red meat: increases risk for diabetes, role of TMAO

 A recent analysis of the Nurses’ Health Studies and Health Professionals' Follow-up Study revealed a relationship between consuming red meat and the development of diabetes in men and women (see dm red meat AmJClinNut2023 in dropbox or https://doi.org/10.1016/j.ajcnut.2023.08.021 )

Details:

-- 216,695 participants from the combination of the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study, all having relied on detailed assessments of their dietary intake, with food frequency questionnaires every 2 to 4 years that semiquantitatively comprised 61 food items initially, which increased in 1984 to 120 items

    -- the studies were started in 1976-1989, with follow-up until at least 2016

    -- 5,483,981 person-years of follow-up were evaluated for intakes of total, processed (eg, hotdogs, bacon), and unprocessed red meat

-- mean age at baseline 36-53yo (all of these baseline values varying by the study), BMI 24-26, physical activity 16-23 METs-hours/week,  current cigarette smoking 1-14 cigarettes per day 2-8%/15-24 cigarettes per day 3-12%/>24 per day 1-10%

-- family history of type II diabetes 18-41%, history of hypertension 5-19%

-- exclusion criteria included those who had a reported baseline history of diabetes, MI, angina, stroke, CABG, or cancer

-- main outcome: relationship between red meat consumption and type II diabetes

  

Results:

-- 22,761 incident cases of type II diabetes

-- incidence of diabetes, stratified by red meat consumption, comparing those in the highest versus the lowest quintile of red meat consumption:

    -- total red meat consumption: 62% increased risk, HR 1.62 (1.53-1.71)

    -- processed red meat consumption: 51% increased risk, HR 1.51 (1.44-1.58)

    -- unprocessed red meat consumption: 40% increased risk, HR 1.40 (1.33-1.47)

        -- p <0.001, for the trend

        -- these results approximated a linear increase in diabetes risk across the five quintiles of red meat consumption per day

-- as a perspective: 

    -- the lowest quintile consumed an average of 0.45 servings of red meat/day, the highest consumed 1.86 servings/day

    -- the graded increase in the risk of diabetes was evident as total, processed and unprocessed red meat consumption increased, all with a p <0.001 for the trend

 

-- The associations noted above were attenuated by around 50% when adjusting for BMI as it varied during the course of the studies; adjusting for that:

    -- total red meat consumption, per servings per day: 12% increased risk, HR 1.12 (1.09-1.15)

    -- processed red meat consumption, per servings per day: 21% increased risk, HR 1.21 (1.15-1.28)

    -- unprocessed red meat consumption, per servings per day: 10% increased risk, HR 1.10 (1.06-1.14)

 

-- mathematical assessment found that substituting one serving of nuts and legumes for red meat consumption:

    -- total red meat consumption: 30% lower risk of type II diabetes, HR 0.70 (0.66-0.74)

    -- processed red meat consumption: 41% lower risk, HR 0.59 (0.55-0.64)

    -- unprocessed red meat consumption: 29% lower risk, HR 0.71 (0.67-0.75)

 

-- there was a higher risk of type II diabetes associated with red meat consumption in those with higher physical activity, those who were past smokers, Black versus White participants, though this increased risk was not found for Asian and Hispanic participants (though the confidence intervals were quite wide for them)

-- the association was also stronger in total red meat assessed within 12 years of the diagnosis of diabetes (versus analysis starting at baseline). Also the strongest association was with cumulative average intake over the follow-up period.

 

Commentary:

-- prior analyses have associated red meat intake with the risk of type II diabetes.

