Animal Pharm: Cardio Controversies: Lp(a) Dangerous at ANY Value

Cardio Controversies: Lp(a) Dangerous at ANY Value

Animal Pharm: Cardio Controversies: Lp(a) Dangerous at ANY Value

Friday, October 2, 2009

What the heck...?

Can Lp(a) create more damage than we previously thought?

Dr. Hecht has apparently showed it with his examination of lipoprotein, cardiac and metabolic parameter comparisons with the real measure of heart disease risk: EBCT-determined plaque burden. Lp(a) was 3rd after HDL and LDL particle diameter in being highly associated with coronary calcifications. See below. Free PDF HERE. Normally at TrackYourPlaque we consider Lp(a) greater than 20 mg/dl as a high contributor toward accelerated plaque burden. When I look at Dr. Hecht's graphs, what I notice is that indeed this may not be true.

It appears to my observations that at ANY Lp(a) value, plaque burden is quite high reaching even 97th, 98th or 99th calcium percentile for CAD risk (of population norms) at severely low Lp(a) levels of 5 mg/dl or 10 mg/dl.

OK...what the heck?

I can make the same observations for my CAD (heart), PVD (peripheral), or CVD (stroke) patients and individuals with extensive diabetic complications. At any Lp(a), the extent of disease can still be quite pronounced.

What other factors are correlated to vascular damage?

1. Low HDL2b

2. High small dense LDL.

These THREE factors determine almost entirely the extent of disease. Both visionaries Dr. Davis and Dr. Hecht focus on these predominantly to control and halt the progression of calcifications.

How are these 3 metabolic parameters created in the first place?
--low fat SAD AHA low cholesterol low saturated fat diet
--saturated fat deficiency
--excessive carbs (>10 g/d, >20 g/d, >50 g/d, >100 g/d -- depending on a person's insulin and insulin sensitivity and pancreas/adipose/hormone status)
--inflammation (excessive omega-6 oils)

Not... necessarily... a Slo-niacin or Niaspan deficiency...

Saturated Fats Like Butter Beat the Cr*pola Out of Canola in Lowering Lp(a)

We've discussed Dr. Mozaffarian earlier in Part IV Benefits of High-Saturated Fat Diets where he showed higher sat fat (> 12.0%), lower n-6 PUFA and lower carb were associated with less coronary artery stenosis; in fact in the quartile of the highest sat fat dietary intake, regression of coronary artery stenosis was signficantly observed. No other parameter was correlated to regression. Right...! ONLY higher dietary saturated fat consumption... (this quartile also was found to smoke more and took less pharmaceuticals).

Is Krauss in the house?? OK, Dr. Mozaffarian at Harvard has come through again (sort of). He did the right study again (though... 'wrong' conclusions). In his most recent publication Mozaffarian showed that after switching human subjects off of various concentrations of dietary trans fats to different fats (saturated and n-6), dramatic changes in cardiac parameters were noticed (Mozaffarian D, Clarke R. Eur J Clin Nutr. 2009 May;63 Suppl 2:S22-33. Free PDF HERE. ) Butter and other saturated fats were shown to lower the baseline Lp(a) to greater degrees than n-6 PUFAs like soybean, cottonseed, or canola oil.

Butter, palm oil and lard beat canola and other n-6 PUFA oils by 3-4-fold.

Mechanism of Action of: B U T T E R

Butter is comprised of part monounsaturated fats and part saturated fatty acids with one of the predominant acids being BUTYRIC ACID, a 4-carbon chain entity. It turns out that ALL the saturated fatty acids behave much like the omega-3 PUFAs that we enjoy for their plaque-regression, lipoprotein improving, immunomodulating and anti-inflammatory properties. Omega-3 PUFAS bind the whole-pan-PPAR receptor family to shift to LDL larger particles and increase HDL2b. Saturated fats bind most strongly to PPAR-gamma which raises HDLs and and lowers both Lp(a) and Small Dense LDL (particularly LDL-IVb, the 'death band'). They bind weakly to PPAR-delta but sufficiently to paradoxically and P-O-T-E-N-T-L-Y lower inflammation (NFkB, TNF-alpha).

