Intramyocellular lipids (IML)

[mccoy]

The LAtest podcast from Peter Attia with Gerald Schulman.

Among other very interesting pieces of info, one I noticed in particular: Schulman studies the flux of glucose in the body tissues, and observed by NMR that intramyocellular lipids (IML), fats inside cell tissues, are responsible for insulin resistance: diminished uptake capacity of glucose in muscle cells (also liver cells if I remember well).

We've briefly discussed in this forum the IML theory, supported by the vegan cardiologist Neil Barnard and other low-fat vegan doctors. At the time Michael Rae discarded this theory as not too useful, but now the evidence Schulman has produced seems indisputable.

In other words, even as too many carbs may cause T2D, too many fats in some people, if absorbed into cells, may cause T2D because of glucose transport blockage due to IML.

The hypothesis from Denise Minger, also discussed in this forum, according to which the extremes (low-carb hi-fat and hi-carbs low fat) may both be beneficial to T2D, seems to have a strong empirical support now.

 

 

 

[Dean Pomerleau]

2 hours ago, mccoy said:

[Schulman] observed by NMR that intramyocellular lipids (IML), fats inside cell tissues, are responsible for insulin resistance: diminished uptake capacity of glucose in muscle cells (also liver cells if I remember well).

This recent paper [1] seems like the relevant reference, with Schulman and Neal Bernard as authors.  It appears to show that a low fat, plant-based diet intervention reduces fat accumulation in the liver and muscles, which correlated with increased insulin sensitivity.

--Dean

1. JAMA Netw Open. 2020 Nov 2;3(11):e2025454. doi: 
10.1001/jamanetworkopen.2020.25454.

Effect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial 
Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight 
Adults: A Randomized Clinical Trial.

Kahleova H(1), Petersen KF(2), Shulman GI(2)(3), Alwarith J(1), Rembert E(1), 
Tura A(4), Hill M(5), Holubkov R(6), Barnard ND(1)(7).

Free Full Text: https://pubmed.ncbi.nlm.nih.gov/33252690/

IMPORTANCE: Excess body weight and insulin resistance lead to type 2 diabetes 

and other major health problems. There is an urgent need for dietary 
interventions to address these conditions.
OBJECTIVE: To measure the effects of a low-fat vegan diet on body weight, 
insulin resistance, postprandial metabolism, and intramyocellular and 
hepatocellular lipid levels in overweight adults.
DESIGN, SETTING, AND PARTICIPANTS: This 16-week randomized clinical trial was 
conducted between January 2017 and February 2019 in Washington, DC. Of 3115 
people who responded to flyers in medical offices and newspaper and radio 
advertisements, 244 met the participation criteria (age 25 to 75 years; body 
mass index of 28 to 40) after having been screened by telephone.
INTERVENTIONS: Participants were randomized in a 1:1 ratio. The intervention 
group (n = 122) was asked to follow a low-fat vegan diet and the control group 
(n = 122) to make no diet changes for 16 weeks.
MAIN OUTCOMES AND MEASURES: At weeks 0 and 16, body weight was assessed using a 
calibrated scale. Body composition and visceral fat were measured by dual x-ray 
absorptiometry. Insulin resistance was assessed with the homeostasis model 
assessment index and the predicted insulin sensitivity index (PREDIM). Thermic 
effect of food was measured by indirect calorimetry over 3 hours after a 
standard liquid breakfast (720 kcal). In a subset of participants (n = 44), 
hepatocellular and intramyocellular lipids were quantified by proton magnetic 
resonance spectroscopy. Repeated measure analysis of variance was used for 
statistical analysis.
RESULTS: Among the 244 participants in the study, 211 (87%) were female, 117 
(48%) were White, and the mean (SD) age was 54.4 (11.6) years. Over the 16 
weeks, body weight decreased in the intervention group by 5.9 kg (95% CI, 
5.0-6.7 kg; P < .001). Thermic effect of food increased in the intervention 
group by 14.1% (95% CI, 6.5-20.4; P < .001). The homeostasis model assessment 
index decreased (-1.3; 95% CI, -2.2 to -0.3; P < .001) and PREDIM increased 
(0.9; 95% CI, 0.5-1.2; P < .001) in the intervention group. Hepatocellular lipid 
levels decreased in the intervention group by 34.4%, from a mean (SD) of 3.2% 
(2.9%) to 2.4% (2.2%) (P = .002), and intramyocellular lipid levels decreased by 
10.4%, from a mean (SD) of 1.6 (1.1) to 1.5 (1.0) (P = .03). None of these 
variables changed significantly in the control group over the 16 weeks. The 
change in PREDIM correlated negatively with the change in body weight 
(r = -0.43; P < .001). Changes in hepatocellular and intramyocellular lipid 
levels correlated with changes in insulin resistance (both r = 0.51; P = .01).
CONCLUSIONS AND RELEVANCE: A low-fat plant-based dietary intervention reduces 
body weight by reducing energy intake and increasing postprandial metabolism. 
The changes are associated with reductions in hepatocellular and 
intramyocellular fat and increased insulin sensitivity.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02939638.

