Yet Another Journal Study that Will Obfuscate Rather than Clarify

A friend sent me a journal link to evaluate and now I have to rant! The journal article was reporting the results of a study comparing the effect on diabetic blood sugar control of a low-carb ketogenic vs a low GI diet:

My response to the study is, in a word: Grrrrr!

Q: So why would anyone, especially trans men, be interested in this study?
A: Diabetes and pre-diabetes are reaching epidemic levels of prevalence with no end in sight. Trans men especially have been observed to have a very high incidence of PCOS (58% in the first study I looked at) and PCOS predisposes one to these diseases of glucose metabolism. For those of us with a tendency for our blood sugar to get too high — whether we know it or not (!) — it behooves us to get this diet thing right because the quality of our lives down the road depends on it. Diabetes is devastating.

So, here’s the study conclusion:

The diet lower in carbohydrate led to greater improvements in glycemic control, and more frequent medication reduction/elimination than the low glycemic index diet. Lifestyle modification using low carbohydrate interventions is effective for improving and reversing type 2 diabetes.

Now that’s really outrageous in my eyes. You would presume from that conclusion that the better diet for a diabetic would be the very low carb, ketogenic diet. Well, if you made that presumption, YOU WOULD BE WRONG. Although every word of that conclusion is TECHNICALLY true, the best diet for a diabetic is really the low GI diet. And that part about reversing type 2 diabetes? Technically true but blatantly false to anyone that truly understands diabetes!!

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What Is the Best Diet for Managing Diabetes? — updated

In my previous post, What Is the Best Diet for Managing Diabetes?, I featured the 1999 Diabetes Care study that was claimed in the EASD podcast to be the most important part of the entire recommendation for managing diabetes. The study’s conclusion was:

The imperative regarding carbs in your diet is that not only must they be high in soluble fiber, but also, whatever processing was done to the food, the cellular structure must not have been disrupted.

Naturally, I was excited to give this a try. I went to Whole Foods the very next day and found some rye bread that looked be just what they were talking about: hard, dense, no fluff here:

Hard Whole Rye Bread from Whole Foods

Hard Whole Rye Bread from Whole Foods

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What Is the Best Diet for Managing Diabetes?

This is really part 2 of a “catch-up” series on what I’ve been researching and thinking about recently that started with yesterday’s, “What Do I Know Now That I Didn’t Know Then?“.

For anyone trying to manage their pre- or full- diabetes through diet and exercise, there are two points I want to make. BTW, by manage I mean keeping your blood sugar below the level at which irreversible retinopathy, neuropathy and all the other opathy’s occur as well as avoiding an early demise. So the points are:

    • Low carb vs low fat is a false dichotomy. The diet answer lies elsewhere and has been known for years and might just be an “inconvenient truth” that the food industry does not want you to know.
    • The order in which you eat the food items on your plate could just make the difference between winning and losing the battle against the opathy’s.

Here’s how I came to these conclusions …

Pubmed

Having good reason to believe that I wasn’t insulin resistant, but was still unable to handle glucose, I started searching pubmed to see what I could find. Almost immediately, I discovered a new (to me) diabetic category: Latent Autoimmune Diabetes in Adults (LADA), which accounts for about 5% – 10% of diabetics. LADA is like T1 diabetes, but it develops later in life, without necessarily developing obesity and insulin resistance first. This was a really interesting discovery, since I could never understand how I could be diabetic and not have any of the lifestyle risk factors.

But although it was interesting, it wasn’t what I needed to know, ie, what’s the best diet for people with insufficient insulin production? I recalled that Plant Positive (PP) had some videos that might apply, and I knew that I could count on him to make the strongest possible case for veganism and probably for high carb. Two points stood out from the last of a number of his videos that I watched.

A Plant Positive Video

First, diabetes cannot be blamed on too many carbs or obesity. The experiment that proves it? Two lean men ate nothing but meat for a year. At the end of the year, one of the men had sugar in his urine, and so, would be diagnosed as diabetic. So, he certainly didn’t overdo the carbs and although the journal article doesn’t say whether or not he became obese, it seems doubtful that a) he would become obese on a meat only diet and b) he would do so and it wouldn’t be reported. And the clincher was, after he returned to his normal diet, his glucose metabolism also returned to normal.

