Insulin Response of Long Term Type 2 Diabetics Improved with Amino Acids

Amino Acid Ingestion Strongly Enhances Insulin Secretion in Patients With Long-Term Type 2 Diabetes

ABSTRACT:

OBJECTIVE—Insulin secretion in response to carbohydrate intake is blunted in type 2 diabetic patients. However, it is not clear whether the insulin response to other stimuli, such as amino acids, is also diminished. Recently, we defined an optimal insulinoptropic mixture containing free leucine, phenylalanine, and a protein hydrolysate that substantially enhances the insulin response in healthy young subjects when coingested with carbohydrate. In this study, we aimed to investigate the insulinotropic capacity of this mixture in long-term type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—Ten type 2 diabetic patients (aged 59.1 ± 2.0 years, BMI 26.5 ± 0.7 kg/m²) and 10 healthy control subjects (58.8 ± 2.1 years, 26.5 ± 0.7 kg/m²) visited our lab twice, during which insulin responses were determined following ingestion of carbohydrate only (CHO) or carbohydrate with the free amino acid/protein mixture (CHO+PRO). All subjects received 0.7 g · kg⁻¹ · h⁻¹ carbohydrate with or without 0.35 g · kg⁻¹ · h⁻¹ of the amino acid/protein mixture.

RESULTS—Insulin responses were dramatically increased in the CHO+PRO trial in both the type 2 diabetic and control groups (189 and 114%, respectively) compared with the CHO trial (P < 0.01). Plasma glucose, glucagon, growth hormone, cortisol, IGF-I, and IGF binding protein 3 responses were not different between trials within the 2-h time frame.

CONCLUSIONS—The insulin secretory capacity in long-term type 2 diabetic patients is substantially underestimated, as the insulin response following carbohydrate intake can be nearly tripled by coingestion of a free amino acid/protein mixture. Future research should be performed to investigate whether such nutritional interventions can improve postprandial glucose disposal.

My Summary:  10 adult males with Type 2 diabetes >8 yrs and ready to switch to insulin therapy were compared to 10 normal adult males.  Each group was fed either a standardized carbohydrate only meal (CHO) or the carb along with a protein mixture containing free amino acids.  The insulin responses were increased in both groups given the protein/AA mixture.

So ... what was the composition of this magical protein mixture?   The dose was 0.35 g · kg⁻¹ · h⁻¹ of an amino acid/protein hydrolysate mixture.  The mixture consisted of a wheat protein hydrolysate (50%, 0.17 g · kg⁻¹ · h⁻¹), free leucine (25%, 0.09 g · kg⁻¹ · h⁻¹), and free phenylalanine (25%, 0.09 g · kg⁻¹ · h⁻¹).  This was administered  in 3 mL/kg boluses  at 0, 30, 60, and 90 min.

For "A", the open symbols are the CHO only, the black symbols are the CHO/PRO group.  The circles are the T2's the squares are the normal controls.  

Remember, these are T2's who are about to become insulin dependent.  We see that the T2's had less than half the insulin response to CHO that the normal controls have (clear bars in "B").  We also see that using the protein along with the CHO, the T2's had an insulin response similar or even a little better than that mounted by the normal "unstimulated" controls as evidenced in both "A" and "B" above.

The results don't impact glucose levels a whole lot, however.

The shape of the normal control curve does show a lower max BG (something that might show up better but for the scale to accomodate the BG levels of the T2's).  The glucose clearance does not seem to be improved by the insulin response in the T2's.  Things that make you go hmmmmmmmmm.  Seems the IR of the T2's is still "in force".  For this treatment to reduce hyperglycemia, it seems the underlying resistance to insulin needs to be addressed.  

However this does demonstrate that long term T2's may not have "worn out" their pancreases with their hyperinsulinemia after all, but rather than chronically elevated BG's may reduce the pancreas' response to acute BG rises.  

Still, this points to me that even long-ongoing T2 diabetes could theoretically be reversed.  The subjects in this study were only mildly overweight.  What is the underlying cause of the IR in these Type 2's?