Recall: PPAR-Delta is the Dagger in the Heart of CAD

Saturated fatty acids in fact behave like hormones and bind like steroid nuclear hormones to the PPAR family of receptors (like vitamin-D-to-VDR, carotenoids-to-RXR, vitamin-A-to-RAR, thyroid-to-TR, estrogen-to-ER, etc). This research was done many years ago by Glaxo researchers Eric Xu and others (Molecular Cell, Vol. 3, 397–403, March, 1999). See below. Other researchers defined further the benefits of butyric acid (butyrate) by elucidating its binding activity of PPAR convincingly.

Our b*tt is made out of saturated fats and we eat saturated fats (almonds, coconuts, olives, fatty fish, grassfed beef, free-range eggs/fowl, wild duck, etc). Our body creates, metabolizes and burns saturated fats all day (recall: palmitic acid) esp when we are between meals, intermittent fasting, carb restricting, ketotic, exercising or starving.

Do we make butyrate??

Make Butter (Butyrate) In Your B*TT

Just kidding... North of the rectum (e.g. b*tt), in the colon , short-chain fatty acids like butyric acid (butyrate) one of the fatty acids found in butter, cream and cheeses is produced via anaerobic fermentation of dietary fiber. Our friendly happy gut flora actually produces butyrate (not us). We either consume it or we absorb it from our intestines from bacterial production.

Yes... *haaa* make BUTTER in your colon from vegetable fibers...

Butyrate Protects Against Colon Cancer by Lowering NFkB by Binding PPAR

Furthermore, butyrate has been shown in trials to be anti-inflammatory and immune-modulating. Deficiencies in luminal butyrate synthesis are associated with chronic bowel inflammation. Schwab M et al state:

"Previously, we have demonstrated that the nuclear hormone erceptors Peroxisome-Proliferator-Activated-Receptor (PPAR) and the vitamin D receptor (VDR), transcription factors with anti-inflammatory capacities, are up-regulated and activated by butyrate (Gaschott and Stein, 2003; Gaschott et al., 2001; Schwab et al., 2006;Wachtershauser et al., 2000). PPAR and VDR are highly expressed in the colonic epithelium indicating that both receptors are important agents in the physiology of the human colon (Desvergne and Wahli, 1999; Nagpal et al., 2005). Ligands for both receptors have been shown to interfere with the activity of NFkB and to influence the ability of olonocytes to express immune-modulatory cytokines (Segain et al., 2000; Sun et al., 2006)."

Independently in two labs in 2007, butyrate was found to control NFkB, one of the most potent pro-inflammatory cytokines of our immune system implicated in ALL chronic and acute diseases known to man, including colon cancer and coronary artery disease (Schwab M et al. Molecular Immunology 2007;44: 3625–3632.; Usame M et al. Nutr Res 2008;28:321–328. See end.) The anti-inflammatory power of lauric acid from coconut and palm oil and butyric acid from butter originates from their ability to bind and activiate PPAR-gamma as shown by these studies. PPAR, like the vitamin D receptor (VDR), is one of the master controllers of inflammation. Schwab shows in several publications that butyrate does in fact configure, bind, and activate PPAR receptors. Butyrate is like a DRUG. It binds the most potent receptor for energy balance, immunomodulation, control of lipids (Lp(a), HDL2b, sdLDL), and inflammation! End result... it knocks out NFkB. For the heart, this translates to kicking the cr*pola out of canola in terms of shifting to Pattern 'A', increasing HDL-2b, annihilating small dense LDL and Lp(a) and eradication of vascular atherosclersis.

See Prior Posts:

Trying to Target Butter-Receptors: How About Grassfed GHEE??

"There is increasing evidence that the expression and activity of PPARg and VDR are under the control of butyrate implying that the receptors may participate in butyrate-mediated suppression of NFB activation (Gaschott and Stein, 2003; Gaschott et al., 2001; Schwab et al., 2006; Wachtershauser et al., 2000). PPARg and VDR are both ligand-activated transcription factors that belong to the nuclear hormone receptor family and participate in a variety of immune processes (Tirona and Kim, 2005). VDR is widely expressed in epithelial tissues, cells of the immune system and several cancer cell lines including colorectal cancer cells (Giuliano et al., 1991; Segaert and Bouillon, 1998). PPARg is activated by natural ligands such as fatty acids and eicosanoids and is highly expressed in colonic epithelium, indicating an important role of the receptor in the physiology of the human colon (Desvergne and Wahli, 1999). All these characteristics make both receptors potential targets in butyrate-mediated inhibition of NFkB signalling."

