icon-folder.gif   Conference Reports for NATAP  
 
  The International Liver Congress™
EASL - European Association for the
Study of the Liver
2019 April 10-14
Vienna Austria
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High red and processed meat consumption is associated with
non-alcoholic fatty liver disease and insulin resistance

 
 
  Jnl of Hepatology June 2018
 
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Diet, Dementia, Cognitive Impairment, Diabetes: type of foods & cooking affects impact
"The current dAGE database demonstrates that a significantly reduced intake of dAGEs can be achieved by increasing the consumption of fish, legumes, low-fat milk products, vegetables, fruits, and whole grains and by reducing intake of solid fats, fatty meats, full-fat dairy products, and highly processed foods." "Equally important, consumers can be educated about low-AGE-generating cooking methods such as poaching, steaming, stewing, and boiling. For example, the high AGE content of broiled chicken (5,828 kU/100 g) and broiled beef (5,963 kU/100 g) can be significantly reduced (1,124 kU/100 g and 2,230 kU/100 g, respectively) when the same piece of meat is either boiled or stewed. The use of acidic marinades, such as lemon juice and vinegar, before cooking can also be encouraged to limit dAGE generation."
 
Diet/Diseases/Inflammation/Survival - Oral Glycotoxins (AGEs) Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan
We previously showed that the content of advanced glycation end products (AGEs) in the diet correlates with serum AGE levels, oxidant stress (OS), organ dysfunction, and lifespan. We now show that the addition of a chemically defined AGE (methyl-glyoxal-BSA) to low-AGE mouse chow increased serum levels of AGEs and OS, demonstrating that dietary AGEs are oxidants that can induce systemic OS. OS predisposes to the development of cardiovascular and chronic kidney diseases.
 
The postulated mechanisms of senescence and aging in organisms from yeast to mammals include environmental and genetic factors, elevated oxidant stress (OS), cumulative DNA damage, altered gene expression, telomere shortening, and energy utilization.1,2,3 Calorie restriction (CR), via restriction of food intake, is the principal nongenetic or environmental intervention that prevents these processes and extends lifespan without significant side effects.4,5 Although the mechanism(s) of CR are complex, the prevention of OS and maintenance of antioxidant reserves are common features.1,2,6,7 The beneficial effects of lowering OS on lifespan have been shown with anti-oxidant mimetics or genetic models of extended lifespan, ie, loss-of-function mutations of the GH/IGF-1 axis,8,9 of p66Shc,10 and the FOXO transcription factors,11 as well as overexpression of catalase.12,13
 
Diet, Dementia, Cognitive Impairment, Diabetes Intersect
Glycotoxins are found in fried or grilled meat, fried eggs and toasted bread - Toxic chemicals found at high concentrations in fried and grilled meats may raise the risk of diabetes and dementia, researchers say.
 
US scientists found that rodents raised on a Western-style diet rich in compounds called glycotoxins showed early signs of diabetes, along with brain changes and symptoms that are seen in Alzheimer's disease. Glycotoxins are widespread in animal products, including meat and dairy produce, and levels increase when food is fried, grilled, pasteurised or smoked, making them abundant in Western diets. The findings matched what the researchers saw in a small number of older people, where those with higher levels of glycotoxins in their circulation had memory and other cognitive problems, and signs of insulin resistance, which precedes diabetes.
 
The results are tentative, but if confirmed by other studies, the work could transform hopes for tackling two major diseases that have reached epidemic proportions in the developed world.
 
The study suggests that changes in cooking practices might lower the risk of both diabetes and dementia, while a greater understanding of the biological mechanisms could lead to drugs that delay their onset.
 
"People will grill bacon and fry eggs for breakfast, or have a toasted bagel or muffin. But they could boil or poach the eggs, and have fresh bread. With meat, we recommend stewing and boiling, making sauces instead of exposing meat to very high dry heat," she said.
 
