Does red meat cause type 2 diabetes?

You probably didn't want to know this much

A new study came out on the relationship between red meat and type 2 diabetes (T2D)*. This always pops up now and again. These types of studies present a challenge because of the inherent weaknesses of observational studies, especially those involving dietary recall. We also have to compare the observational data to controlled data to see if we can see consistencies and understand what might be going on and most of this data is conflicting.

This one is messy and I would probably conclude by saying if your goal is to prevent T2D, avoiding high intakes of red meat seems sensible, especially if you are male. Controversial? Read on.

I am a scientific advisor to Beyond Meat. I think I have reviewed the evidence objectively, but I want to make that clear so people can identify if they think I am biased.

Photo by Sven Brandsma on Unsplash

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I am not going to go through the observational data and limitations thereof because other people are better at doing that.

However, I do think it’s important that if we see an observation between an exposure and an outcome that we should have clinical evidence (not just biological plausibility) explaining the link. I think there are several candidates and I want to go through these in turn so you can see my thought process:

Potentially mechanisms are

• Amino acid content

• Saturated fat content

• TMAO

• Inflammation

• Iron (or something else)

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Amino acid content

Meat (all meats) have high branched chain amino acid (BCAA) content. There’s observational data suggesting that circulating BCAA are associated with insulin resistance and T2D. But, it could just be that elevated circulating BCAAs are a marker of the dysfunctional tissue insulin signalling which occurs as a result of a chronic fuel surfeit, excess adiposity and/or inactivity which we know all increase the risk of T2D. In this sense the increased BCAA are a marker of underlying tissue dysfunction, not a cause.

We can tease this out by doing experimental studies. And supplementation with BCAA does not show impairment in glucose metabolism, nor does it ameliorate the improvements in glucose control seen with weight loss.

It also seems unlikely to me that meat causes T2D because of its BCAA content because other high BCAA foods (chicken, dairy) are not associated with an increased risk of T2D.

In conclusion, I don’t think the BCAA content of meat could explain why we observe a relationship between red meat and T2D.

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Photo by Sorin Gheorghita on Unsplash

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Saturated fat content

I often hear people say that meat causes T2D because it’s high in SFA, but I’m not aware of much evidence at all that saturated fat increases the risk of T2D.

The only cases I can think of where it could be a potential risk factor is when when overall fat intake (eg 50%kcal) and saturated fat intakes (eg 25%kcal) are both high. But this does not apply to many people anyway.

There is some evidence that diets high in PUFA and MUFA help prevent T2D but the mechanism is unknown. So maybe the ratio of saturated fat to unsaturated fats is important. Nevertheless, even foods which have a high saturated fat to unsaturated fat ratio (eg butter) aren’t related to risk of T2D.

In conclusion, I don’t think saturated fat explains any of it.

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TMAO

Trimethylamine N-oxide (TMAO) is a compound that is produced in the body when gut bacteria break down certain nutrients which include those in red meat. TMAO has gained a ton of attention in recent years after a correlation was found between people who had clogged arteries and levels of TMAO, and pre-clinical studies identified biological roles for TMAO in stuff like inflammatory responses and platelet activation. Naturally everyone and their mum then starting investigating whether TMAO could be related to other diseases like T2D. In fact, the latest paper on red meat and T2D invokes TMAO as a potential explanation for the link they found.

However, far better studies showed that TMAO is probably a marker for these diseases, not a cause; and in controlled feeding studies TMAO is produced in response to the consumption of fish, high fibre diets, and possibly also to soy. Fish and soy have little relationship to T2D, and high fibre diets are protective.

So I am skeptical that TMAO explains the observed relationship between red meat and T2D.

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Inflammation

Inflammation is a sort of vague concept, but it does seem that having a high BMI and a generally unhealthy lifestyle is associated with a “pro-inflammatory state”. (See my article iNfLaMaTiOn for more). However, the evidence doesn’t suggest red meat per se is associated with inflammation.

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(This is a bit misleading because it seems to be haem but not non-haem iron which is related to the risk of T2D but it’ss the only pic I could find).