In Vivo (Live Humans) High Intake of Butter Associated with Reduced Colon Cancer

Of course Swedish researchers examined their nutrition data registry for the Swedish Mammagraphy Cohort and lo and behold found distinct correlations between high dairy intake and low colon cancer (Am J Clin Nutr. 2005 Oct;82(4):894-900.) Those in the upper 2 quartiles of CLA consumption and > 4 servings daily of high-fat dairy was highly associated with reduced colon cancer risk. The author's conclusions were: These prospective data suggest that high intakes of high-fat dairy foods and CLA may reduce the risk of colorectal cancer.

Diary Fat Potential Anti-Carcinogenic Agents

Parodi reviews the literature and reports that... "About one third of all milk triacylglycerols contain one molecule of butyric acid, a potent inhibitor of proliferation and inducer of differentiation and apoptosis in a wide range of neoplastic cell lines. Although butyrate produced by colonic fermentation is considered important for colon cancer protection, an animal study suggests dietary butyrate may inhibit mammary tumorigenesis. The dairy cow also has the ability to extract other potential anticarcinogenic agents such as beta-carotene, beta-ionone and gossypol from its feed and transfer them to milk (J Nutr. 1997 Jun;127(6):1055-60. Free PDF HERE). Grassfed cheese, cultured milk, yogurt, ghee, and butter also contain CLA. Parodi discusses that, "Recent research shows that milk fat contains a number of potential anticarcinogenic components including conjugated linoleic acid, sphingomyelin, butyric acid and ether lipids. Conjugated linoleic acid inhibited proliferation of human malignant melanoma, colorectal, breast and lung cancer cell lines. In animals, it reduced the incidence of chemically induced mouse epidermal tumors, mouse forestomach neoplasia and aberrant crypt foci in the rat colon. In a number of studies, conjugated linoleic acid, at near-physiological concentrations, inhibited mammary tumorigenesis independently of the amount and type of fat in the diet."

Beef Tallow SYNERGISTICALLY Beats the Cr*pola Out of Corn Oil (n-6 PUFA)

In another interesting animal study (mice), beef tallow (25% palmitic acid; 50% oleic acid) increased the potency of CLA in decreasing mouse mammary tumor metastasis. (J Nutr. 2006 Jan;136(1):88-93.) "Linoleic, oleic, stearic, and palmitic acids, either did not change or enhanced the cytolytic effects of CLA isomers on mouse mammary tumor cells in culture." The authors found that oleic + palmitic enhanced cytolytic CLA-derived tumor cell death, whereas n-6 PUFAs (linoleic acid) were associated with dose-dependent increases in tumorigenesis and blocking CLA-benefits.

See Prior Post:
Happy Cows and CLA (CLA is found in grassfed beef, dairy, lamb, pastured pork)

Rat Study: ONLY Olive Oil and n-6 PUFAs Associated with Cancer Model in High-Fat Diets

Rats are not humans but they have no gall bladders... so they are not unlike 80% of the individuals that I see who fail to have functioning gallbladders. Anyhow in this one study 4 high fat diets (corn, lard, beef tallow and coconut oil) and 1 low fat corn oil were used in 5 rat groups (Chan PC et al. Cancer Res. 1983 Mar;43(3):1079-83.). Mammary tumors were induced with N-nitrosomethylurea. Incidence of tumors in the high-fat groups was the lowest in the coconut oil group. Upon further analyses (these researchers were GOOD), they concluded, " the total oleic and linoleic acid intake in the five groups of rats correlated positively (r = 0.95) with mammary tumor incidence."

Role of Oliv-ola (Canola+Olive oil) Induced Colon Carcinogenesis:
Coconut Oil Beats the Cr*pola Out of OLIVOLA

Nair J et al in Germany have been conducting research in DNA damage associated with oils (Nair J et al. Mutat Res. 2007 Nov 1;624(1-2):71-9.) They tested LA (linoleic acid, n-6 PUFA), oleic acid and coconut oil in rats by lavaging them for 30day, sacrificing, then measuring etheno-DNA adducts in the organs. Etheno-DNA adducts are associated with j*cked up gene expression, mutations and carcinogenesis. They are produced by oxidative stress and lipid peroxidation. Their research showed that n-6 PUFAs have gender-specific toxicity and other surprising results. Not unlike the Israeli 'Paradox' (see below), female LA-treated rats showed increases in etheno-DNA adducts in the DNA of their circulating immune cells, the all important WBC (white blood cells). For both genders, colon was the target for stress-derived DNA-adducts in omega-6-PUFA treated rats, which supports the role for omega-6 induced colon cancer, the authors concluded.