More Biochemistry Animations

Boyer - Interactive Biochemistry

A screen shot of the Menu:

A Neat Gluconeogenesis Tutorial

Interactive Gluconeogenesis Tutorial

Effects of aerobic exercise and dietary carbohydrate on energy expenditure and body composition during weight reduction in obese women

Effects of aerobic exercise and dietary carbohydrate on energy expenditure and body composition during weight reduction in obese women

My Summary:

Subjects:  23 Obese (44 +/- 4% BF), Healthy, Premenopausal Women (Range 21-47, late 30's on average) 

Compared:  Two diets -- one low fat LF , one low carb LC,  and Two exercise states -- one aerobic EX, one no exercise  NX -- Four groups were compared LF/NX, LF/EX, LC/NX, LC/EX.

Study Length:  12 Weeks of weight loss, preceded by 5 weeks maintenance (MI), and followed by 6 weeks maintenance (MII).

Diets - Carb/Protein/Fat:  Maintenance - 45/20/35 ; LC - 25/25/50 ; LF - 60/25/15  It is worth noting that the LC vs. LF comparison kept protein constant.  The caloric content of the reducing diets was individualized to each participant to be ~75% of measured RMR.

Exercise:   3X/week, 45 minutes = 15 min on each of three different cardio machines, 60-65% VO2max

Measured:  Changes in body composition, Resting Metabolic Rate (RMR), thermic effect of a meal (TEM aka TEF), and total daily energy expenditure (TDEE).

Results:

• LC lost a bit more weight than LF:  10.6 kg ± 2.0 vs  8.1 ± 3.0 kg   (P 0.037)  
• Diet composition did not significantly influence body composition or energy expenditure changes
• RMR was reduced similarly for both diets:  0.54 MJ/d (~130 calories)
• TEM/TEF did not differ between the two diets
• Exercise resulted in greater loss of fat mass 8.8 ± 2.1 kg vs. 6.1 ± 2.3 kg  (P = 0.008) 
• Exercise maintained TDEE better +0.07 ± 1.23  vs. -1.46 ± 1.04  (P 0.004) due directly to exercise, and  +0.75 ± 1.06 for the exercisers vs -0.61 ± 1.03 MJ/d  (P = 0.006) for the non-exercisers not solely attributed to the exercise sessions.   I'm not sure these are additive, but +0.82 MJ vs -2.07 MJ between the two.  This is a swing of almost 3 MJ or ~ 700 calories!!

Some of the tabulated hormone & blood glucose findings:  (You can click to enlarge)

Interestingly, the LF/NX group had the same fasting insulin as the LC/EX group during the reducing phase., the LC/NX group had the highest fasting insulin.  I don't think these were statistically significant (especially because it looks like some samples were lost), but this counters the general belief that low carb diets necessarily impact fasting insulin levels.  One can see that fasting insulin decreased in all groups probably attributed to weight loss in general.

From the Discussion:

More important than total weight losses, however, are the relative changes in FFM and FM. Exercise training was a major determinant of the changes in body composition, with FM comprising 89.4% of the weight loss in the Ex group, compared with only 71.3% in the Nx group.

Exercise led to more FAT loss irrespective of diet.

The increased fat loss in the Ex group indicates a greater energy deficit, but this cannot be attributed to the energy costs of the exercise sessions alone because the diet prescriptions for the Ex subjects were increased to compensate for the energy expended during the exercise sessions. The rationale for this compensation was to avoid a greater energy deficit in the Ex subjects relative to the Nx group, because changes in FFM (6) and RMR (30, 35) have been shown to depend on the degree of energy restriction.  

So they held the calorie deficit constant for the caloric expenditure associated with the exercise session itself.  But interestingly:  

.

The increased fat loss in the Ex group cannot be attributed to maintenance of RMR, because in this study aerobic exercise failed to have a protective effect on RMR. ... In the present study, RMR, which comprised 58 ± 6% of the subjects’ daily energy expenditure, demonstrated the commonly observed decrease during the reducing diet in all treatment groups.

RMR was also measured during MII after the subjects consumed an isoenergetic diet for 4 wk. RMR values increased relative to energy restriction levels, but remained significantly depressed during MII.  

That second quote is depressing and probably is what causes relapses and regain.  I contend that a goodly portion of the adult obesity epidemic (especially in women) is probably due to dieting in the first place.  Repeated bouts of caloric restriction depress RMR (and thus TDEE), and there's a "hangover" effect that is not attributable just to reduced caloric needs to maintain a lower mass.