    -- A systematic review and meta-analysis of RCTs, however, did not find a significant impact of red meat intake versus no red meat intake on insulin sensitivity, insulin resistance, fasting glucose, fasting insulin, A1c, pancreatic beta cell function, or GLP-1 levels, though it did decrease postprandial glucose somewhat (https://pubmed.ncbi.nlm.nih.gov/35513448/ )

        -- however, in this systematic review, for most outcomes the quality of evidence was rated as low to moderate; many of the studies had relatively low levels of red meat consumption overall (as opposed to the study above), and subgroup analysis did find that there was a small increase in fasting glucose with increasing red meat consumption

    -- the EPIC- InterAct study, which accumulated 12,403 incident diabetes cases, found an 18-20% increased incidence of diabetes associated with every 50 g increase in red meat (slightly more so with processed red meat intake)

       -- of note, this study as well as others, assessed diet only at baseline and did not have information on changes in diet. The current study did find a higher risk of red meat associated diabetes in those within 10-15 years prior to the onset of the diabetes, and long-term studies that only had baseline measurements might therefore reveal a lower risk

 

-- in this new study, it was clear that there was a strong relationship between higher intensity red meat consumption (and especially the cumulative amount of red meat consumed) and type II diabetes:

    -- this risk was a nearly linear one, with increasing risk as each quintile of red meat consumption increased

    -- processed red meat consumption had a stronger relationship with type II diabetes vs unprocessed red meat

    -- BMI (which has a very strong association with diabetes) attenuated the risk by half, though the associated risk remained statistically robust

    -- increasing nuts and legumes as well as dairy was associated with decreased risk, per mathematical modeling

    -- this study did have the benefit of long-term follow-up, regular assessments of diet and diabetes over three decades, and lots of incident cases of type II diabetes

-- hard to know why there was an increased risk of diabetes in those with did more physical activity. This unexpected finding suggests the possibility that there were unmeasured confounders leading to the association between those who ate red meat but exercised more having more diabetes. Were they exercising because they were under lots of stress, and exercise helped control their stress (stress has been shown to increase diabetes risk: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319684/ )? other factors??

 

-- There are many potential mechanisms for the association between red meat consumption and type II diabetes:

    -- saturated fat, notably higher in red meats, is associated with reduced pancreatic beta cell function and insulin sensitivity; and a lower dietary content of polyunsaturated fats, more prevalent in red meat consumers, may make matter worse: linoleic acid (the most common plant-based polyunsaturated fatty acid), is an agonist of PPAR-gamma, and PPAR-gamma (as is stimulated by pioglitazone) increases tissue sensitivity to insulin action

    -- plasma ferritin levels are increased in those consuming red meat, and heme iron is a strong pro-oxidant; plasma ferritin levels seem to be independently associated with diabetes risk

    -- tryptophan, mainly derived from animal protein, seem to increase diabetes risk: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162192

    -- processed red meats have higher nitrate levels, which promote endothelial dysfunction, and insulin resistance

    -- red meat consumption is also associated with increased weight, more so than plant-derived protein sources, and excess adiposity is a strong stimulus for diabetes development

    -- another possible mechanism for the increased risk of diabetes is mediated through the increase in TMAO (trimethylamine-N-oxide), associated with red meat consumption (see cad red meat TMAO nature medicine 2013 in dropbox; or a more recent article: https://www.sciencedirect.com/science/article/pii/S1931524420302036 ), as well as in a blog from 2013 https://gmodestmedblogs.blogspot.com/2013/04/red-meat-and-heart-dz.html . these references highlight the relationship of TMAO with heart disease, and was brought up in a 2013 NY Times report (https://www.nytimes.com/2013/04/08/health/study-points-to-new-culprit-in-heart-disease.html?nl=todaysheadlines&emc=edit_th_20130408&_r=0).seems )

        -- TMAO is a very potent atherogen: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300890/?report=reader 

        -- TMAO is associated with a dose-dependent increase in inflammatory cytokines (https://www.mdpi.com/2219270 ), and inflammation is associated with diabetes, with a dose-dependent association with the risk of diabetes (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343234/pdf/dmso-15-2197.pdf ) 

        -- dietary L-carnitine (abundant in red meat, particularly in beef) leads to the synthesis of TMAO, apparently through a 2-step process:

            -- baseline gut microbiota assessment in vegans/vegetarians differ substantially from omnivores/carnivores (ie, it is much healthier in the former) 

            -- in humans, small studies of vegans/vegetarians have found no significant increase in TMAO concentrations following L-carnitine ingestion; omnivores having very high TMAO levels soon after consuming carnitine 

            -- vegans fed carnitine and an 8-ounce sirloin steak (not sure how consent was obtained….) had no increase in TMAO afterwards