'Unexpectedly, olive oil treatment enhanced entheno-adduct levels in prostate 3-9-fold' the researchers observed.

What... the... H E C K ?

So... olive oil (n-9 monounsaturated) is highly implicated in TWO studies with cancer: mammary and prostate. Is this only seen in certain situations?

Lame-o retard-o dietary fat composition?

Saturated fatty acid deficiencies?

Omega-3 deficiencies?

Most lab rats are vitamin D deficient as well...

Here is other provocative (ok, not really) research showing the same thing in more in vivo animal cancer model studies:
--coconut oil beats the cr*pola out of n-6 PUFAs
--MCT oil (50% of coconut oil) beats the cr*pola out of n-6 PUFAs
--the lower the rat cholesterol, the higher the incidence of mammary tumorogenesis... in other words (switch around), the larger the LDL particles induced by saturated fatty acids which results in a higher total cholesterol, the lower the risk of breast cancer in rats. Applies to humans too.

Dietary fat and mammary cancer. II. Modulation of serum and tumor lipid composition and tumor prostaglandins by different dietary fats: association with tumor incidence patterns.
Cohen LA, Thompson DO, Choi K, Karmali RA, Rose DP.
J Natl Cancer Inst. 1986 Jul;77(1):43-51.

Dietary fat and mammary cancer. I. Promoting effects of different dietary fats on N-nitrosomethylurea-induced rat mammary tumorigenesis.
Cohen LA, Thompson DO, Maeura Y, Choi K, Blank ME, Rose DP.
J Natl Cancer Inst. 1986 Jul;77(1):33-42.

Influence of dietary medium-chain triglycerides on the development of N-methylnitrosourea-induced rat mammary tumors.
Cohen LA, Thompson DO, Maeura Y, Weisburger JH.
Cancer Res. 1984 Nov;44(11):5023-8.
Medium chain triglycerides (MCT) in aging and arteriosclerosis.
Kaunitz H.
J Environ Pathol Toxicol Oncol. 1986 Mar-Apr;6(3-4):115-21.

So I've digressed... let's get back to the heart of the matter...

n-6 PUFAs Shrink LDL-Particles... To Pattern B (BAD)

Shrinkage... Not. Good. The rest of the Mozaffarian and Clarke's conclusions are not so justified by the medical literature. They further try to discuss the cardiac benefits of the n-6 vegetable oils without acknowledging the metabolic parameters that Drs. Hecht, Krauss, Superko and Davis support as the factors that are most highly correlated to plaque burden: LDL particle size, HDL2b and Lp(a). Unfortunately I find their so-called cardiac assertions kinda b-u-n-k-y. They employ parameters (TC/HDL ratio, apoB/AI ratio, CRP) that are not borne out to be associated with coronary calcium plaque burden or serial plaque progression according to Hecht's 2003 publication.

n-6 PUFA and olive oil are necessarily heart healthy?? No. In a study with rapeseed, olive oil or sunflower oil, LDL particles significantly (p=0.012) shifted to smaller, dense particles with all the oils tested, after a switch from a two-week saturated fat diet. BUNKY!!! See below.

Dietary mono- and polyunsaturated fatty acids similarly affect LDL size in healthy men and women.

Kratz M, et al. J Nutr. 2002 Apr;132(4):715-8.

The goal of this study was to investigate the effect of the dietary fat composition on LDL peak particle diameter. Therefore, we measured LDL size by gradient gel electrophoresis in 56 (30 men, 26 women) healthy participants in a controlled dietary study. First, all participants received a baseline diet rich in saturated fat for 2 wk; they were then randomly assigned to one of three dietary treatments, which contained refined olive oil [rich in monounsaturated fatty acids (MUFA), n = 18], rapeseed oil [rich in MUFA and (n-3)-polyunsaturated fatty acids (PUFA), n = 18], or sunflower oil [rich in (n-6)-PUFA, n = 20] as the principal source of fat for 4 wk. Repeated-measures ANOVA revealed a small, but significant reduction in LDL size during the oil diet phase (-0.36 nm, P = 0.012), which did not differ significantly among the three groups (P = 0.384). Furthermore, affiliation with one of the three diet groups did not contribute significantly to the observed variation in LDL size (P = 0.690). In conclusion, our data indicate that dietary unsaturated fat similarly R E D U C E S LDL size relative to saturated fat. However, the small magnitude of this reduction also suggests that the composition of dietary fat is not a major factor affecting LDL size.
PMID: 11925466