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Iron

This, I think, is where things get interesting.

It’s been known for a long time that iron influences glucose control because of the relationship between hemochromatosis and diabetes. Haemochromatosis is an inherited condition where iron levels in the body slowly build up over many years. When phlebotomy was first used to treat hemochromatosis in the 1950s (because it was known that too much iron causes lots of damage to the body generally), clinicians observed that glucose control improved in a large proportion of patients.

Trials have confirmed this relationship. For example, people with T2D and high ferritin (>450microgram/L) were randomised to 3 phlebotomies (500ml every 2 weeks) or observation. Measures of glucose control were taken 4 and 12 months after. Phlebotomies lowered serum ferritin (to 230 microgram/L) as expected in the phlebotomy group, but there was no change in the observation group. Likewise, HbA1c was lower in the people who were randomised to phlebotomy alongside improvements in insulin sensitivity.

But - there’s also evidence iron status (below the levels you get in haemochromatosis) are related to glucose dysfunction and T2D.

Let me note here measuring iron status is challenging and each of the commonly used measures has some limitations. Serum ferritin tends to be used in most of the studies.

In the general population, body iron stores assessed by serum ferritin are positively associated with beta-cell dysfunction and insulin resistance; and the development of type 2 diabetes and gestational diabetes**, although the relationship does not appear to be linear. It’s important to note that serum ferritin is not a perfect reflection of iron stores because its concentration can be affected by things like inflammation, and low-level inflammation can occur in obesity and T2D. Nevertheless, the relationship between serum ferritin and poor glucose tolerance is found even after adjusting for BMI, waist-hip ratio and family history of T2D.

But we have more than big observational studies here:

Frequent blood donations (ie multiple donations over weeks) leading to decreased iron stores (serum ferritin: 188 microgram/L to 105 microgram/L), have been demonstrated to improve glucose tolerance. While some studies do and some studies don’t show a reduced incidence of T2D, it’s possible the amount of “blood removal” in these larger prospective studies was not large enough/frequent enough to have an effect.

In this very cool but small study, investigators looked at iron stores and glucose tolerance in a group of 30 meat eaters and 30 lacto-vegetarians. The lacto-ovo-vegetarians had lower ferritin and better insulin sensitivity. You might be thinking CROSS-SECTIONAL, SHMOSS-SECTIONAL so what. You’d be right. BUT, the investigators then lowered body iron (serum ferritin: 72 microgram/L) by phlebotomy in six male meat-eaters to levels similar to that seen in vegetarians (serum ferritin: 35 microgram/L), and found a 40 % increase in insulin-mediated glucose disposal (a measure of insulin sensitivity).

What I think is interesting here is that 72 microgram/L isn’t that high, and yet a small reduction seems to improve insulin sensitivity. Of course, this is just one study and the sample size is small.

And I don’t want to pretend this data is a slam-dunk.

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Trials on red meat don’t show an increase in T2D risk markers

If we really want to know the relationship between red meat and risk of T2D, why don’t we look at trials? Ok, so we can’t look at development of T2D as an outcome because that takes years and decades, but we can look at relevant markers like fasting glucose, insulin sensitivity and beta-cell function. And the great news is we have a meta-analysis of randomised controlled trials!!!

What this meta-analysis shows is that there is no relationship between red meat intake and insulin sensitivity, fasting glucose, fasting insulin, HbA1c, beta-cell function, or GLP-1.

So does this mean red meat definitely doesn’t increase the risk of T2D because meta-analyses of randomised controlled trials are the highest form of evidence? Not so fast. Firstly the quality of any meta-analysis depends on the quality of the trials included - and the investigators identified important weaknesses in the data (imprecise, inconsistent and indirect) and described the quality of evidence as evidence “low to moderate”.