DOI: 10.1001/jamanetworkopen.2020.25454
PMCID: PMC7705596
PMID: 33252690

Conflict of interest statement: Conflict of Interest Disclosures: Dr Kahleova 
reported being director of clinical research at the Physicians Committee, a 
nonprofit organization that provides nutrition education and research. Dr 
Rembert reported compensation from the Physicians Committee for Responsible 
Medicine outside the submitted work. Dr Holubkov reported receiving personal 
fees from the Physicians Committee for Responsible Medicine during the conduct 
of the study. Dr Barnard reported to serving as president of the Physicians 
Committee for Responsible Medicine and Barnard Medical Center; receiving 
royalties from Hachette Book Group, Penguin Random House, Rodale, and Da Capo 
publishers; and receiving honoraria from Yale, Rush, George Washington, Loma 
Linda, Rockford Universities, Montefiore Medical Center, the Mayo Clinic, 
Northwell Health, Christiana Care, Oticon, and the National Organization of 
Professional Athletes. No other disclosures were reported.

[Todd Allen]

6 hours ago, mccoy said:

In other words, even as too many carbs may cause T2D, too many fats in some people, if absorbed into cells, may cause T2D because of glucose transport blockage due to IML.

The hypothesis from Denise Minger, also discussed in this forum, according to which the extremes (low-carb hi-fat and hi-carbs low fat) may both be beneficial to T2D, seems to have a strong empirical support now.

There's quite a bit of evidence accumulation of IML plays a big role in the pathology of my disease SBMA.  Which is why I've been doing my best to track it.  Being too frugal to get repeated whole body MRIs, probably the most accurate option, I've opted for getting DEXA scans every 3 to 4 months.  Those don't directly measure intramuscular fat but I guesstimate it by subtracting the results from skin fold calipers which estimate subcutaneous fat %.  While doing this I've experimented with many dietary approaches and chasing best progress I've transitioned to eating one or sometimes two meals a day with 90% of my calories from fatty beef, eggs, fatty fish, coconut oil and dairy fat.  I'd like to see Neal Barnard test this approach against ones minimizing saturated fat. It would be interesting to see in a larger cohort how many thrive at each end of the dietary spectrum.  I believe this approach works well for me because it minimizes blood glucose (and probably insulin) and triglycerides when averaged over the day minimizing energy substrate uptake by muscle while shifting muscle to mostly burning fatty acids.

[Mike41]

Thanks McCoy for this interesting hypothesis. It appears to be Another plus for a high whole food carb low fat diet. 

 Considering this emerging concept coupled with the whole TMAO situation where we see animal based foods increasing levels; The Ornish/esseltyne/pritikin studies which were small but still showed significant reversal of CAD appear to have unknowingly been quite consistent with major risk factors like TMAO, insulin resistance, LDL, plant polyphenols etc.

I could also mention THE CHINA STUDY slammed here years ago when I posted it, but it was certainly on the right page it appears more and more as time goes on.