Here’s a screen shot from the journal article showing the 2 glucose tolerance tests (OGTT), one (upper, solid line) at the end of the year-long meat-fest and the other after he adjusted back to a more normal diet:

OGTT in meat only experiment

The disturbing part for me in seeing this was how similar that solid upper line is to my OGTTs (see part 1). The magnitude of the numbers is the same as mine. Does this means I probably have sugar in my urine too? But the good news is, maybe mine is just as reversible as the study subject’s was. The baffling part for me in this was I wasn’t eating an all meat diet; I was trying to increase the carb content of my diet from about 30% to 50%. It makes no sense.

The second point that grabbed me was that PP was in agreement with Evelyn aka CarbSane that free fatty acids (FFA) might contribute or even be responsible for insulin resistance. From PP’s video:

Back in 1963, low-carb diets were investigated for their effects on free fatty acids and blood glucose. These researchers studied normal people as well as diabetics.

In the normal people, insulin, free fatty acids, and glucose all soared after carbohydrate restriction. These researchers saw a parallel between carbohydrate restriction and diabetes.

Insulin and blood glucose returned to normal after their diets added back carbs.

So, the good news is that, at least in this 5-day instance, low-carb diet induced glucose metabolism dysfunction was reversible, as was the case for the year long meat diet. The bad news is the problem with a low carb diet is even worse than PP reported, at least in my eyes. I went to the original journal article and found that the researchers reported that after 5 days on a 50g / day low-carb diet, gluco-normal men’s fasting FFAs had more than doubled, so as to be well into the range of diabetic fasting FFA. With a good possibility that these elevated FFAs are indeed toxic to beta-cells, I’m really glad I never went for the very low version of low-carb.

A Portugeuse LADA Study

OK, so I get from this that for gluco-normal people and people with insulin resistance, carb restriction might be a really bad idea.  But what about people who aren’t normal or insulin resistant, ie type I or  type 1.5 diabetics (as LADA is sometimes called)? Is carbohydrate restriction beneficial or detrimental? According to this, using insulin to reduce demand on beta cell function has a preservative effect on the beta cells:

The use of insulin reduces the activity of beta-cells, antigen expression and decreases the autoimmune process, with consequent reduction of cell destruction 

By early insulinization of diabetic patients over 35 years and GADA> 20 U / ml, we observed that there was, during the follow-up of 48 months, significant changes in C-peptide levels, indicating preservation of beta-cell function

So why wouldn’t the reduced demand on beta cell function achieved by a lower carb diet work equally well?

Well, one answer might be that the carb calories have to be replaced with something. If they are replaced in part by protein, per gram, protein evokes an even greater insulin response from the beta cell than do carbs. So it is clear that if any benefit is to be realized, fat, not protein must be substituted for the fewer carb calories. But, we’ve learned that the fatty meal is going to elevate free fatty acids levels which will lead to beta cell loss just as much as elevated serum glucose will. It’s looking like that rock and hard place all over again.

Beans, beans, the magical fruit!

I was feeling very discouraged until I found this. It’s a podcast presentation from the 2013 EASD Annual Meeting in Barcelona. The EASD is the European Association for the Study of Diabetes. The talk, delivered by Prof. Jim I Mann who, BTW, actually did some of the landmark studies he discusses, totally clears up certain dietary confusions — confusions which may have been intentionally created by the food industry. Back in the day, the question for diabetes, it seems, was never about low carb vs high carb; it was about low carb vs high soluble fiber. That question was totally answered back in 1981 with a study by Simpson et al published in the Lancet. The results speak for themselves:

Simpson et al

HL = high leguminous fiber diet, LC = low carb

HL vs LC, 24 hour BG

Low carb (solid line above) vs high legume, 24 hour BG

But, if numbers and charts make your head spin, I will explain. The top slide shows the bean diet (HL) reducing bad cholesterol (LDL) by about 20% down to just about 100 mg/DL (in US numbers). The slide on the bottom shows the utter superiority of the bean diet for 24-hour glucose control.

These results have been replicated time and again, in studies all over the world, in all kinds of permutations and combinations, and with type I, type II, pre, whatever diabetics. The high soluble fiber diet wins hands down in every measure of diabetic and serum lipid control, as well as achieving a 44% reduction in CHD and overall mortality for type I diabetics in this 2012 study (see “Tertiles of Sol fibre” on the right):

T1DM mortality, HL vs SFA

 

“Whole Food” concept re-examined

The rest of the podcast presentation clears up a confusion regarding the fact that all high carb diets are not created equal when it comes to BG control. The imperative regarding carbs in your diet is that not only must they be high in soluble fiber, but also, whatever processing was done to the food, the cellular structure must not have been disrupted. So for instance, even if your bread claims to be organic, non-GMO, whole grain and stone ground, if it’s not hard and dense enough to serve as a ship’s anchor, you shouldn’t be eating it.