A unique feature of this study is that we measured free-living TDEE. Aerobic exercise played an important role in maintaining TDEE during weight reduction. The lack of a significant change in TDEE in the Ex group (+ 1.2 ± 12.2%) is in sharp contrast with the decrease of 12.3 ± 8.8% observed in the Nx group during low-energy feeding. The major effect of Ex on TDEE during weight reduction was its effect on physical activity. Because the change in TDEE is equal to the sum of the changes in RMR, TEM/TEF, and physical activity, and because the changes in RMR and TEM/TEF were comparable in the Ex and Nx groups, we were able to deduce that the significant TDEE difference between groups was attributable to a difference in physical activity (Figure 3). Although compensatory reductions in spontaneous physical activity are classic responses to undernutrition and must also be considered as part of the energy balance picture during energy restriction (43), the addition of aerobic exercise during the reducing diet proved to be an effective method for preventing this decrease. In contrast with the Nx group, the Ex group increased their physical activity by 0.75 ± 1.06 MJ/d, offsetting the decreases in RMR and TEM/TEF, yielding virtually no change in TDEE.   Note:  0.1 MJ (mega joule) is roughly equal to 25 food calories.

What this says to me is that ELMM IS the most effective method to lose weight after all.  I gotta say, my personal journey included rapid weight loss without formal exercise, but I'm a more active person by nature.  As weight was lost, I did become more physically active (taking stairs, parking further away from destination, etc.) so I think I probably staved off some of the TDEE reductions.  But this can be highly individual as the large variation in the mean (>140%) meant that for some of the exercisers, TDEE was not maintained and/or was still reduced.  Still, your chances seem better when including moderate aerobic exercise into the mix.

Glyceroneogenesis

Glyceroneogenesis and the Source of Glycerol for Hepatic Triacylglycerol Synthesis in Humans

Glyceroneogenesis,i.e. the synthesis of the glycerol moiety of triacylglycerol from pyruvate, has been suggested to be quantitatively important in both the liver and adipose tissue during fasting. However, the actual contribution of glyceroneogenesis to triacylglycerol synthesis has not been quantified in vivo in human studies. In the present study we have measured the contribution of glycerol and pyruvate to in vivo synthesis of hepatic triacylglycerol in nonpregnant and pregnant women after an overnight fast. 

After a 16-h fast, ∼6.1% of the plasma triacylglycerol pool was derived from plasma glycerol, whereas 10 to 60% was derived from pyruvate in nonpregnant women and pregnant women early in gestation. Our data suggest that glyceroneogenesis from pyruvate is quantitatively a major contributor to plasma triacylglycerol synthesis and may be important for the regulation of very low density lipoprotein triacylglycerol production. 

Our data also suggest that 3-glycerol phosphate is in rapid equilibrium with the triosephosphate pool, resulting in rapid labeling of the triose pool by the administered tracer glycerol. Because the rate of flux of triosephosphate to glucose during fasting far exceeds that to triacylglycerol, more glycerol ends up in glucose than in triacylglycerol. 

Alternatively, there may be two distinct pools of 3-glycerol phosphate in the liver, one involved in generating triosephosphate from glycerol and the other involved in glyceride-glycerol synthesis.

The synthesis of triacylglycerol in the liver, adipose tissue, and skeletal muscle following a meal is an important metabolic pathway for the deposition of fat and in the maintenance of energy homeostasis in all vertebrates. Even after an overnight fast in adult humans, and following a brief fast in newborn infants, a substantial re-esterification of fatty acids has been documented using isotopic tracer methods (1-3). The source of glycerol for the esterification of fatty acids in various tissues has generally been considered to be plasma glucose or glycerol; however direct evidence for such an inference has not been documented.

Triacylglycerol synthesis requires both fatty acids and a source of 3-glycerol phosphate. During fasting, the source of 3-glycerol phosphate can either be plasma glucose via glycolysis or glycerol released from the hydrolysis of triacylglycerol. In the adipose tissue in particular, the glycerol released from the hydrolysis of triacylglycerol cannot be re-utilized for the esterification of fatty acids because of absence of glycerol kinase. It has been proposed that during fasting adipose tissue generates the 3-glycerol phosphate required for triacylglycerol synthesis, either from glucose via glycolysis or, alternatively, from pyruvate via an abbreviated or truncated version of gluconeogenesis, termed glyceroneogenesis (4-7). The key enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK;¹ EC 4.1.1.32). The transcription of the gene for PEPCK is stimulated by cAMP during periods of fasting (8, 9), resulting in an increase in enzyme activity in both adipose tissue and liver. In isolated epididymal adipose tissue from the rat, the rate of re-esterification of free fatty acids was greatly increased by the provision of a glyceroneogenic precursor such as pyruvate (10). In addition, hepatic glyceroneogenesis has been shown to account for ∼89% of glyceride-glycerol in the triacylglycerol synthesized by rats fed a high protein diet (11).

