pharmaceuticals because the liver and other tissues have the ability to make ANYTHING into glucose. Protein, fatty acids, glycogen via gluconeogenesis turns into blood glucose for the brain and other vital tissues (eyes, kidneys/adrenals, peripheral/central nervous system). So after a good 8-hour sleep, your blood glucose continues churning on at 70s-83 g/dl (non-diabetic, normal range) when the sun glows on your happy shining face every morning.

When protein, carbs and fat (eg, FOOD) become scarce, by default, ketones become the currency of brain-energy. Our brains are hard-wired to run well on two different types of fuel depending on the energy 'environment'. Ketones can be generated from ANYTHING with prefential production from fatty acids. Proteins from muscles are protected as long as possible. Muscle-wasting was NOT an evolutionary advantage for survival. This is why with intermittent fasting, I rarely notice any degradation of my hard-earned HIIT, Crossfit and jogging muscles! Atrophy occurs when I sit on my b*tt all day.

IR at the Skeletal Muscle Level

From the skeletal muscle point of view, a bunch of the same inaccurate inferences have been made by researchers de Wilde et al (Physiol Genomics. 2008 Feb 19;32(3):360-9. Free PDF HERE). They looked at the induction of genes and glucose/insulin levels in mice on high-HIGH-carb, 10%-Palmitate v. HIGH-carb, 45%-Palmitate diets in skeletal muscle. Mice were sacrificed at Day 3 v. Day 28 and their quadricep genetic and fatty acid profiles were compared (quads are a mixture of Type 1 Slow and predominant Type II Fast twitch muscles). At the skeletal muscle level, with both diets, both glucose and insulin increased over time. The researchers have concluded that insulin resistance has occurred to a higher extent however in the high-fat group. This makes sense if evolution-wise, little carbs existed and Paleo man intermittently hunted and ate gamey-meat. In this experiment, high carbs enter into the picture and sets off another metabolic pathway. Insulin (?and IR) appears to have spiked exponentially in the high-fat +carb group; blood glucose actually declined by Day 28 in this group.

Bizarre Love Triangle

In nature, paleotologically speaking, 3 things never rarely occurred together at one time as they do in research trials such as the ones that Stephan, Peter or the one highlighted here.

--high carb + high SFA ('large kill') + no omega-3 DHA
--high carb + low SFA ('small kill')+ no omega-3 DHA
--high carb + no SFA (no kill) + no omega-3 DHA

Palmitic acid is always consumed with DHA if one is eating grassfed meat/fowl or wild seafood. Or if I ate these study mice. :) J/k. And . . . in a 'paleo' environment... with scarce dietary carbohydrates.

So paleolithically speaking, high carb was not an environmental norm and therefore no genetic norm was ever established. Studies show human metabolic machinery is mainly set up for intermittent/daily consumption of fats and proteins (Huss, Kelly. Circ Res. 2004). However... the machinery for carbs does exist and for survival, these ancestral pathways seem to override and take precedence above all else. The ability to store fat for the purpose of reproduction, growth, and surviving harsh winters may have been key in determining that genetic material would be passed along in certain geographic niches. Anabolism of adipose is the metabolic pathway chosen when environmental 'carbohydrates' became readily available, eg fruit harvest at the end of summer (+/- big game 'kills'). Ingested carbs become post-prandial triglycerides, then small LDL and oxLDL, then into adipose eventually. Dr. T discusses a role for small LDL in evolutionary terms. It makes sense. Some research suggests a role for small LDL in delivering triglyerides to non-LDL-receptor sites perhaps for the same reason ultimately, fat storage for winter, a winter that never comes.

You can see inherently in mice (despite eating lab chow), in the muscle fat breakdown of the experimental mice -- DHA is about 10% of the total fatty acids in the quad muscles. Palmitic about 25-30%. DHA is an omega-3 PUFA associated with longevity and reduced cancer and coronary artery disease. Consuming more saturated fat and less carbohydrates, these mice had a noticable increase in DHA content and lower content of toxic omega-6 in their muscle-meat in the high-palmitate group (see below).