"We report that age-related dementia (AD) and MS may be causally linked to high levels of food AGEs, specifically MG. The data extend our previous findings on AGEs promoting the MS in older animals and humans (22-24). The mouse study further reproduces the cognitive and metabolic conditions recently found to be linked in humans (1, 4, 5). The clinical study validates the mouse model and demonstrates that high sMG, a marker of dietary AGE intake and IR (23), may also be a determinant of dementia in older adults (17). It further validates the relevance of dietary AGEs to MS and AD in humans. Because AGEs can be modified in humans, recognition that this underappreciated risk factor plays a role in AD and MS may open unique therapeutic avenues.......Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG)......the highest AGE levels were observed in animal products high in protein and fat, such as meats and cheeses. Furthermore, high AGE levels were observed in (industrially) preprocessed foods from animal products like frankfurters, bacon, and powdered egg whites, compared with the unprocessed forms. Across all categories, exposure to higher temperature raised the AGE and ALE content (for equal food weights). The temperature level appeared to be more critical than the duration. Also, microwaving increased AGE content more rapidly compared with conventional cooking methods"
 
Highlights
 
• High consumption of red and/or processed meat is related to NAFLD and insulin resistance.
• Consumption of meat cooked in unhealthy methods is related to insulin resistance.
• Consumption of HCAs is related with insulin resistance.
• These associations are independent of saturated fat and cholesterol intake.
• If confirmed prospectively, limiting the consumption of unhealthy meats may be advised.
 
Multivariate analysis of the association between meat subtypes consumption and NAFLD or IR
High total meat intake (above the median) was independently associated with higher odds for both NAFLD (OR 1.49; 95% CI 1.05-2.13; p = 0.028) and IR (OR 1.63; 95% CI 1.12-2.37; p = 0.011), adjusting for potential confounders (Table 2). Similarly, high red and/or processed meat (joint categories) intake was independently associated with higher odds for both NAFLD (OR 1.47; 95% CI 1.04-2.09; p = 0.031) and IR (OR 1.55; 95% CI 1.07-2.23; p = 0.020), adjusting for potential confounders (Table 2). High processed meat intake did not remain significantly associated with IR or with NAFLD in the fully adjusted model (Table 2). Further adjustment of the association between high red and/or processed meat and NAFLD for type 2 diabetes did not change the results (OR 1.45; 95% CI 1.01-2.07; p = 0.042).
 
Background & Aims
High red and processed meat consumption is related to type 2 diabetes. In addition, cooking meat at high temperatures for a long duration forms heterocyclic amines (HCAs), which are related to oxidative stress. However, the association between meat consumption and non-alcoholic fatty liver disease (NAFLD) is yet to be thoroughly tested. Therefore, we aimed to test the association of meat type and cooking method with NAFLD and insulin resistance (IR).
 
Methods
This was a cross-sectional study in individuals who were 40-70 years old and underwent screening colonoscopy between 2013 and 2015 in a single center in Israel. NAFLD and IR were evaluated by ultrasonography and homeostasis model assessment. Meat type and cooking method were measured by a food frequency questionnaire (FFQ) and a detailed meat questionnaire. Unhealthy cooking methods were considered as frying and grilling to a level of well done and very well done. Dietary HCA intake was calculated.
 
Results
A total of 789 individuals had a valid FFQ and 357 had a valid meat questionnaire. High consumption of total meat (portions/day above the median) (odds ratio [OR] 1.49; 95% CI 1.05-2.13; p = 0.028; OR 1.63; 1.12-2.37; p = 0.011), red and/or processed meat (OR 1.47; 95% CI 1.04-2.09; p = 0.031; OR 1.55; 1.07-2.23; p = 0.020) was independently associated with higher odds of NAFLD and IR, respectively, when adjusted for: body mass index, physical activity, smoking, alcohol, energy, saturated fat and cholesterol intake. High intake of meat cooked using unhealthy methods (OR 1.92; 95% CI 1.12-3.30; p = 0.018) and HCAs (OR 2.22; 95% CI 1.28-3.86; p = 0.005) were independently associated with higher odds of IR.
 
Conclusion
High consumption of red and/or processed meat is associated with both NAFLD and IR. High HCA intake is associated with IR. If confirmed in prospective studies, limiting the consumption of unhealthy meat types and improving preparation methods may be considered as part of NAFLD lifestyle treatment.
 