Edited December 11, 2020 by Mike41

[Ron Put]

Endurance Runners with Intramyocellular Lipid Accumulation and High Insulin Sensitivity Have Enhanced Expression of Genes Related to Lipid Metabolism in Muscle

We analyzed the gene expression profiles in skeletal muscle of endurance runners using microarray analysis. A previous study investigating the skeletal muscle gene profile of endurance cyclists with microarray analysis showed enhanced expression of gene clusters related to mitochondrial and oxidative capacity [14]. In the present study, as shown in the hierarchical cluster analysis, gene expression was not clearly divided by controls versus endurance athletes, suggesting that endurance runners are not significantly characterized by gene expression patterns in muscle. It may also be possible that control subjects in the present study had relatively higher maximum oxygen uptake than those of a previous study [14], leading to no clear significant differences in gene expression levels between the groups in the microarray analysis. Nonetheless, in the GSEA, “RESPONSE TO LIPID” was upregulated in the athlete group compared to that in the control group, suggesting that this gene cluster might be important in characterizing endurance runners among healthy young people.

It has been suggested that the oxidative capacity of skeletal muscle may be an important modulator of the association between IMCL accumulation and insulin sensitivity [8]. Previous studies have suggested that fatty acid influx into myocytes increases oxidative capacity in muscle. For example, it has been reported that endurance runners have increased FABPpm and LPL [32,33] expression levels, and free fatty acid uptake in skeletal muscle is enhanced in endurance athletes [34]. In addition, overexpression of FABPpm, FATP-1, and LPL increases fatty acid oxidative capacity and mitochondrial content in muscle [35,36,37]. Moreover, a high-fat diet stimulates mitochondrial fatty acid oxidation and increases muscle expression levels of PGC1A, HADHB, and CPT-1 in rodents [38]. Taken together, higher expression levels of genes including FATP1, FABPpm, and LPL may facilitate IMCL accumulation and promote oxidative capacity in muscle and may characterize the athlete’s paradox.

In the present study, expression levels of PPARA, PGC1A, AdipoRs, and several fatty acid transporters were higher in the athlete group compared with the control group. PPARA is a transcriptional factor activated by fatty acids, leading to the induction of genes involved in fatty acid import and β-oxidation [39,40,41,42]. In addition, in vitro and in vivo studies have demonstrated that PGC1A overexpression results in increased expression of CD36, FABPpm, FATPs, mitochondrial content, and oxidative capacity in muscle [43]. We previously showed that overexpression of FABPpm in C2C12 myotubes results in enhanced expression levels of PPARA, PGC1A, AdipoR1, and AdipoR2, while fatty acid uptake and oxidation were both increased in the myotube [16]. PPARα and PGC-1α activation are partly regulated by adiponectin via AdipoR2 and AdipoR1, respectively [3,22]. Exercise training increases muscle AdipoRs [2,3,4], PGC1A, and PPARA expression [5,6,7]. Thus, it has been suggested that PPARA, PGC1A, AdipoRs, and fatty acid transporters are upregulated by endurance exercise and fatty acid incorporation into myocytes, leading to both higher IMCL levels and higher oxidative capacity in endurance athletes.

[mccoy]

6 hours ago, Mike41 said:

Thanks McCoy for this interesting hypothesis. It appears to be Another plus for a high whole food carb low fat diet. 

 Considering this emerging concept coupled with the whole TMAO situation where we see animal based foods increasing levels; The Ornish/esseltyne/pritikin studies which were small but still showed significant reversal of CAD appear to have unknowingly been quite consistent with major risk factors like TMAO, insulin resistance, LDL, plant polyphenols etc.

I could also mention THE CHINA STUDY slammed here years ago when I posted it, but it was certainly on the right page it appears more and more as time goes on.

Mike, the hypothesis is sure interesting, but what causes IML is not yet very clear. In the study posted by Dean, for example, it stands out that in the intervention group, where IML decreased, energy intake also decreased, together with protein. Bodyweight also decreased. So, there may be some confounding factor

 

 

Quote

 

Dietary Intake and Physical Activity

Self-reported energy intake decreased in both groups but more so in the intervention group (treatment effect, −354.9 kcal/d; 95% CI, −519.0 to −190.8 kcal/d; P < .001) (Table 2). In the intervention group, mean intakes of carbohydrate and fiber increased, whereas mean fat, protein, and cholesterol intake decreased. These values did not change significantly in the control group.