High-carb scenarios did not exist as humans evolved over 200,000 years.
-- Fruit didn't grow on acres of groves. Honey and ripe fruit were available for only a very short weeks at the end of summer.
-- Tubers, potatoes and yams didn't grow in 50 lb bushels at Costco
-- Grains and legumes were pre-ag

High carb actually has little bearing for those who are LC and semi-Paleo. After a 'kill', Paleo man was glycogen-depleted and running on ketones (if not already earlier). His BGs had already flat-lined at 70-80s g/dl for who knows how many days the tribe had been tracking and following herds of game. Gluconeogenesis and ketotic processes were in full force to keep Slow twitch Type I fibers on the go (walking muscles Gastronemius/ Gluts, Heart, lower back Trapezius, Psoas ('filet mignon' like other dark meats). Below table courtesy of Drobson. Type I Slow Twitch muscles require less glycogen (stored carbohydrates) than Fast Twitch. Conversion to Type I Slow Twitch musculature makes some evolutionary sense to prepare for certain physical tasks and energy demands when one considers the nature of how food was scarce and how it was intermittently obtained (hunting v. foraging v. fishing).

Insulin Resistance Increases with HIGH CARBS

Naturally IR increases with HIGHER Palmitic Acid/HIGH-carb digestion MORE than with the high-HIGH-carb, lower Palmitic Acid mouse diet. The mouse metabolic system was utterly CONFUSED -- two energetic systems were switched on concurrently:
(1) HIGH CARB/ Metabolic Syndrome (MetSyn), related to fat storage
(2) HIGH Palmitic Acid/Ketotic Efficiency, related to fat burning

Dr. T talks about MetSyn as 'evolutionary suicide' in some recent wonderful, concise and explicit posts (Part I and Part II). PPAR-gamma, the nuclear steroid involved with carbohydrate metabolism and energy balance, are normally whacked out and completely degraded in those with obesity and diabetes. In these mice, on the other hand, both groups exhibit expression of PPAR-gamma. This is not expected. Both 10% and 45% saturated Palmitate did it. (that's because Palmitate like omega-3 EPA DHA are agonists and activate the PPARs gamma and delta).

In fact, PPAR-gamma is turned ON in similar fashions with diabetic drugs (Avandia Actos which are PPAR-agonists), life-extending Resveratrol, ketosis, niacin and omega-3 PUFAs (fish oil EPA DHA). How PPAR-gamma is related are in prior animal pharm posts HERE.

Authors Conclusions Are Correct Except...

The authors are in fact correct -- insulin resistance occurs as Stephan and Peter agree as well and it is a good thing under certain circumstances. Low carb. Under high carb circumstances, it appears that MetSyn consequences are unavoidable and perhaps even hastened by Palmitic acid (perhaps via two ancient metabolic pathways both being induced simultaneously). When food sources are low and we need to continue walking/moving/hunting/foraging/carrying carcasses etc, we want to turn on the ox phos in the Type I slow twitch muscles as these authors discovered so that we can obtain more ATP which requires phosphorylation. We want morphogenesis -- change more muscles to Type 1 slow twitch as we are going to keep physically exerting ourselves after consuming a nice tasty high fat/protein-containing meal or in preparation for the next physical demand. If carbs are very scarce, we want some insulin resistance to continue to shunt any available glucose to the brain and eyes and nerve endings to the ears to see/listen for predators. We want decreased protein and carb catabolism (save all the stores in the muscles). We want increased fat catabolism.

Repeat... increased fatty acid (FA) catabolism. Easy release of the palmitate OFF of our cheeky b*tts.

They are CORRECT in the genetic analysis... Except... The authors surmise (see above Figure 3) that the entry of saturated fats like palmitate into the cellular membranes is associated with poor benefits including reduction in detox and immune function. How did they get that?!? They also extrapolated to the membranes of mitochondria. I think that these researchers have failed to take into account that again humans never consumed palmitate alone, always with omega-3 PUFAs DHA and EPA, and paleolithically always low carb. Palmitate and n-3 PUFAs balance the fatty acids and cholesterol of the cell membranes, providing structure and rigidity and important hormone signalling (see Hulbert below). The authors appear to also have forgotten or failed to reconcile the evidence for Palmitic acid in IMPROVING immune function (see last 2 citations below). Additionally the authors fail to recognize the role of high dietary carbohydrates, its downstream increase of LA omega-6 content in muscles, high dietary omega-6 intake or the role of dietary omega-3 PUFA deficiencies in instigating Metabolic Syndrome.


Helen said...

This is interesting, but I find it hard to back up inferences made about paleo people's diets and metabolism with research about mice, which evolved on a really different diet than the one you posit for paleo humans. What do you think?

Dr. B G said...

I don't either. Can we really make any inferences about really anything? What do any of us really know about Paleo eating?