Lay summary
High red and processed meat consumption is related to several diseases. In addition, cooking meat at high temperatures for a long duration forms heterocyclic amines, which have harmful health effects. Non-alcoholic fatty liver disease is a significant public health burden and its formation is strongly related to insulin resistance. In this study, both were found to be more frequent in people who consume relatively high quantities of red and processed meat. In addition, a high intake of heterocyclic amines was associated with insulin resistance.
 
Discussion
World meat consumption has increased in the last decades,36 while evidence of its harmful effect is mounting, particularly of red and processed meat consumption. Meat consumption has been linked to induction of impaired glucose and insulin homeostasis,15 diabetes and cardiovascular disease (CVD).16 In parallel, the prevalence of NAFLD is growing1 and expected to grow further, leading to an exponential increase in disease burden.41 This increased prevalence may be attributed, at least in part, to the adoption of Western diets high in processed and red meat, as suggested according to the results of the current study. We have demonstrated an independent positive association of high consumption of total, and specifically red and/or processed meat, with both NAFLD and IR. Furthermore, consumption of meat cooked by unhealthy methods was independently associated with HCAs and IR. Within the group of patients with NAFLD, similar positive associations of red and/or processed meat, meat cooked in unhealthy methods and HCAs were demonstrated with IR, which is a risk factor for disease severity.42 Our results are in accordance with the few studies published on this topic, indicating an association between total meat consumption and NAFLD20 and a potential protective role of a vegetarian diet43 or a low animal protein diet.44 In terms of food preparation methods, in a case-control study,5 grilled meat or fish intake more than once a week increased the odds for NAFLD by about twofold.5 Furthermore, indirect support for our findings stems from the protective effect of the Mediterranean diet in NAFLD,45 advocating low red meat and especially processed meat intake, and actually defined as "primarily a plant-based diet".46

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In contrast to NAFLD, the association between meat consumption and type 2 diabetes and CVD, which coexist and share common pathogenic pathways with NAFLD and IR,47 was extensively studied. In a meta-analysis of prospective cohort studies, processed meat consumption was associated with the risk of all-cause and CVD-related mortality,48 and with 42% higher risk of CVD and 19% higher risk of diabetes per 50 g serving/day,49 but no clear association was observed with unprocessed red meat. Conversely, in the Women's Health study, intake of both red and processed meat was associated with increased risk of type 2 diabetes.50 Other cohort studies support these findings, mostly linking diabetes with the intake of processed red meat, and to a lesser extent and consistency with red meat in general.51, 52, 53 In the current study, there was only an association between processed meat per se with IR, but not with NAFLD, perhaps because of a relatively low consumption in this study population.
 
The mechanisms by which meat intake is related to NAFLD are unknown. It can be claimed that the harmful association with meat may, at least partially, be related to a generally less healthy diet or lifestyle characterizing people who eat more red or processed meat, rather than a causal effect of meat. However, in the current study we meticulously adjusted the association with meat for other nutritional and lifestyle parameters to minimize confounding as much as possible. Indeed, there are several plausible mechanisms that can explain the observed associations, including a role for; SFA and cholesterol, AGEs, sodium, nitrates/nitrites and heme-iron, based on data from clinical trials and animal models.8, 9, 10, 11, 12 Several epidemiological studies demonstrated a positive association between high SFA intake and risk of diabetes mellitus or IR.54, 55, 56 In addition, intervention studies showed that a high SFA diet leads to reduced insulin sensitivity57, 58 and, in fact, SFA ingestion rapidly increases hepatic lipid storage and IR.8 However, in this study, the full multivariate analysis adjusted for SFA and cholesterol intake, indicating a sustainable association of meat with NAFLD and IR, beyond the potential mediating effect of these dietary fats. Iron causes cellular oxidative stress which decreases insulin action,59 and in a meta-analysis heme-iron intake was associated with 30% higher risk of diabetes.60 High levels of sodium, that are about 400% higher in processed meats,36 may also play a role since salt intake was suggested to be associated with increased risk of NAFLD.13 Processed meat also contains an average of about 50% more nitrates than unprocessed red meat.49 Nitrites and nitrates used in the preservation of processed meat are converted into nitrosamines, which are related to IR and diabetes in animal studies.12
 