 

 

[mccoy]

Bodyweight decreased in the intervention group. So, is a high-fat diet a direct cause of IML or is it an indirect cause because of higher bodyweight?

Quote

Mean body weight decreased by 6.4 kg in the intervention group compared with 0.5 kg in the control group (treatment effect, −5.9 kg; 95% CI, −6.7 to −5.0; interaction between group and time, P < .001). 

The authors are ready to acknowledge this point:

Quote

The study also has limitations. Self-reports of dietary intake have well-known limitations.⁴⁴ However, it is reassuring that the reported diet changes were paralleled by changes in weight and plasma lipid levels. Health-conscious participants may not be representative of the general population but may be representative of a clinical population seeking help for weight problems or type 2 diabetes. We followed the participants for 16 weeks and were not able to estimate the effects of the diet over a longer period. In addition, the study design did not allow separation of the specific effects of the low-fat vegan diet from the weight loss it causes.

 

Edited December 11, 2020 by mccoy

[mccoy]

At the end of it, although I consider very strong evidence the NMR imaging on radioactive glucose observed by Schulman, the framework is not very clear yet.

One possible take-home lesson is that an energy-restricted, high carbs and very low fat regime might not cause prediabetes or T2D as long as low IMLs allow an efficient, blockage-free transport into hepatic and muscle cells.

But many other factors may intervene, such the sheer volume of glucose which reaches the circulatory system and cannot be uptaken by muscle cells, increased gluconeogenesis, damage to pancreas beta-cells....

 

Edited December 11, 2020 by mccoy

[mccoy]

The conclusions of the study underline the benefits of a vegan, low-fat, low-calories diet to treat overweight adults. The authors do not cite prediabetes or T2D though. Just now I realized the participants' BMI ranged from 28 to 40, most of'em being obese.

The control group ate less  calories, so the weight decrease in the lowfat group does not come as a surprise; it remains the possibility that a low-calories, lowfat diet may be more effective in loosing weight than a low-calories, normo-lipidic diet because of increased insulin sensitivity but the article does not prove it.

What I found very interesting is the list of references, with lots of articles on the vegetarian-vegan diet and T2D .

Quote

This randomized clinical trial found that a low-fat plant-based dietary intervention reduces body weight by reducing energy intake and increasing postprandial metabolism, apparently owing to increased insulin sensitivity resulting from reduced hepatocellular and intramyocellular fat. This intervention may be an effective treatment for overweight adults.

 

Edited December 12, 2020 by mccoy

[Dean Pomerleau]

19 hours ago, mccoy said:

Bodyweight decreased in the intervention group. So, is a high-fat diet a direct cause of IML or is it an indirect cause because of higher bodyweight?

This one [1] seems relevant. After three days of an isocaloric 10%-fat diet, lean endurance athletes had 30% lower IMCL than the same athletes after three days on a 35%-fat diet.

--Dean

-----------------

[1] Med Sci Sports Exerc. 2008 May;40(5):892-902. doi: 10.1249/MSS.0b013e318164cb33.

Effect of dietary fat on serum and intramyocellular lipids and running performance.

Larson-Meyer DE(1), Borkhsenious ON, Gullett JC, Russell RR, Devries MC, Smith SR, Ravussin E.