Here’s the study that he described as being the most important of all, comparing the effect on BG throughout the day of 2 diets with the same amounts of carb and fiber. The difference was the cellular structure of carbs in the diet corresponding to the triangles (lower line) had been left intact, whereas for that of the other diet – because the beans, whole grains, etc,  had been ground up – it was destroyed.

Triangles (lower) = minimally processed carbs

Triangles (lower) = minimally processed carbs

Lipid levels were similarly improved, although I haven’t reproduced the slide here.

As an aside from the EASD podcast, here is a widely cited 2012 paper that I had read quite a while ago that supports this concept of “whole foods”. But it is whole foods not in the sense that nothing has been removed, but that the food has been left whole, ie, intact. The paper  examines the effect of eating foods whose cellular structure is no longer intact: Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity and a very interesting chart from that paper. Even if you don’t want to read the whole paper, the chart will definitely give you something to think about.

Dietary Recommendation Summary

The concluding dietary recommendations for diabetics from the podcast is that we aim for low GI, but that this leaves too much wiggle room for people to, perhaps willfully, misinterpret. How is a net low GI meal achieved? To be more specific:

  • Carb intake can be 40% – 60% of calories, as tolerated by your glucose metabolism.
  • Simple sugars can be up to 50 grams/day as tolerated by your glucose metabolism.
  • Fiber intake should be at least 40 grams/day, aiming for mostly soluble fiber.
  • Fiber must not be ground up, extracted or synthesized in the lab.
  • Fiber should not be listed as an ingredient.
  • Cellular structure must remain intact, thus eliminating most whole grain breads and cereals.
  • Carbs from legumes, pulses and “genuine” whole grains are best.
  • Avoid starchy vegetables, cereals and grains, such as rice, potatoes, most breads.

 

Meal item order makes a huge difference – original research

I was very excited by all this information. I had done my diet experiment all wrong. I thought the higher carb part gave me license to eat all the stuff I had been avoiding while I was eating low carb, as long as I didn’t put in any added sugar. I wanted to give it another try, this time building around beans, raising my carb intake very gradually and as a final twist, I came up with the idea that, wherever possible, I would try eating my beans (or other carbs) after I ate the protein and fat portion of the meal.

It had taken me 11 days to find that podcast. The morning of April 12, for breakfast (breakfast is always the most problematic meal) I replaced my (fluffy) 100% organic sprouted whole grain bread with beans that were eaten last . The result? I was absolutely blown away by how low my 50 min BG was (114)! I didn’t really trust it, so I repeated the exact same meal for the next 3 days with BGs of 102, 104, 103.

Long story short, it finally occurred to me that the order in which I ate the food items in the meal might actually making the biggest contribution to those low numbers. I started switching the order every other day on the same breakfast. The meal is about 31-17-21 (%P – %F – %C). Here’s my result for a month:

50 min PPs

So, again, if charts make your eyes lose focus and glaze over, I will explain. All those bars represent days for which I had the (almost) exact same breakfast and got a valid glucometer reading within a few minutes of 50 from the start of my breakfast. The blue bars represent my readings on the days that I ate my beans first and then followed them with a salmon patty and avocado. The average BG reading for the blue days is 147. On the red bar days, I ate my salmon and avocado first. The average for those days is 112.

Why is this significant? Because right around 140-150 mg/dl is where irreversible opathy damage starts to occur. Yes, I know that Evelyn (aka CarbSane) thinks Jenny (Blood Sugar 101) pulled this number out of her you-know-where, but surely some of the many studies mentioned here have merit. And right around 110? That’s where a gluco-normal person’s blood sugar would be.

BTW, I haven’t seen this result mentioned anywhere and was wondering if it could be replicated. I was sorta hoping I could get one of my diabetic or pre-diabetic readers to try a similar experiment with meal item order and report back.

Meanwhile, next in this series, I’ll be sharing some very interesting journal article finds.

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What Do I Know Now That I Didn’t Know Then? — part 1

With the exception of yesterday’s post, I’ve neglected my blog for over a year now, thinking I had resolved all the controversies that applied to my situation, at least to my own satisfaction. Ah, me of great arrogance and little humility … little did I know.