Regarding the cooking method, exposure to dry heat and high temperature can generate high levels of both HCAs and AGEs in meat.7, 23, 24, 61 Because of the involvement of myoglobin in the formation of AGEs, red meat and particularly processed red meat have the highest AGEs content.12 Indeed, when compared to simple steatosis and controls, serum AGEs have been demonstrated to be related with non-alcoholic steatohepatitis (NASH), and to positively correlate with IR and negatively with adiponectin.14 In addition, lowering dietary AGEs by mild steam cooking instead of high-temperature cooking lowers IR in healthy people.61 In contrast to AGEs, the role of HCAs in NAFLD formation was never tested and should be explored. Potential mechanisms for NAFLD may be related to the formation of reactive species during HCA metabolism, which can cause oxidation of lipids, proteins and nucleic acids, resulting in oxidative stress, cell damage and loss of biological function.27 HCAs were also demonstrated to be bioactive in adipocytes in vitro, leading to increased expression of genes related to inflammation, diabetes and cancer risk.62
 
In view of the evidence-based harmful effect of red and processed meat, the dietary guidelines for cardiometabolic health limit the recommended intake of unprocessed red meats to no more than 1-2 servings/week of 100 g, and of processed meats to no more than 1 serving/week of 50 g.16 In agreement with these recommendations, in our study, one portion of meat translates to about 100 g, meaning that a weekly consumption of more than two servings (of 100 g) of red and/or processed meat is associated with NAFLD and IR and a weekly consumption of more than one portion of processed meat (of 50 g) tends to be associated with IR. Although the specific effect of different types of meat and their quantities in NAFLD requires further research, these recommendations may be helpful in the treatment of patients with NAFLD at least in terms of CVD and diabetes prevention, and maybe for NAFLD prevention by reducing IR.
 
This study has several limitations. Firstly, the cross-sectional design of the study does not allow causal inference. Secondly, meat consumption was self-reported and thus prone to reporting bias. However, since the participants and the research team were blinded to the AUS and blood tests results, it is a non-differential reporting bias and therefore it may have only weakened the observed associations. Thirdly, NAFLD was determined non-invasively as appropriate for a general population study. However, ultrasonography, in contrast to liver biopsy, did not enable us to study the association between meat consumption and NASH. With regard to NAFLD detection, AUS was performed in all individuals using the same equipment and by the same experienced radiologist across all levels of meat consumption, meaning that this potential non-differential bias can only weaken the observed associations. Lastly, nutritional data has been collected within a single country, which may impact on the generalizability across populations with differing dietary patterns.
 
In conclusion, high meat consumption in general, and specifically high red and processed meat consumption, are independently associated with NAFLD and IR, regardless of saturated fat intake. In addition, high consumption of meat cooked by unhealthy methods and high HCA intake are independently associated with IR and thus may have a role in the pathogenesis of NAFLD.

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Introduction
Non-alcoholic Fatty liver disease (NAFLD) is becoming a major global health burden in both developed and developing countries.1 NAFLD is considered as the hepatic component of the metabolic syndrome, with insulin resistance (IR) as the key factor in its pathophysiology.2 Unhealthy Western lifestyle plays a major role in the development and progression of NAFLD,3 namely, lack of physical activity and high consumption of fructose and saturated fat.4, 5 There are other common foods in the Western diet, namely red and processed meats, which may also increase the risk for NAFLD.6 Meat in general contains valuable nutrients for human health including protein, iron, zinc and vitamin B12.7 However, meat also contains saturated fatty acids (SFA) and cholesterol, both harmful for patients with NAFLD,8, 9, 10, 11 as well as other potentially harmful compounds such as heme-iron,12 sodium,13 other preservatives12 and advanced glycation end products (AGEs).12, 14 Indeed, high meat consumption has been demonstrated to be associated with IR and type 2 diabetes,15, 16, 17 the metabolic syndrome17 and oxidative stress.18 More specifically, red meat has been shown to be associated with a higher risk of mortality, owing to chronic liver disease and hepatocellular carcinoma.19 The association between meat consumption and NAFLD was demonstrated in a few studies,5, 6, 20, 21 in which meat type and cooking method were not fully addressed. We have previously demonstrated an independent association between high meat consumption and NAFLD,20 with no distinction between meat types or cooking methods, because of a small sample size and lack of information on the cooking methods in the standard food frequency questionnaire (FFQ).
 