Guinea pigs are actually better to make inferences on (even though they are herbivores) and have gallbladders like mice. I like this trial b/c it was not unlike human IR trial outcomes.

What do you think?

susan allport said...

Thought you would appreciate this new take on omega-3s:

Anonymous said...

Hi G,
Hope you're well. Could you enlighten me about these issues a little bit? Palmitic acid for blood glucose level preservation and temporary insulin resistance. I read Peter's and Stephan's blog and yours twice. (I know, maybe it's not enough.)
I ask because about 2 and a half hours after a breakfast consisting of sausages, egg, bacon and a few tomatoes I got blurry vision on the edges. This might mean that my eyes needed glucose and didn't get it and the palmitic acid wasn't working yet as Stephan says it clicks after about 4 hours. Obviously the liver wasn't giving me glucose either although glycogen wasn't depleted. Can you tell me what does this say about my metabolism? I had some dark chocolate and nuts. I don't even know if it was the right thing to do. Dr. Harris recommends a bit of fruit if hypoglycemic, I suppose the sugar is absorbed quicker. (It happened before but I don't remember the circumstances, it's a rare thing.)

lightcan said...

Hi, Dr. B.G.
I thought I posted a comment yesterday.
Anyway, can I ask you the same question again, maybe rephrased in case the post is going to appear later on.
If somebody gets blurry vision 2 and a half hours after a low carb, moderate fat breakfast (sausages, fried egg, bacon, tomatoes) does it mean that the switch for fat metabolism has been turned off recently? (by eating too many carbs?) What should happen is that the brain senses the palmitic acid, orders the insulin resistance and the glucose level is maintained. Plus, glycogen from the liver should be pumped out or fatty acids from the fat reserves for ketones. I suppose there was a delay until the body figured it out. Was it?

Neonomide said...

Hi again!

Dr B G said...

"Slow twitch Type I fibers on the go (walking muscles Gastronemius/ Gluts, Heart, lower back Trapezius, Psoas ('filet mignon' like other dark meats)."

Ah, this brings to mind that carnosine (& anserine) also help Type I muscle fibers, although less than type II. I think that Carns role comes to play esp when fatigue jumps in - there have been a couple nice trials recently that show exactly that! Fast bursts that were needed to catch game & run from predators definitely got boost from carn, don't you think?

I first noticed Carns great effects on my muscles during long distance running - not in the gym.

I have to think that wild game has/had a LOT more carn/anserine than modern standing/eating/boring farm animals anywhere, which just *might* be another slam dunk for these cool paleo food theories, don't you think? ;-)

By the way, how is your training going? :-)

I just got my Vibram five fingers shoes and I think I'm ready to fly... (had a birthday yesterday)

Dr. B G said...

Hey Neo,

Happy Belated Bday!! Hope you had a wonderful day and celebration :)

I have done more reading on carn (an b-ala) -- yes it is amazing stuff and does replicate the effects of meat-eating and why Paleo ROCKS! The regenerative properties of various amino acids are quite substantial. I don't know if it has helped but the entire antioxidant regime I do has definitely helped my recovery!

Hope you are getting in your long runs and fun play time! Hope the weather is not too restrictive.

My training! As all winter seasons go, not as much training as I'd like! I resumed some Xfit and a lot of longer runs which are great!


Anonymous said...

Reading the Cordain paper you link to (Dietary Fat Quality and CHD PRevention: A unified Theory...), they state that palmitic acid raises LDL cholesterol levels. Is there some mitigating factor to this, such as LDL-elevation only happening in high-carb, or in low EPA/DHA, or only a rise in large bouyant LDL?


Neonomide said...

Hi G!

I can't find our original carnosine spectacle, but I guess I said something about wound healing and carnosine. Then I found this paper:

"Since beta-alanine, the other degradation product of carnosine, was found to stimulate the biosynthesis of nucleic acids and collagen, histamine derived from carnosine is considered to have enhanced the process of wound healing by stimulating effusion at the initial stage of inflammation. Thus, the enhancement by carnosine of wound healing may be ascribed to stimulation of early effusion by histamine and of collagen biosynthesis by beta-alanine. The wound-healing effects of carnosine were further demonstrated by the observation that carnosine significantly increased granulation suppressed by cortisone, mitomycin C, 5-fluorouracil, and bleomycin."

Pretty interesting, eh?

Now I must find the papers that may explain how hearing and olfaction (sense of smell?) have improved by carn suppl.