            -- human carnivores given antibiotics no longer had high TMAO levels in their blood after consuming carnitine, suggesting that microbiome bacteria obliterated by antibiotics were responsible for the carnitine-to-TMAO pathway 

                -- ie, vegans, with little TMAO in their blood, and no increase in TMAO with an initial consumption of carnitine, but did have significant TMAO production after more consistent carnitine ingestion (as they morph into omnivores)

            -- so the likely 2-step process: carnitine ingestion from meat induces changes in the microbiota to promoting bacteria that produce TMAO as found after repeated exposure to carnitine (these microbiome changes were replicated with further advances in a 2020 study: https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00912-y ) and then leading to the bad effects of TMAO on the body (specifically, cardiovascular and diabetic ones)        

        -- and, by the way, “carnitine” has the same Latin route as “carnivore”)

        -- a recent study found that similar quantities of plant-derived protein vs carnitine produce lower TMAO concentrations (https://ajcn.nutrition.org/article/S0002-9165(22)00890-5/pdf )

 

Limitations:

-- these were observational studies, which limit definitive causal relationships. For example, did those who have less red meat consumption do other things that were healthier, such as differences in exercise, or differences in social conditions that might affect their access to healthier foods (social economic status, where they live and access to healthier foods, cultural dietary norms, etc).  The unexpected finding of the association between exercise and increased diabetes risk exemplifies that observational studies are only associations and do not point to causality

        -- however, one cannot do very long-term clinical trials (RCTs) given the difficulty of randomizing people to very different diets and following for potentially decades to assess diabetes outcomes...

-- their data relied on self-report, and there may be inaccuracies

-- there was a narrow group of participants in the study, limited to health professionals and with more than 90% white people, all of this limiting potential generalizability of the results. They did have sufficient numbers of Black participants to note no difference in outcomes, though Asian and Hispanic participants did not have sufficient statistical power for clear outcomes (though it was suggested they were less likely to develop diabetes)

 

So, further evidence that red meat is bad for one’s health, as well as other bad effects:

    -- bad for the environment: a single cow producing 154-264 pounds of methane per year (a greenhouse gas with >80-times the warming power of carbon dioxide)

    -- antibiotics are used in livestock:  approximately 80% of the total consumption of medically-important antibiotics are used in livestock, per the WHO (see https://www.who.int/news/item/07-11-2017-stop-using-antibiotics-in-healthy-animals-to-prevent-the-spread-of-antibiotic-resistance ) and these antibiotics are associated with the development of antibiotic-resistant bacteria

        -- a report from the US Geological Survey in 2016 found antibiotics in streams, groundwater, and drinking water in the early 2000s, as well as methicillin-resistant staph in Great Lake beaches. Antibiotics were detected in 60% of beef:  https://www.hhs.gov/sites/default/files/carrie-givens-fin-remediated.pdf​ , and antibiotic-resistant genes were frequently found in livestock

        -- as a cautionary tale, a woman in the US had the first case of colistin-resistant e coli infection.  Colistin (also called polymixin E) is a very powerful antibiotic sometimes used for multi-drug resistant gram-negative infections (eg pseudomonas). and, very unfortunately, resistance to colistin is conferred by a plasmid-mediated piece of DNA that can be passed from one person to another: https://gmodestmedblogs.blogspot.com/2016/06/e-coli-superbug-is-spreading.html . colistin is used frequently in animals, with a prior report in China of colistin resistant bacteria infecting many people, associated with meat consumption: https://gmodestmedblogs.blogspot.com/2015/11/troubling-microbiome-changes.html ; 

    -- it is interesting/very concerning that red meat has such a multitude of adverse human clinical effects, from affecting pancreatic function, being anti-oxidant, having high nitrate levels in its processed form (and likely also increasing colon cancer), leading to weight gain, leading to increased TMAO production (promoting atherosclerosis, as well as found in a study of increased heart failure), being pro-inflammatory, etc. And all of this is likely part of the increased risk of diabetes and its many major complications

    -- there really should be public health messaging about this point, though no doubt with hugh pushback by the meat industry....

geoff

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