There has not been a quantitative analysis of the relative rates of glyceride-glycerol synthesis from its precursors, plasma glycerol, pyruvate, or glucose in humans. In the present study we have quantified the relative contribution of plasma glycerol and pyruvate (plus lactate, alanine, etc.) to glyceride-glycerol in nonpregnant and pregnant women during fasting. Pregnant women were studied because of the higher concentration of plasma triacylglycerol during pregnancy, particularly in the third trimester. Our data show that the source of glyceride-glycerol following a brief fast is predominantly pyruvate. Because the synthesis of glucose and glyceride-glycerol from plasma glycerol share common enzymatic reactions, our data also suggest a functional separation of the pathways of glycerol entry into the liver and the 3-glycerol phosphate precursor pool for triacylglycerol synthesis.

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When doing LC, our metabolisms are essentially the same as the fasted state.  More than half of the triglycerides that are broken down to free fatty acids are re-esterified to triglycerides even in the fasted state.  Where do we get the G3P?  Glyceroneogenesis.  And there's that pesky PEPCK again.

This blows one of Taubes' central theories out of the water!

PEPCK Website

http://pepck-and-the-ketogenic-diet.com/index.html

There's some interesting information on this -- apparently -- "amateur" website.  PEPCK is an important enzyme regulating blood glucose and free fatty acid levels.  It is involved in gluconeogenesis and glyceroneogenesis.

Ketones, Anaplerosis & Insulin

Acetoacetate and β-hydroxybutyrate in combination with other metabolites release insulin from INS-1 cells and provide clues about pathways in insulin secretion

Putting this here for my own orgnization

Conclusions:

The synergistic insulin release by compounds that can be metabolized to mitochondrial acetyl-CoA, such as KIC, β-hydroxybutyrate, or acetoacetate, in combination with methyl succinate that can be metabolized to mitochondrial oxaloacetate, suggests that acetyl-CoA and oxaloacetate condense in the citrate synthase reaction to form citrate. Numerous compounds can be formed from citrate, and citrate can carry acetyl-CoA and oxaloacetate out of the mitochondria to the cytosol. Many compounds, including most short-chain acyl-CoAs, can be formed from acetyl-CoA in the cytosol. KIC and β-hydroxybutyrate can also be directly converted to acetoacetate and acetyl-CoA in the mitochondria. Acetoacetate can be exported to the cytosol and converted to acetoacetyl-CoA to form several other short-chain acyl-CoAs. The results support the idea that anaplerosis is important for insulin secretion and suggest that multiple short-chain acyl-CoAs may be some of the products of anaplerosis in the β-cell.

Protein Metabolism

Looking for some info on protein, I came across this link:
http://www.nutrition-partner.com/index.cfm?C27B8FF7FABF494CAA480EF21E0D228D

The page focuses on changes in dietary requirements and/or the impact on the body of malnutrition, disease and stress, but I found this site through the following graphic on protein metabolism:

Something in the numbers doesn't add up here, but I was surprised to see how much protein is "recycled" in our guts.  Perhaps the total protein synthesis is balanced by catabolism/turnover and that is the missing number?  Not sure.  Here is the quoted text referring to this diagram (my apologies for the messed up formatting).  