So, what do I know now that I didn’t know then? I’ll put up a preliminary list here, just off the top of my head, and perhaps add to it later:

  • When my thyroid hormones are at the proper level and I’m eating a mostly whole food, unprocessed, plant-based diet along with the recommended amount of exercise, it is actually easier to lose a few pounds than it is to gain them back.
  • My high fat, high protein diet may have graduated me from pre-diabetic to full-fledged. … Or not.
  • Beans, beans, the magical fruit!
  • The order in which I eat the individual items in a meal can greatly affect the magnitude of my postprandial (PP) blood glucose (BG) spike.
  • Whether the effect of high or low protein in your diet is beneficial or detrimental seems to be age dependent.
  • I’ve been a huge believer in letting PRAL be my food balancing guide, but according to Dr Greger, “The decades-old dogma that the acid-forming quality of animal protein leads to bone loss has been called into question.”
  • The placebo effect can be enormous and is nothing to be trifled with.
  • I have a tendency (perhaps shared with most of humanity) to leap to conclusions before they have been fully justified.

I don’t want to get into all of these exhaustively right now, but I do want to say at least a little.

Thyroid Hormones

If you’re around my age and still having trouble with that ever increasing poundage, the problem may be with your thyroid. According to the NIH Medline:

Men often gain weight until about age 55, and then begin to lose weight later in life. … Women usually gain weight until age 65, and then begin to lose weight. 

If you’re over 65, the chances your thyroid isn’t doing it’s job is 1 in 10, increasing with age. And even if you’re younger, if you are having trouble keeping the weight from piling up, there’s still a substantial chance of hypothyroidism, especially if you are female and/or have other symptoms of low thyroid. It’s a cheap test; ‘nuf said.

That said, I have come to realize that although I thought I knew something about weight loss, everything I’ve done in the last 5 years is confounded by the fact that I got older and there is a natural downturn in weight around this age. Did my low carb diet help me lose weight or did my age help me lose weight? Will losing that weight even be beneficial to me in the long term? I don’t think anyone can answer those questions.

High Fat Diets and Diabetes

This is a huge topic, so I just want to touch on it right now. I first became aware that the low carb version of Paleo might have adverse consequences on glucose metabolism thanks to Evelyn aka CarbSane. Evelyn’s posted on numerous occasions about the connection between high fat diets, elevated postprandial free fatty acids and pancreatic islet damage. Here’s one of them.

I resisted following up on it because I thought I had all the answers. Then at the beginning of this year, I had an extended email discussion about this with a fellow Yahoo group member who is a nutritionist and a consultant for the Mcdougall Program. He now eats a plant-based high carb and has sterling blood glucose control, although years ago did have blood sugar problems on the SAD. This email exchange with the nutritionist came after a previous lengthy email exchange with fellow blogger, Maria Mae Stevens, where she was hinting (well, maybe stronger than that) that my high fat diet might not be benign.

The nutritionist suggested I have my fasting insulin tested in order to determine whether I was insulin resistant or insulin insufficient, and so I did. My fasting glucose was reported at 82 mg/dL — this was very good — with no detectable insulin to the limits of the test sensitivity ( < 2.0 uIU/mL) — this not so good. Insulin resistance is usually diagnosed at fasting insulin > 8.6 uIU/mL. The online HOMA calculator I found estimated my insulin sensitivity at 4 times more sensitive than the average. So in other words, I wasn’t showing up  as insulin resistant. So, I decided to do a home oral glucose tolerance test (OGTT) to see just how bad things were. Here’s my results:

Jan 19 OGTT

In case you are not familiar with the OGTT, it is a brutal test for anyone with glucose disposal problems. You down 75 grams of glucose in a 10 minute interval and then watch your blood sugar levels go crazy. After 2 hours, my blood glucose, already high enough for a diabetes diagnosis, was seemingly still rising. The test being officially over, I went for a walk with my glucometer. It took a full hour of walking to get my BG back to normal levels and about a week for my PP BG numbers to return to what they were pre-test. It was during this week that I started using exercise after meals (especially breakfast) to keep my BG numbers down.