Author information: (1)Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA. enette@uwyo.edu

Free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182469/

PURPOSE: This study evaluated whether lowering IMCL stores via 3-d consumption of very-low-fat (LFAT) diet impairs endurance performance relative to a moderate-fat diet (MFAT), and whether such a diet unfavorably alters lipid profiles. METHODS: Twenty-one male and female endurance-trained runners followed a controlled diet and training regimen for 3 d prior to consuming either a LFAT (10% fat) or MFAT (35% fat) isoenergetic diet for another 3 d in random crossover fashion. On day 7, runners followed a glycogen normalization protocol (to equalize glycogen stores) and then underwent performance testing (90-min preload run at 62 +/- 1% VO2max followed by a 10-km time trial) on the morning of day 8. Muscle biopsies obtained from vastus lateralis before and after performance testing were analyzed for IMCL (via electron microscopy) and glycogen content (via enzymatic methodology). RESULTS: Despite approximately 30% lower IMCL (0.220 +/- 0.032% LFAT, 0.316 +/- 0.049% MFAT; P = 0.045) and approximately 22% higher muscle glycogen stores at the start of performance testing (P = 0.10), 10-km performance time was not significantly different following the two diet treatments (43.5 +/- 1.4 min LFAT vs 43.7 +/- 1.2 min MFAT). However, LFAT produced less favorable lipid profiles (P < 0.01) by increasing fasting triglycerides (baseline = 84.9 +/- 8.6; LFAT = 118.7 +/- 10.0 mg.dL(-1)) and the total cholesterol:HDL cholesterol ratio (baseline = 3.42 +/- 0.13:1; LFAT = 3.75 +/- 0.20:1), whereas MFAT lowered triglycerides (baseline = 97.5 +/- 12.2; MFAT = 70.9 +/- 7.1 mg.dL(-1)) and the total cholesterol:HDL cholesterol ratio (baseline = 3.47 +/- 0.18:1; MFAT = 3.33 +/- 0.14:1). CONCLUSION: The results suggest that reducing IMCL via 3-d consumption of a LFAT diet does not impair running performance lasting a little over 2 h (compared with 3-d consumption of a MFAT diet plus 1-d glycogen normalization), but that even short-term consumption of a LFAT diet may unfavorably alter serum lipids, even in healthy, endurance-trained runners.

DOI: 10.1249/MSS.0b013e318164cb33 PMCID: PMC3182469 PMID: 18408608 [Indexed for MEDLINE]
 

[Todd Allen]

11 minutes ago, Dean Pomerleau said:

CONCLUSION: The results suggest that reducing IMCL via 3-d consumption of a LFAT diet does not impair running performance lasting a little over 2 h (compared with 3-d consumption of a MFAT diet plus 1-d glycogen normalization), but that even short-term consumption of a LFAT diet may unfavorably alter serum lipids, even in healthy, endurance-trained runners.

Good thing they stopped at 2 hours and didn't push the LFAT diet impaired runners to hit the wall.

[Mike41]

3 hours ago, Todd Allen said:

Good thing they stopped at 2 hours and didn't push the LFAT diet impaired runners to hit the wall.

Low fat diets do generally raise triglycerides and lower HDL levels, but if the they are WFPB diets and very low fat that can have a profound ldl lowering effect. As for lipids it’s a mixed bag and not sure what to make of it. Ornish and Esseltyne have both claimed hdl is lower. They describe it as needing less garbage trucks in the case of HDL

Not everything that raises HDL is good for you. For example, if you increase the amount of fat and cholesterol in your diet (e.g., an Atkins diet), you may increase your HDL, because your body is trying to  get rid of the extra “garbage” (fat and cholesterol) by increasing the number of available garbage trucks  (HDL), if you are genetically able to do so. Eating a stick of butter will raise HDL in those who are able to do so, but that does not mean that butter is good for your heart. It isn’t

Edited December 12, 2020 by Mike41

[Todd Allen]

5 hours ago, Mike41 said:

but if the they are WFPB diets and very low fat that can have a profound ldl lowering effect

People with low LDL have increased mortality.  The theory that dietary saturated fat from animal sources is causal to heart disease was tested in an Ancel Keys designed RCT, the Minnesota Coronary Experiment, and the Sydney Diet-Heart Study and each found the opposite, despite lowering LDL there were shocking increases in mortality and heart disease when replacing animal sourced fats with less saturated plant derived fats.  The massive Women's Health Initiative an 8 year long interventional trial of a "healthy" lowfat diet emphasizing fruits, vegetables and grains was also a failure spun as not showing significant benefits when the data showed increased cardiovascular events in the intervention group for women with preexisting CVD despite lowering LDL.