Protein in the body is not static; protein synthesis and breakdown is constantly taking place. However, the total body protein pool in a healthy adult is constant. Synthesis of protein from endogenous and exogenous amino acids is equal to degradation and external losses. Some proteins have a long lifetime, such as muscle protein and plasma albumin, while others have a high turnover rate. Muscle protein constitutes up to approximately 50% of total body protein, but contributes only approximately 30% of the protein turnover in the body, because in visceral and other organs, protein turnover rates are several times higher than in muscle tissue.  Protein metabolism is dependent on a vast number of endogenous mediators. These mediators define the balance between anabolic and catabolic processes. Insulin is the major anabolic hormone and also has an important role in amino acid and protein homeostasis. During injury and stress two major alterations in insulin are noted: a catecholamine-mediated suppression of insulin release and an insulin resistance, leading to a release of skeletal muscle amino acid for gluconeogenesis and, at the same time, a decreased utilisation of glucose by insulin-dependent tissues. This mechanism provides glucose to the insulin-dependent tissues that are important for survival and the healing of injury, such as the central nervous system (CNS), immune system and red blood cells. Other hormones, like glucagon and the catecholamines, control or counteract the effects of insulin and are more or less proteolytic; the exact role of catecholamines is still under discussion, however. In order to define protein requirements, an overview of protein metabolism is necessary. By determining the renewal of proteins susceptible to measurement, such as plasma, muscle and digestive secretion proteins, it has been possible to estimate the daily turnover in proteins. Considerable recycling of endogenous amino acids seems to occur, the quantity amounting to twice the daily intake.   Hence, normal protein metabolism incorporates about 100 g of dietary amino acids and over 200 g of endogenous amino acids daily. Allowance must therefore be made for increased losses of endogenous proteins when assessing patients´ protein intake.

So fully 2/3rds of our daily protein metabolism comes from proteins in our body -- the amino acid pool in our cells and/or breakdown of tissues.  Another factoid:  Structural proteins have about a 6 month half life, while hormones/peptides/etc. can have half-lives of a matter of minutes.  However hormones etc. constitute a very small amount of protein weight wise.

Protein in optimal health: heart disease and type 2 diabetes

Protein in optimal health: heart disease and type 2 diabetes

Aside:  The lead author (I believe), is affiliated with the Australian CSIRO research group that is well regarded in the LC community -- except when, in the end, CSIRO's highly successful weight loss plan does not advocate for high fat  VLC after all.  I would also point out that the authors and the summit from which this article originated were highly subsidized by "Big Egg", "Big Dairy", "Big Beef" and "Big Pork".  I point this out not because I question the findings that seem pretty sound, but to point out that discounting research based on the sponsor just because one doesn't like the outcome is common practice amongst "debunkers".

So, that said, on to this article.  I won't repeat the whole thing.  It is a review, and although requires slow reading to digest, it's not overly clouded with technical lingo.  Some highlights of interest in no particular order:

• Regardless of dietary makeup, LDL seems to be ultimately related to one's weight status  both in terms of degree of excess weight and whether one is maintaining, losing or gaining weight.
• Protein's  "power" in weight loss may and glycemic control may well be its insulin stimulating action (particularly, leucine and glycine) -- this goes counter to LC theory, but makes sense to me.  If the post prandrial insulin response is increased by protein with reduced carb intake, BG's will not rise as high, and will fall more rapidly.  Protein seems to help insulin sensitivity.  If this occurs, chronic (basal) insulin levels should go down b/c the insulin manufactured in response to food is more effective, hence the pancreas is not pumping out more and more insulin in response to chronically elevated BG's.  Eggs, BTW, are particularly high in leucine.  Carbs and fats are still the prefered energy substrates, so insulin in-and-of-itself does NOT drive net fat storage, it merely directs energy traffic to the priority of available glucose or more towards fats when carbs are restricted.
• Infused amino acids raised BG levels and insulin, while ingested whole proteins seem to have the opposite effect.  I've seen many studies demonstrating similar effects for infused vs. ingested fats, and liquid glucose vs. whole carbs.  As the review points out, this underscores the involvement of our digestive systems and livers in the whole picture.

High protein is not defined here.  But there is some info on diets in which carbs are replaced with protein (as opposed to fats as is highly recommended in the LC world these days).  For me, this seems to be where it's at for weight loss.

Soluble Fiber and Net Carbs

I believe that, like sugar alcohols, soluble dietary fiber should be counted on a 0.5g carb/gram fiber basis.  However since most dietary fiber is not listed as to whether it is soluble or insoluble, this can be difficult to do.  Erring on the side of caution, a 1g for every 3g total dietary fiber would be a good compromise.  But many of the LC "fibers" such as polydextrose, inulin and glucomannan (shiritaki noodles) are essentially all soluble so 1g counted for 2g is a better count.