I felt like I had a problem that needed to be dealt with. Although it wasn’t clear that a strategy to reduce insulin resistance, ie lowering my fat intake, would have any positive effect in my case, I decided it was time for another diet experiment. I’d had some lab work done at the end of Feb that reported an A1c of 5.2, so I felt confident that even if my insulin was completely inadequate, I could keep my BG in check with exercise and give my β-cells a chance to come back a little. It didn’t seem like I could make matters worse and the upside potential was more dietary freedom, better glucose control and less worry about continued long term β-cell impairment.

Just to be clear, I am NOT saying that my high fat diet trashed my β-cells. A certain percentage of pre-diabetics graduate to the full monte all the time; I don’t think it’s been established who will progress and why. Perhaps my low carb diet was even beneficial and possibly delayed the inevitable. We just don’t know. Regardless, the diet experiment was to replace 20% of my caloric intake that was formerly fat with carbs, use exercise to prevent horrendous PP glucose spikes and after my glucose metabolism was hopefully upregulated, recheck my lipid panel and A1c.

Long story short, the diet was a dismal failure. The good news was, I re-discovered my long lost ability to exercise at my aerobic threshold for 25 min and after I recovered from the experiment, I found my legs to be hella stronger. The bad news was that with all that exercise and only being able to consume a limited amount of carbs at each meal without overwhelming my glucose disposal strategy, I was in an energy deficit situation. My weight plummeted and I couldn’t sleep through the night. My doctor advised that I go back to low carb, and so I terminated the diet experiment on April 1, after only 22 days. In the chart below, you can see my weight dropping from 114 to 111 in 3 weeks (the vertical cyan lines are only slightly relevant – they are days that I did resistance training).

3 Week Diet Experiment, Mar 10 – Mar 31

Before contacting my doctor, I had done a second home OGTT to see if there had been any improvement. To my utter dismay, it seemed to be quite the opposite. Here’s the March 28 OGTT (in red) vs the previous January 19 (in blue):

Home OGTT towards the end of the diet experiment

Home OGTT towards the end of the diet experiment in red

Now, just looking at the chart, one might infer that there had been a huge improvement. Sadly, not so! There was an immediate, obviously unopposed, glucose spike that so totally freaked me out that I decided to abandon the test and instead of sitting quietly for the OGTT as you are supposed to do, I grabbed my glucometer and started up a 400 foot elevation climb just outside of my house as fast as I could go. It took almost a half hour at my anaerobic threshold to bring my BG back down below 140, so I patted myself on the back and sat down to rest … only to see my BG bounce back up again 20 minutes later. I repeated the whole sequence, including observing a second BG bounce until finally it was down and stayed down.

Now maybe somebody out there knows more about this stuff than I do and can set me straight, but to me, this March OGTT was showing that whatever minuscule β-cell function I had, it was totally overwhelmed by 75g of glucose. Not only that, my β-cells were less functional than they had been 2 months prior.

So, yes, I abandoned my diet experiment and if that was the total end of the story, I wouldn’t have written so much about this. Along with returning to my higher fat diet, I also hit pubmed to see what I could learn about my situation. So bear with me here; there is a light at the end of this tunnel and there is stuff I’ve learned that may be helpful to others.

Continue to part 2 here: What Is the Best Diet for Managing Diabetes?

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ApoE4 and PCOS, Metabolic Syndrome, Female-to-Male TS – Part 2

This is not the part 2 continuation that I had originally planned. As I continued to pursue my original line of thought, it became apparent that the results of this study were problematic as I attempted to fit them into the overall picture of ApoE research in Turkey. This is important, because as I have since come to understand, the whole matrix of disease, epigenetics and genetic predisposition, is nuanced and complicated. A single SNP in context A can have an entirely different effect when in context B.

What was the problem?

The results of the study would seem to suggest that the APO ε2 allele that is expressed worldwide at a 7% incidence is present in healthy individuals in Western Anatolia, Turkey at 17%. OK, that’s strange. But, additionally, in the PCOS group, ε2 was found at the more usual level (4%), while the presence of the most common ApoE genetic variant, ε3, was found to be detrimental. How can this be? What would be the evolutionary pressure that would favor a disease situation? Is it as Finch suggests that higher ApoE4 favored higher fertility at the expense of longevity and in this case, by means of protection from PCOS?   This is indeed an extraordinary claim, and, as we know, extraordinary claims require extraordinary evidence. We need to use common sense, look at the journal reputation and look at other studies.