n-6 PUFAs Cause Inflammation and Cancer: Israeli Experience

Shapiri discusses how changing from traditional oils (saturated fats like schmaltz (rendered goose or chicken fat w/onions) or beef tallow) to a high consumption of n-6 PUFA oil is postulated to have lead to the astronomic rise in cancer in Israeli Jewish women (Eur J Cancer Prev. 2007 Oct;16(5):486-94.)

It is discussed HERE as well.

Wanna CUPPA of CANCER? Increase your n-6 PUFAs, reduce your saturated fatty acids.

Small Dense LDL, OxLDL and Lp(a) SYNERGISTICALLY Grow Plaque

Why is Lp(a) so extremely toxic and an accelerant for all damage whether it is diabetic complications (microvascular: eyes - kidney - nerves - penile - brain (e.g. Type 3.0 Diabetes)) or atherosclerotic disease (macrovascular: heart, carotid, peripheral)? Apparently Lp(a) binds oxidized phospholipids of apoB 100 which is attached to all LDL, including Lp(a). What is Lp(a)? It is just LDL + apo(a) combined. Large LDL are rarely oxidized -- they are protected by size, buoyancy, high cholesterol content (yes, cholesterol is an 'antioxidant') and a high content of vitamins and fat-soluble antioxidants (ubiquinols, carotenoids, menaquinones (vitamin K2s), tocopherols, tocotrienols) and apo E (carriers of minerals and other vital micronutrients).

A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.

Bergmark C, et al. J Lipid Res. 2008 Oct;49(10):2230-9. Free PDF HERE.

Oxidized phospholipids (OxPLs) on apolipoprotein B-100 (apoB-100) particles are strongly associated with lipoprotein [a] (Lp[a]). In this study, we evaluated whether Lp[a] is preferentially the carrier of OxPL in human plasma. The content of OxPL on apoB-100 particles was measured with monoclonal antibody E06, which recognizes the phosphocholine (PC) headgroup of oxidized but not native phospholipids. To assess whether OxPLs were preferentially bound by Lp[a] as opposed to other lipoproteins, immunoprecipitation and ultracentrifugation experiments, in vitro transfer studies, and chemiluminescent ELISAs were performed. Immunoprecipitation of Lp[a] from human plasma with an apolipoprotein [a] (apo[a])-specific antibody demonstrated that more than 85% of E06 reactivity (i.e., OxPL) coimmunoprecipitated with Lp[a]. Ultracentrifugation experiments showed that nearly all OxPLs were found in fractions containing apo[a], as opposed to other apolipoproteins. In vitro transfer studies showed that oxidized LDL preferentially donates OxPLs to Lp[a], as opposed to LDL, in a time- and temperature-dependent manner, even in aqueous buffer. Approximately 50% of E06 immunoreactivity could be extracted from isolated Lp[a] following exposure of plasma to various lipid solvents. These data demonstrate that Lp[a] is the preferential carrier of PC-containing OxPL in human plasma. This unique property of Lp[a] suggests novel insights into its physiological function and mechanisms of atherogenicity.

Butyrate NFkB References

Involvement of different nuclear hormone receptors in butyrate-mediated inhibition of inducible NF kappa B signalling.
Schwab M, Reynders V, Loitsch S, Steinhilber D, Stein J, Schröder O.
Mol Immunol. 2007 Jul;44(15):3625-32. Epub 2007 May 22.

Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells.
Schwab M, Reynders V, Shastri Y, Loitsch S, Stein J, Schröder O.
Mol Immunol. 2007 Mar;44(8):2107-14. Epub 2006 Oct 19.

PPARgamma is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2.
Schwab M, Reynders V, Ulrich S, Zahn N, Stein J, Schröder O.
Apoptosis. 2006 Oct;11(10):1801-11.

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.