Insoluble dietary fiber, IDF, passes through the human digestive system unchanged so it is non-nutritive in all aspects. Further, since it adds bulk to food and assists in stool formation and "moving things along" IDF can reduce the nutrient absorbtion from the food we do eat.  This is essentially the rap of the "fiber is overrated" contingent.

SDF may not be metabolized by the body, but it is fermented in the large intestine to short chain fatty acids (SCFA) that are absorbed in the large intestine and metabolized. Some of these SCFA's are used by the intestines themselves as fuel, but the rest go mainly to the liver to be metabolized.

The "joys" of SDF are many from a weight loss and general health POV. To list a few I've read we have:

• When SDF absorbs water it swells forming a gel. This gives a feeling of fullness in the stomach and slows the progression through the digestive tract so you may feel full longer.
• This slowing of the digestion has been shown to improve the stability of BG levels in diabetics.
• SDF's are fermented in the large intestine to produce short chain fatty acids (SCFA's) that can be used by the intestine's cells as well as absorbed by the body. These SCFA's are believed to help with irritable bowel syndrome (IBS) by boosting the mucosal cells and perhaps reduce colorectal cancer risks. They are also believed to contribute to lowering LDL levels.
• SDF's do have a smaller than normal caloric nutritive value to us humans as compared to other carbs (1.5 cal/g to 2.5 cal/g, so I'll use an average of 2 cal/g)

What becomes of the rest of the SCFA's? We hear "fatty acid" and presume these are metabolized like other dietary fats, so eating soluble fiber has all the bennies above plus they are like ingesting fats!  But these are metabolized more like carbs -- the SCFA's are prime substrates for gluconeogenesis!!

According to this http://books.google.com/books?id=y2rvBwM...#PPA141,M1 (which focuses on inulin type SDF's) the major byproducts of SDF fermentation are lactate (15%) and SCFA's (40% of which these are further classified as approx 15% butyrate, 28% propionate and 67% acetate respectively). The SCFA's are absorbed or otherwise utilized for energy at a rather high 90-95% rate, and the latter two are either entirely (propionate) or partially (acetate) metabolized by the liver to PRODUCE GLUCOSE via gluconeogenesis (and lactate is also listed as a substrate for gluconeogenesis). Scroll down at this citation. 

I have read several reports around the LC webosphere of BG increases with low carb breads and pastas. And, of course, the numerous reported stalls many seem to experience when including these products in their diet. This may well be why. Those "fibers" are like eating half their grams in sugar.

Also consider that, like all bacteria, the population will increase when their food supply increases. So more SDF is feeding these. Sounds great for digestion, but these same bacteria also ferment something else -- "regular" carbs that have not been completely digested previously. So in addition to adding to your carbs, you are very likely increasing the digestion/absorbtion of the other carbs in your diet.  Be consoled that you have a healthy and efficient digestive system, but you may be getting more carbs than you accounted for.

There may well be some mitigating factors to this in terms of the inefficiency and/or energy requirements for the gluconeogenesis pathways for these substrates, but to me it seems pretty clear now that soluble fibers should NOT be subtracted on a 1:1 ratio to find net carbs. At best they could be subtracted as 1:2. Here's a link to one source of fiber content for a pretty good sized list of foods: http://huhs.harvard.edu/assets/File/OurS..._Fiber.pdf

Fatty Acid Contents of Foods: Beef Fat vs. Seal Oil

Another random listing from fatty acid compositions at www.nutritiondata.com

This post was precipitated by the oft cited Inuit as an example of the benefit of an almost all "meat", very high fat diet.  I've noticed that many of those practicing this version of a "Paleolithic" diet, tend to consume a lot of beef and rarely eat even the fish which are another staple of the Inuit diet.  So I decided to compare beef fat to that in seal oil.  The contrasts are quite stark!!

Beef fat is roughly 50% saturated fat vs. just over 10% for the seal oil.  Palmitic acid makes up around half of the sat fat in both.  Interestingly, the seal oil has 15 and 17C chain length sat fats.   

The MUFA content is roughly comparable at around 47% with a slight edge to the seal oil.  Most in the beef is oleic acid (18C) while the predominant acids in the seal oil are both oleic and palmitoleic (16C).  Again of note is the odd chain length acids.