Although the study fails the common sense test, the journal, JARG, is among the top 50 in developmental biology. So, in checking further, I looked at other genetic studies from Turkey and came up with the following list (click on the table to view it separately in order to see the actual numbers):


The study in question is positioned at the top, pubmed ID 2649336. Notice, (columns AD-AF, highlighted in red), they are reporting a 17% incidence for Apo ε2 and a 75% incidence for ε3 in the healthy control population. (BTW, I marked the other anomalous study entries also in red.) In light of the allele distributions reported in the other studies, how likely is it that these numbers are truly representative of the local population?

The study was conducted in Izmir in the Aegean region on the Western coastline of Turkey:

Turkey, map

Istanbul is about 200 mi away. A study there (line 9, PMC22277050) reports ε2, ε3 incidence in healthy controls at the more expected 5% and 88%, respectively, whereas another, PMC19368142 on line 13, has these numbers at 9% and 80%. For Ankara, about 250 miles away, one study, PMC21500980 (line 22), reports 3% and 92% for ε2, ε3, while another, PMC2935837 (line 16), says the control population there is 10% and 52% for the ε2, ε3 alleles. Meanwhile, the Turkish Adult Risk Factor Study (n=1774) collected data from all 7 regions and found the ε2, ε3 allele representation to be 7% and 87%.

These are huge differences, especially in Ankara. In these small Turkish studies, how are they collecting their control samples? If the control sample can vary by that much, how do they ensure that the control sample is applicable to the study question and hasn’t introduced ascertainment bias?

Another problem that bothered me was that if we were trying to show an evolutionary pressure raising ApoE4 for fertility protection at the expense of reduced ε3 and reduced longevity, then why are these studies (highlighted in red in column P under “Case as %”) showing higher ε3 associated with disease?

The clincher was the Hardy-Weinberg Equilibrium calculation (see columns at the right). This calculation is used to check for ascertainment bias. It looks at the internal consistency between the various genotypes. The original study paper failed to report the HW calculation, so I did it myself. For the study in question, the HW calculated probability estimates about a 92% chance that the sampling was in error.

To try to answer some of my questions, I drafted a very polite inquiry as to how the study control sample had been acquired and what had been done to protect against ascertainment bias. I then had a friend with some academic credentials send it off to the study author. Over a year has passed; we have not received a reply.

And the conclusion?

The Turkish population is rapidly growing and is ancestrally very diverse. The bottom line is that with a 92% likelihood that there was sampling error, I would hesitate to draw conclusions from this study. I could have just deleted my previous, part 1 post, but decided to leave it in with this as a follow up to remind both myself and others to be careful about attributing too much to a single study, especially when the sample size is small and the numbers just don’t make sense.

 

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ApoE4 and PCOS, Metabolic Syndrome, Female-to-Male TS – Part 1

The ε4 allele has been alleged by many to be contributory to a number of Western disease outcomes. Not only that, the differing responses of the human organism having the various alleles of apoE has created, I think, a nightmare of misunderstanding and opportunity for the flourishing of a gaggle of half-baked dietary gurus.  I was surprised to find out that in people of European descent, ε4 is far more prevalent than I had thought: 20% – 25% of us have it. And now, it’s been confirmed that I have it too, although for me, it’s in the less problematic form, E3/E4. So, it’s become greatly interesting to me, and I would think it should be of great interest to just about anyone concerned with health, diet and nutrition.

And so it is that I’m taking a little detour from single-mindedly pursuing whether LDLc causes heart disease, in order to get up to speed on Apolipoprotein E (apoE).

ApoE is one of the lipoproteins that help cart cholesterol around in your bloodstream. The genes that code for apoE have 3 main variants (called alleles): ε2, ε3, ε4, which since you get one from your father and one from your mother, generate 6 genotypes: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4.

I just read Evelyn AKA CarbSane’s recent book review of PCOS Unlocked by Stefani Ruper  and it’s led me to decide me that looking at whether there might be an association between apoE variants and the basic gender identity mismatch behind FtM might be as good a place as any to start.

Ha! You might well be wondering how I got from PCOS to thinking about FtM issues?

PCOS and FtM

Being an FtM myself, I’ve known for years that there is a strong correlation between PCOS and female-to-male transsexual (FtM) incidence. No need to PubMed research it – somebody already has. And just google “FtM PCOS” – you’ll find pages and pages of relevant hits. So when I see PCOS, I automatically think FtM, forgetting that women without gender identity issues also get PCOS.