But I think there are two bigger issues which mean we need to be cautious about these controlled trials: the longest was 10 weeks, most were around 4-5 weeks and many were acute. In the phlebotomy in T2D and high ferritin trial cited above, improvements occurs over months, and actually appeared to be greater at 12 months compared to 4 months. So it looks like if too much iron is a reason underlying the relationship between red meat and T2D, the harm seems to be done over the long-term, so I don’t think we would see it in these short studies. This is supported by an acute study showing that acute IV administration of 1000 mg of iron does not impair glucose-induced insulin secretion.

And the second is that…..

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…Trials also don’t show convincing changes in iron status with red meat consumption. Could the dose be the poison?

There’s no change in serum ferritin for example in women on reproductive age with 135g of red meat a day over 8 weeks. Of course menstruating women probably lose enough iron that they would need a ton of red meat to see an impact on serum ferritin or other marker of iron status. However, a follow-up study of males and females found no change in markers of iron storage with 200g raw weight (which is probably about 150g cooked) of lean red meat per day for 8 weeks.

I would propose there are several caveats to these data:

1. I wonder whether the dose is the poison - ie you need upwards of eg 250g a day to see an impact (men, I am looking at you here HAHA).

2. There does seem to be some adjustments in non-haem iron absorption with iron supplementation, but much less so for haem-iron absorption. So perhaps for people who get most of their iron from haem-iron sources, their iron status would increase with high red meat intake.

Finally, we have very little idea what it is about iron status which increases the risk of T2D - is it free iron, is it iron which gets deposited in a given organ? Do these effects differ between people?

This excellent review notes that differences in where iron is stored, and how iron is metabolised and moved around the body may influence the effect iron has on the body. There also seems to be quite a bit of variation (this paper mentions ethnicity but also other genetic causes) in how people absorb and metabolise iron and maybe this also explains why we see inconsistent data on red meat, iron stores and T2D.

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Could there be something else in red meat?

Finally, it’s possible that there is another compound in red meat which we don’t know about/can’t measure/haven’t looked at properly which is also mediating the observed effect. This study finds that haem-iron explains 65% of the relationship between red meat intake and T2D, so maybe there are other factors which are contributing or even may interact with haem-iron?

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OH GOD THIS IS MESSY

You can see why I haven’t got a podcast where I just make over-simplified, wildly inaccurate statements about nutrition can’t you? HAHAHA.

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Converting all this into any practical advice?

Disclaimer: There are a lot of unknowns - we don’t know what aspect of iron (circulating/hepatic/metabolism thereof) is damaging, we don’t know the best way to measure it/ look for it. (So please don’t go away to your doctor and ask for a ferritin check). I am not a medical doctor and these are just my musings. Also be mindful that compared to adiposity, and physical activity, the effect of everything else on T2D tends to be small.

But based on the following rationale:

1. I think there is convincing evidence that iron excess is somehow involved in the pathogenesis of T2D, and I think there is reasonable evidence this increase in risk could start at levels of iron status that are not uncommon in the population.

2. I think most people would need a lot of red meat, and under certain conditions (maybe with a diet low in non-haem iron) to increase iron stores, and this is far more likely to be relevant to men. For example men have higher serum ferritin than women, with this study showing double the concentration; and men also eat more meat in general including red meat.

3. If you eat a ton of red meat, and reduce it a bit, it’s not going to do you any harm.

So I think for people - especially males - who consume a lot of red meat (I know blokes who’ll have 500g of meat a day and think nothing of it) and are worried about their risk of T2D, the following are sensible:

• Beef and veal contain much more more iron than do pork and lamb so the latter are better options if you like to consume meat.

• If you consume red meat every day, switch out the other things a few days a week:

  • Replace red meat some days with fish, eggs, legumes, tofu, tempeh or other plant-based meat alternatives***.

• Reduce your serving sizes when you do have red meat:

  • Replace half the mince/meatballs in recipes with eg lentils or butter beans.

    • Also you get the benefit of phytonutrients and fibre etc in the legumes.

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*It also found a relationship between red and processed meat but I’ll leave the latter for another time so this isn’t too wordy.

**when serum ferritin is measured in the first trimester

*** again, remember I am a scientific advisor to Beyond Meat