The PUFA content of beef is a paltry less than 4%, while it is 33% of seal oil!   But that’s not all on the PUFA front – the Omega 6:Omega 3 ratio for beef fat is more than 5:1 … for seal oil it’s 1:26 – yes, that’s right more than 25:1 in favor of the Omega 3’s!!   Ounce for ounce, one gets 48X the dose of Omega 3’s from the seal oil vs. beef fat.  This is astounding.  The almost 8g of Omega 3’s is a huge dose if one were to try to get that from supplements – and that’s for only 1oz (~2T) of seal oil. 

The quality of the essential fatty acids in seal oil is also of note:

   2719 mg DPA, 1572 mg DPA and 3485 mg DHA

So … what of grass-fed beef?  I can’t find an analysis for grass-fed beef tallow, but, again from nutritiondata.com, the fatty acid breakdown of the fat in grass-fed beef is not impressive.  The PUFA content is still less than 4% of total fat and insignificantly more (3.94% vs. 3.93% for the commercial beef tallow).  The Omega 6:Omega 3 ratio?  It is improved slightly – from the 5.17:1 for the commercial to 4.85:1 – hardly approaching the “ideal” of 1-2:1 – such ratios can only be attained through marine and certain non-animal sources, or by eating brains and such.   Oh but surely nutritiondata.com is a biased thus incorrect source.  I suspected such, but when looking at every source I could find – many champions of the burgeoning grass-fed beef market – for more than an hour one day, I could find no other source even as specific as this one.  Claims of better O6:O3 ratio abound – but no specifics, leading me to believe that the “gains” are modest at best as seen in nutritiondata’s numbers.  What of absolute “dose”?  This probably comes out in favor of the commercial beef that is higher in total fat content.

Bottom line, beef fat is a poor source of PUFA’s in general and Omega 3 fatty acids in particular.  And it does not have a favorable O6:O3 ratio.  Sure, ~5:1 is better than the ratios for most seed oils, but the beef consuming VLC or ZC’er is not getting a significant dose of O3, nor is the O6:O3 ratio of ~5 favorable.

I believe the Inuit is a poor model to point compared to what many consume in modern high fat diets because it bears little resemblance to these diets.

Fatty Acid Contents of Foods: Butter & Coconut Oil

On occasion I look up this type of info on www.nutritiondata.com -- it comes from the pull-down analysis of the fats.  This is for one ounce (28g) of butter.  (NOTE:  I suspect there is an error here on the serving size vs. fat content.  Normally 1T butter has ~11g total fat)

Of note, a little more than 3% (~1/2 g) of the total fat is butyric acid, the short chain fatty acid product that is the byproduct of some soluble fiber metabolism.  Butter also contains 3.6% of capric and caprylic acids combined -- these are the 8 & 10 carbon medium chain triglycerides in "MCT oil".  Lauric acid (12C)  is 2.7% (this is the longest chain length characterized as medium chain, that is almost 50% of the fatty acid content of coconut oil).  All in all, the short and medium chain triglyceride content of butter is 11.6%, of which ~8.4% are classified as MCT's.  By contrast, coconut oil (source: wikipedia) is a little more than 60% MCT's.

The PUFA's are all Omega 6

Apoptosis - Programmed Cell Death

Here is a link to a website dedicated to Apoptosis/PCD:  Apoptosis Info.com

Apoptosis is the term given when programmed cell death (PCD) occurs in multicellular organisms. Apoptosis is one of the main types of programmed cell death which involves a series of biochemical events leading to specific cell morphology characteristics and ultimately death of cells. Characteristic cell morphology of cells undergoing apoptosis include blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Apoptosis differentiates from necrosis as the processes associated with apoptosis in disposal of cellular debris do not damage the organism in apoptosis.

Necrosis is a form of traumatic cell death that results from acute cellular injury. Apoptosis in contrast to necrosis, confers advantages during an organism's life cycle. For instance during the development of the fetus in the mother, the differentiation of fingers and toes occurs because cells between the fingers apoptose with the end result that the digits are separate. Approximately between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight.

Since the 1990's research has increased substantially in the field of apoptosis. It has been shown that defective apoptotic processes in humans and animals are related to a variety of diseases. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.

A lot of the inflammation and CVD issues associated with metabolic syndrome, diabetes, etc. lead to discussions of premature apoptosis which is how I came across this website and thought I would post it here for future reference.

Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans

Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity.

PDH is the enzyme thought to control the entry of acetyl CoA from glycolysis into the Kreb's / TCA /Citric Acid Cycle.