The link between the two might be higher than normal androgen levels in bio-women. It’s undisputed that PCOS goes along with elevated androgen. For example, here[1] free testosterone was found to be more than twice as high in PCOS patients vs controls. And, there are a few studies suggesting that maternal exposure to androgens late in female fetal development masculinizes the brain and could account for a male gender identity (see this and this[3]). But for whatever reason, FtM and PCOS are definitely correlated.

PCOS and MetX

The same article[1] above that showed elevated T levels in PCOS patients also documents the high total / LDL-cholesterol and the impaired glucose metabolism associated with MetX problems within the PCOS group:

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

The middle 2 columns (“Patients” w 129 women and “Controls” w 91 women)  compare lab results of women w PCOS and women not affected by PCOS. The final column, “P”, is the probablity those results would be due to random chance; the lower the P, the more significant the finding. I highlighted the significant differences showing that PCOS is accompanied by a slew of symptoms of a systemic endocrine system disorder, ie, MetX.

ApoE4 and PCOS?

Having shown that a  FtM-PCOS-MetX connection exists, since both MetX and apoE4 have elevated LDLc, the question has to arise in everyone’s mind, could they be genetically related at all? After all, if E4 has elevated cholesterol levels, since the sex hormones are derived from cholesterol, could that not also elevate maternal androgens during pregnancy? Which would link in the FtM connection.

Finch[6] says essentially that we couldn’t have apoE4 today unless there was some positive association with fertility and then, confusingly, goes on to deny it in observation:

Caleb E. Finch (2007) - The Biology of Human Longevity - Inflammation, Nutrition, and Aging, p 369

Caleb E. Finch (2007) – The Biology of Human Longevity – Inflammation, Nutrition, and Aging, p 369

Can a relation between PCOS and apoE can be found?

Dr. B G at Animal Pharm cites Corbo et al[2] saying that in a pre-industrial environment the ApoE4 allele would confer higher fertility and more offspring, but with the E4 carriers’ adverse sensitivity to the “anti-HG diet (e.g. refined, non-ancestral)” of our modern world, the result is:

“the preponderance of small dense, oxidizable LDL and a hyperactive immune system which searches and scars, yes of course, will result in higher rates of infertility, fibroids, ovarian cysts, PCOS and less pregnancies, as countless PubMed articles report.”

So, how do the cited study authors rationalize the enhanced fertility among the apoE4 group for pre-industrial women, but decreased fertility relative to E3 now? And can I find PubMed documentation of this more recent decreased fertility relative to E3 in industrialized regions? Answering the first question, Corbo et al says:

A possible explanation for this inconsistency could be due to genotype–environment interactions. Most pre-industrial populations have lower plasma cholesterol levels than those observed in western countries. In these populations individuals carrying e*3 and the hypercholesterolaemic e*4 allele would be favoured because this allele could help in rebalancing cholesterol  levels which would otherwise be too low

BTW, as an aside, this explanation doesn’t sound too supportive of Plant Positive’s thesis in his How Much LDL? video that LDLc can never be too low. Apparently, fertility is negatively impacted by low LDLc.

For the second question, here’s the start my PubMed mini-review:

  1. Apolipoprotein E alleles in women with polycystic ovary syndrome[4] (2001) – The study results: “The frequency of the apo ϵ4 allele was 17.2% among women with polycystic ovary syndrome and was 18.7% among healthy fertile women, which is close to the rate in the general population in our area (19%). …  ϵ4 was not associated with the clinical disease.” The area in question was Kuopio, Finland.
  2. Functional genetic polymorphisms and female reproductive disorders …[5] – This was a review that located 139 publications involving genetics and PCOS up until Aug 2007 and found only the one I found (above) relating apoE and PCOS. No genetic association of any kind w PCOS was reported.
  3. Apolipoprotein E gene polymorphism and polycystic ovary syndrome …[1] – This 2009 study of a Turkish population found a highly significant protective effect of E2/E3 for PCOS and a surprising susceptibility of E3/E3 towards PCOS; E3/E4 didn’t quite reach significance and was also in the unexpected direction!

ApoE3 and PCOS?