Meat cooking methods have clinical significance, as unfavorable heterocyclic amines (HCAs) may be formed during cooking,22 as a result of the interaction between creatine, amino acids and sugars, especially in protein-rich foods cooked under dry conditions, high temperature (above 150 C) and prolonged cooking time.5, 7, 23, 24 The quantity of HCAs in cooked meat is affected by meat type, cooking method, cooking time and temperature.23, 25 In general, frying, broiling and grilling are methods that produce a greater quantity of HCAs.25 These compounds have been extensively demonstrated to be associated with some types of cancer.23 A positive association between HCA intake and increased oxidative stress has been demonstrated in vitro26 and in human studies, implying that it may consequently increase the risk of chronic diseases.27 However, human studies testing the association of dietary HCAs with IR and NAFLD are lacking. Therefore, the current study aimed to assess the independent association of meat type, cooking method and HCA intake with NAFLD and IR in a large well characterized general population sample.
 
Results
 
Description of the study population and comparison between high and low (by median) meat eaters

Out of 970 individuals who participated in the study, 933 completed all tests (i.e. blood test and AUS), 18 were excluded because of viral liver disease and five because of alcohol abuse. Individuals with unreasonable reported caloric intake29 were excluded (57 women and 64 men). Finally, 789 individuals were included in the main analysis, and of those, a sub-sample of 357 completed the meat questionnaire (Fig. 1).
 
In the entire sample, 52.60% were men, the proportion of participants with type 2 diabetes was 14.8% (n = 117), mean age was 58.83 ± 6.58 years and mean body mass index (BMI) was 28.54 ± 5.43 kg/m2 (the meat questionnaire sub-sample had very similar characteristics). NAFLD was diagnosed in 38.70% of participants, and IR was diagnosed in 30.5% (34.2% and 28.5% in the meat questionnaire sub-sample, respectively). The proportion of red and white meat intake was about 1/3 and 2/3 respectively, which are similar to the usual intake of the Israeli population (OECD data: https://data.oecd.org/agroutput/meat-consumption.htm). High meat eaters were slightly younger, were more likely to be men, had a higher BMI and caloric intake, as well as a worse metabolic profile, including higher HOMA-IR, serum uric acid and lipids. The prevalence of NAFLD was higher among the high meat eaters, supported by higher mean levels of HRI, as well as higher alanine aminotransferase (ALT) and Gamma-glutamyl transferase (GGT) serum levels. High meat eaters did not have significantly worse lifestyle habits, with similar levels of physical activity, smoking and sugared drink consumption, but had slightly higher alcohol consumption within the range of adequate intake, and as expected, higher consumption of saturated fat and cholesterol which were adjusted for in the multivariate analysis as potential confounding or mediating factors (Table 1).
 
Multivariate analysis of the association between meat subtypes consumption and NAFLD or IR
High total meat intake (above the median) was independently associated with higher odds for both NAFLD (OR 1.49; 95% CI 1.05-2.13; p = 0.028) and IR (OR 1.63; 95% CI 1.12-2.37; p = 0.011), adjusting for potential confounders (Table 2). Similarly, high red and/or processed meat (joint categories) intake was independently associated with higher odds for both NAFLD (OR 1.47; 95% CI 1.04-2.09; p = 0.031) and IR (OR 1.55; 95% CI 1.07-2.23; p = 0.020), adjusting for potential confounders (Table 2). High processed meat intake did not remain significantly associated with IR or with NAFLD in the fully adjusted model (Table 2). Further adjustment of the association between high red and/or processed meat and NAFLD for type 2 diabetes did not change the results (OR 1.45; 95% CI 1.01-2.07; p = 0.042).

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