The Women's Health Initiative Randomized Controlled Dietary Modification Trial: An inconvenient finding and the diet-heart hypothesis

Quote

The study's only statistically significant finding, reported on the seventh page of the published manuscript (p. 661),^[1] has yet to enter the scientific discourse: 'The H(azard)R(atio) for the 3.4% of women with CVD at baseline was 1.26 (95% CI, 1.03-1.54)'.

This shows that women with diagnosed CVD at the start of the trial who adopted the 'healthy heart' low-fat eating option had a risk of developing future cardiovascular complications that was 26% higher than that of the non-intervention group. This finding is not discussed and a key line of text is missing from Fig. 3 (Fig. 1).

 

Edited December 13, 2020 by Todd Allen

[mccoy]

On 12/12/2020 at 6:11 PM, Dean Pomerleau said:

This one [1] seems relevant. After three days of an isocaloric 10%-fat diet, lean endurance athletes had 30% lower IMCL than the same athletes after three days on a 35%-fat diet.

Dean, I'm curious about your opinion on the IML issue. In the article you cited, IML was lower in the LFAT group and this resulted in 30% less IML and concurrently +20% muscle glycogen. That seems to be a clear indicator of increased muscle uptake of glucose. Fasting blood glucose was the same in both groups, pre and post-exercise. Ditto for insulin. So, lesser IML would equate to higher GLUT4 activity and glucose uptake. Strangely, +20% glycogen provided no competitive advantage.

And the bottom line, is that a 3-days LFAT diet seems to provide no metabolic advantages (same insulin, same fasting glucose), on the contrary, one distinct disadvantage (worse lipids profile).

Of course, the trial was very short. So it may not be applicable to longer regimen durations. Another aspect, is that on an isocaloric - isoproteic base, LFAT equates to higher carbs, so that the beneficial effect on IML might be counteracted by the effect of higher dietary glucose.

Is there any take-home lesson in all of the above, what's the best strategy to keep at bay blood glucose, LFAT - HCARBS or MFAT/HFAT and LCARBS? 

Personally, I think I would not be able to sustain such a LFAT diet, and the additional carbs might even increase glycemia. Whereas, HFATs low carbs may bring about unfavorable lipids profile. 

Edited December 13, 2020 by mccoy

[Dean Pomerleau]

1 hour ago, mccoy said:

Dean, I'm curious about your opinion on the IML issue.

Personally I'm glad my current diet is relatively low fat (~20% of calories). Many years ago in 2002, when I was eating a 37%-fat strict low-cal CR diet, my glucose tolerance test was terrible during an OGTT at WUSTL as part of the human CR study (discussed here). My post-meal glucose spike is much attenuated when I last checked (which admittedly was quite a while ago and not under conditions of just sitting around like an official OGTT). And of course I've changed a lot of other things since 2002 (e.g. cold exposure, much more exercise and more calories, although my weight is just a couple pounds heavier).

I now suspect that the combination of low insulin and relatively low muscle mass as a result of CR plus high IML as a result of a higher fat diet could explain issues some of us have had with impaired glucose tolerance in the past (discussed extensively here and here).

--Dean

[Mike41]

On 12/13/2020 at 5:55 PM, Dean Pomerleau said:

Personally I'm glad my current diet is relatively low fat (~20% of calories). Many years ago in 2002, when I was eating a 37%-fat strict low-cal CR diet, my glucose tolerance test was terrible during an OGTT at WUSTL as part of the human CR study (discussed here). My post-meal glucose spike is much attenuated when I last checked (which admittedly was quite a while ago and not under conditions of just sitting around like an official OGTT). And of course I've changed a lot of other things since 2002 (e.g. cold exposure, much more exercise and more calories, although my weight is just a couple pounds heavier).

I now suspect that the combination of low insulin and relatively low muscle mass as a result of CR plus high IML as a result of a higher fat diet could explain issues some of us have had with impaired glucose tolerance in the past (discussed extensively here and here).

--Dean

Interesting because two of the most respected members seem to be in a disagreement on this very fundamental dietary issue FAT!