The 2009 study took me by surprise. So much so that I stopped my PubMed search to look at it in depth. What’s up with E3 and PCOS? This is the exact opposite from what Dr. B G at Animal Pharm said I would find in PubMed. Here’s  the raw study numbers (circled):

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

To explain, the patient group (129 women – in red) has PCOS, the control group (91 women – in blue) does not. This is again that very same study that sourced the “Table 1” above. Here’s little graph I made to visualize the two distributions; again the PCOS group is in red, behind the healthy women in blue:

Population Distributions, PCOS vs Healthy

The differences in the distributions of the apoE variants between the women w PCOS and the women without PCOS is striking! The apoE4 appears to be somewhat protective; the apoE2 highly protective. The study numbers say it is highly unlikely that this difference would be due to chance.

What to make of this? This is just one study and of a Turkish population, so it would be unwise to give it too much weight. But it is highly significant and it does seem to put a damper on Dr. B G’s thought that there’s a need for apoE4’s to eat low-carb Paleo in order to protect themselves from PCOS.

But is there another way to interpret this study? … To be continued in part 2.

References

  1. Cetinkalp et al (2008) – Apolipoprotein E gene polymorphism and polycystic ovary syndrome patients in Western Anatolia, Turkey, J Assist Reprod Genet. 2009 January; 26(1): 1–6.
  2. Corbo et al (2004) – Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations, Mol Hum Reprod. 2004 Aug;10(8):617-20.
  3. Meyer-Bahlburg HF et al – Prenatal androgenization affects gender-related behavior …, Arch Sex Behav. 2004 Apr;33(2):97-104.
  4. Heinonen et al (2001) – Apolipoprotein E alleles in women with polycystic ovary syndrome, Fertil Steril. 2001;75:878–880.
  5. M. Simoni et al (2007) – Functional genetic polymorphisms and female reproductive disorders …, Hum Reprod Update. 2008 Sep-Oct; 14(5): 459–484.
  6. Finch, Caleb E (2007) – The Biology of Human Longevity:: Inflammation, Nutrition, and Aging, Academic Press, Amsterdam, p 369
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My Current Diet Experiment – Surprising Weight Loss Continues!

— Good Carbs, Bad Carbs?

My latest diet experiment was started in response to the lab tests  that concluded my previous diet experiment because despite a significant reduction in sat fat, my LDLc number didn’t really budge (actually, it went up a tad). I thought I would try sacrificing satiety in favor of more carbs, less fat and, hopefully drop those damn LDLc numbers. (See also my prev post on this experiment.)

So, what I’m eating now is about

    • 40% of calories as beans and veggies
    • 40% of calories from ultra high oleic acid fats

Life is fun ‘cuz it’s full of surprises! What actually happened is, contrary to what Gary Taubes would have me believe, adding more carbs did NOT:

    • make me hungrier
    • jack up my insulin
    • jack up my glucose
    • make me gain weight

Here’s my weight log, graphed:

Weight log as of Feb 10, 2013

Weight log as of Feb 10, 2013

The red triangles marked weight from my previous experiment where I was maintaining on 1530 cal/day, P/F/C = 21 /  47 / 32. The blue squares (Jan 15 – Feb 10) is the new experiment where I’m UNINTENTIONALLY losing weight on 1400 cal/day, P/F/C = 22 /  39 / 39.

So, I say it was unintentional, because I wasn’t trying to lose weight; I was just eating when I was hungry and stopping when I was not. Same as I was during the maintenance period prior to that.

What’s the Magic Element?

I think it’s beans! When I planned this experiment, I decided to try substituting bean calories for some of my high fat/ sat fat foods. I thought I was between a rock and a hard place, having to restrict fats because of LDLc problems, having to restrict carbs cuz of high glucose problems and having to restrict protein for the usual reasons. I had no idea beans would be so slow digesting that they could slip through the cracks and avoid carb metabolism problems. And, BTW, I had no idea they could be prepared to taste SO good!

Am I a happy camper? You betcha, I am!!

BTW, if you’re one of my readers, you know that I started taking thyroid meds (T4) on Jan 28. So, it could be argued that it was the T4 making the difference. But, if you look at the mini-graph above on the right, there’s a vertical line through the center. That just about marks when I started taking the T4. The changes were well in progress before that. I don’t think being satisfied on less calories is a side effect of thyroid meds.

Meanwhile, today’s weight measurement has compelled me to up my calorie intake by 25% (with beans). I did that for my first meal today and my 1-hour blood glucose reading was only 123. Yay! I’m good to go with this.

Maybe I should write a book entitled, Good Carbs, Bad Carbs!  (Just kidding; I’ll stick with my blog, thank you.)

Posted in Low carb, Nutrition, Personal | Tagged , , , | 2 Comments