These authors did an in vitro study with human cells to see if the results compared with those seen both in vitro and in vivo in rats.  While in vitro observations don't always correlate with what we see in whole organisms, this did correlate for the rat.  Therefore it is reasonable to believe that the results of this experiment are applicable to human metabolism.

Human islets were obtained from the β-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/l palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/l glucose) inhibited the postculture insulin response to 27 mmol/l glucose by 40% and 42% (P<0.01 for difference). Inhibition was partly prevented by coculture with 1 μmol/l etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P<0.05 for effect of etomoxir).

Etomoxir inhibits fatty acid oxidation.  Recent developments employ this to treat chronic heart failure associated with Type II Diabetes.   

Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/l). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 μmol/l added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P<0.01). These effects were partly prevented by etomoxir (P<0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P<0.05) υs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P<0.05).

This underlines that high levels of both -- glucose/carbs and fatty acids -- wreak havoc on the body.

The effects of ketones were tested by 48-h exposure to β-hydroxybutyrate (β-D-OHB). Ten millimoles of D-β-OHB per L inbibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P<0.001). Half-maximal inhibitory effects of D-β-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/l. Inhibition by D-β-OHB was partially reversed by etomoxir, whereas exposure to D-β-OHB failed to affect PDH and PDH kinase activities. 

We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in botb type 1 and type 2 diabetes.

I don't have access to the full-text.  Seems "long term exposure" consisted of 48 hours.  I am curious what long term exposure of a ketogenic VHF diet  does to someone in the long haul.  At least early on, Type II's make insulin just fine -- just that they make too much of it b/c their cells are insulin resistant.  In researching to determine for myself if my low carb diet is healthy for the long haul, I've come across a lot of disturbing information on free fatty acids.  If by lowering BG we send FFA levels skyrocketing through the roof, do we mask a problem that still exists?  

I see no reason why IR cannot be reversed.  Indeed I believe the "lose 10% of weight cure" for T2 basically demonstrates this for persons whose pancreas has not yet been compromised (e.g. still able to produce insulin).  Indeed even the T2's with insufficient insulin responses may well have that inhibited by high NEFA/FFA -- restore fuel balance and there's no reason to believe this too can be reversed.

The relationship between high NEFA and sudden cardiac death continues to haunt me, and VLC/VHF diets have been shown to dramatically increase these!  So I remain skeptical of LC for weight maintenance and/or especially if one is gaining weight on such a diet.

Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle

Everyone who believes Taubes' theories about Glycerol-3-P and not being able to store fat if you don't ingest dietary carbs should read this article.

Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle

We make glucose via gluconeogenesis.  So, too, we make glycerol via glyceroneogenesis.  And we recycle ~50-65% of the FA's released via lipolysis back to trigs.

One interesting thing is the behavior of brown adipose tissue.  The enzyme responsible for re-esterification, PEPCK-C is high in BAT.  But interestingly enough insulin INHIBITS this enzyme while a high protein zero carb diet stimulates it.  

There's lots more  here to digest.  I'll revisit this post and update.

Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man

Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man.

ABSTRACT:   The metabolic balance method was performed on three men to investigate the fate of large excesses of carbohydrate. Glycogen stores, which were first depleted by diet (3 d, 8.35 ± 0.27 MJ [1994 ± 65 kcal] decreasing to 5.70 ± 1.03 MJ [1361 ± 247 kcal], 15% protein, 75% fat, 10% carbohydrate) and exercise, were repleted during 7 d carbohydrate overfeeding (11% protein, 3% fat, and 86% carbohydrate) providing 15.25 1. 10 MJ (3642 ± 263 kcal) on the first day, increasing progressively to 20.64 ± 1 .30 MJ (4930 ± 3 1 1 kcal) on the last day of overfeeding. Glycogen depletion was again accomplished with 2 d of carbohydrate restriction (2.52 MJ/d [602 kcal/d], 85% protein, and 15% fat). Glycogen storage capacity in man is ~15 g/kg body weight and can accommodate a gain of ~500 g before net lipid synthesis contributes to increasing body fat mass. When the glycogen stores are saturated, massive intakes of carbohydrate are disposed of by high carbohydrate-oxidation rates and substantial de novo lipid synthesis (150 g lipid/d using ~475 g CHO/d) without postabsorptive hyperglycemia. 

 I just thought this was interesting.