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The effect of TCF7L2 polymorphisms on inflammatory markers after 16weeks of legume-based dietary approach to stop hypertension (DASH) diet versus a standard DASH diet: a randomised controlled trial

The effect of TCF7L2 polymorphisms on inflammatory markers after 16weeks of legume-based dietary... Backgrounds: This randomized controlled trial aimed to investigate the effects of replacing red meat with legumes in the dietary approach to stop hypertension (DASH) diet on inflammatory markers over 16 weeks in overweight and obese individuals with type 2 diabetes. Also, the modulatory effects of TCF7L2 rs7903146 variant on this effect were assessed. Methods: In this trial, 300 participants with type 2 diabetes, aged 30–65 years with an identified TCF7L2 rs7903146 genotype, were studied. The participants were randomly assigned to the DASH diet or the legume‑based DASH diet over 16 weeks. In the DASH diet group, the participants were instructed to follow the standard DASH diet. The legume‑based DASH diet was similar to the standard DASH diet, with the exception that one serving of red meat was replaced with one serving of legumes at least five days a week. At the beginning of the study and 16‑ week follow‑up, venous blood samples were collected from all participants who fasted for 12–14 h overnight. The serum concentration of High‑sensitivity C‑reactive protein (hs‑ CRP), tumor necrosis factor‑α ( TNF‑α) and interleukin‑6 (IL ‑6) was measured using an enzyme‑linked immunosorbent assay (ELISA) kit. Also, the serum malondialdehyde (MDA) concentration was assessed based on a colorimetric method using a commercial kit. The primary outcome was the difference in hs‑ CRP changes between the diets. A secondary outcomes was the difference in IL ‑6, TNF‑α, and MDA between the groups among total population and based on TCF7L2 rs7903146 risk allele (CT + TT ) and non‑risk allele (CC) separately. Results: The hs‑ CRP level reduced in the legume‑based DASH diet group as compared to the DASH diet group in the 16‑ week follow‑up group. The levels of TNF‑α, IL ‑6, and MDA reduced after the legume ‑based DASH diet relative to the DASH diet. Reduction of inflammatory markers was observed in both carriers of rs7903146 risk allele and non‑risk allele. *Correspondence: mirmiran@endocrine.ac.ir Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, No. 24, A’rabi St., Yeman Av., Velenjak, Tehran 19395‑4763, Iran Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 2 of 10 Conclusions: Substituting one serving of red meat with one serving of legumes in DASH diet, at least five days a week, could improve the hs‑ CRP, TNF‑α, IL ‑6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non‑risk allele. Trial registration IRCT, IRCT20090203001640N17. Keywords: Legumes, Type 2 diabetes, Inflammatory markers, Oxidative stress Introduction common comorbidity [22, 23]. Although the associa- Type 2 diabetes is a cause of long-term micro- and mac- tion between insulin resistance and abnormal secre- rovascular complications [1]. These vascular complica - tion of inflammatory markers is well established [24, tions are the main morbidities in individuals with type 25], the effect of TCF7L2 gene on inflammatory mark - 2 diabetes [2]. Despite the focus on the management of ers and also the effect of interaction between environ - conventional cardiovascular risk factors, such as dyslipi- mental factors and this gene on inflammatory markers demia, hypertension, and dysglycemia to prevent mor- have been less investigated [26, 27]. Some studies docu- bidity and mortality in these patients, inflammation plays mented that TCF7L2 gene did not modify the effect of an important role in the development and progression of medications, such as fenofibrate, or diets rich in func - these disorders [3]. High-sensitivity C-reactive protein tional foods on inflammatory biomarkers [26, 28]. (hs-CRP), as a markers of inflammation, is independently Considering the conflicting evidence on the effect of associated with cardiovascular disease (CVD) and its red meat consumption on inflammation, besides the risk factors [4, 5]. Reduction of hs-CRP leads to the risk limited number of studies on the modulatory effect of reduction of micro- and macrovascular complications TCF7L2 rs7903146 polymorphism on the relationship and decreases the mortality of CVD in patients with type between diet and inflammation, the primary outcome 2 diabetes [3, 6]. of this randomized controlled trial was to investigate The most common strategy for the management of the effect of replacing red meat with legumes in the inflammation in type 2 diabetes is a healthy diet [7]. One Dietary Approach to Stop Hypertension (DASH) diet of the most challenging aspects of dietary modification on hs-CRP over 16 weeks in overweight and obese indi- for the prevention and management of cardiovascu- vidual with type 2 diabetes. The secondary outcome of lar risk factors, such as inflammation, is the selection of this study was to assess the effect of substituting red protein sources. Red meat is a major source of protein in meat with legumes on other inflammatory markers, most diets. However, the effect of red meat consumption such as tumor necrosis factor-α (TNF-α) and inter- on inflammation is ambiguous. Epidemiological studies leukin-6 (IL-6), and oxidative stress markers including have reported a positive association between red meat malondialdehyde (MDA). Another secondary outcome consumption and dietary patterns rich in red meat and of this study was assessment of the effect of including inflammation and oxidative stress [8–12]. On the other legumes in the DASH diet on inflammatory biomarkers hand, substituting red meat with alternative protein food in TCF7L2 rs7903146 risk allele (CT + TT) and non- sources (i.e., poultry, fish, legumes, or nuts) seems to risk allele (CC) carriers separately. have beneficial effects on the cardiometabolic risk factors [8]. However, there is no clear evidence on the beneficial effects of reducing red meat consumption and replac - Materials and methods ing red meat with other protein sources in clinical trials This randomized controlled trial was registered in the [13–18]. Iranian Registry of Clinical Trials (Trial registration: The effect of genetic factors on the risk of diabetes is IRCT, IRCT20090203001640N17. Registered 20 may estimated at 30–70% [19]. Transcription factor 7-like 2 2020, https:// en. irct. ir/ trial/ 46855). Ethical approval (TCF7L2) gene  rs7903146 polymorphism is a common was obtained from the Ethics Committee of Research type 2 diabetes-associated variant [20]. This polymor - Institute for Endocrine Sciences of Shahid Beheshti phism has been also associated with the progression of University of Medical Sciences, Tehran, Iran (No. common complications of type 2 diabetes, especially IR.SBMU.ENDOCRINE.REC.1399.001). All partici- CVD [21]. Impairment of hepatic insulin sensitivity and pants provided written informed consent forms before induction of insulin resistance are among molecular recruitment. According to the principles of the Dec- mechanisms through which TCF7L2 rs7903146 vari- laration of Helsinki, the study procedures, purpose, ant increases the risk of type 2 diabetes and its most and adverse events were explained to each participant (written and orally). Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 3 of 10 Participants, randomization, and allocation concealment subject’s allocation to treatment was concealed from all This randomized controlled trial was conducted in the staff members and the principal investigator; they were framework of Tehran Lipid and Glucose Study (TLGS). only opened sequentially by the dietitian in the presence The TLGS is a large long-term community-based pro - of eligible participants in the first visit. spective study being conducted on a representative sam- ple of residents from district No. 13 of Tehran, Iran. The Blinding population of this district represents the urban popula- In the nutritional interventions, blinding of the par- tion of Tehran. The details of this study are described ticipants was practically impossible. However, the elsewhere [29]. Briefly, the first examination was initi - participants were unaware of their assignment to the ated in March 1999. Using multistage stratified clus - intervention groups before enrolment. Individuals who ter random sampling, more than 15,000 individuals, assessed the outcomes, including laboratory techni- aged ≥ 3  years, were enrolled. Overall, since 1999, the cians and staff members, were blind to the participants’ TLGS participants have undergone assessments for soci- assignment, and dietary interventions were provided by odemographic factors, lifestyle, medication use, socio- a dietitian. economic status, anthropometric indices, and medical history of cardiovascular risk factors. The information is Dietary interventions documented every three years in face-to-face visits by the First, 307 individuals participated in a two-week run-in local research team to update the previous data. Phases period when they consumed their usual diet while elimi- II, III, IV, V, and VI of this study were prospective follow- nating the legume intake. In the run-in period, seven par- ups conducted during 2002–2004, 2005–2008, 2008– ticipants were unwilling to continue the study and were 2011, 2012–2015, and 2016–2018, respectively. excluded. At the end of the run-in period, 300 partici- Of 10,927 individuals participating in phase VI of the pants, stratified based on risk and non-risk alleles, were TLGS study, TCF7L2 rs7903146 genotype was ran- randomly assigned to the DASH diet group or legume- domly determined in 8399 participants. Of these, 662 based DASH diet group over 16 weeks. participants, aged 30–65  years, had type 2 diabetes The participants’ energy requirements were esti - with available information on TCF7L2 rs7903146 geno- mated from the resting energy expenditure, based on type (CC genotype, n = 240; TT genotype, n = 128, the Mifflin-St Jeor formula and multiplied by the physi - and CT genotype, n = 294). The criteria  for  diagnos - cal activity coefficient [30]. Because the participants were ing  diabetes  included a fasting plasma glucose (FPG) overweight and obese, 500–700  kcal/d was deducted level ≥ 126  mg/dL, two-hour plasma glucose ≥ 200  mg/ from their energy requirements. Based on each partici- dL, or using antihyperglycemic medications. Other pant’s energy requirement, the dietitian determined the inclusion criteria were being overweight or obese (BMI: diet, which contained approximately 25–30% fat, 15% 25–40  kg/m ); no weight changes in the last three protein, and 55–60% carbohydrate. In the DASH diet months before enrollment; consumption of red meat ≥ 1 group, the participants were instructed to follow the serving/d; and willingness to consume legumes in the DASH diet (2000–3000  kcal based on the participant’s diet. On the other hand, participants with pregnancy or energy requirement), composed of 8–12 servings/day of lactation, cardiac, hepatic, or renal impairment (creati- fruits and vegetables, 7–15 servings of whole grains, 2–3 nine ≥ 1.4  mg/dL in men and ≥ 1.3  mg/dL in women), servings of low-fat dairy products, two servings of red and insulin use were excluded. meat, one serving of nuts and seeds, and limited intake of Randomization was carried out to generate the ran- sweets (five servings per week). The legume-based DASH domization sequence using the randomization website diet was similar to the standard DASH diet, with the (www. rando mizat ion. com). The randomization sequence exception that one serving of red meat was replaced with was separately generated for participants with TCF7L2 one serving of legumes at least five days a week. Also, rs7903146 risk allele (CT + TT) and non-risk allele (CC). because legumes are equivalent to one serving of whole Among participants eligible for this study, we selected grains, one serving of bread was also deducted from the 150 participants with genotype CC and 150 participants legume-based DASH diet. In both diets, the participants with genotype TT + CT and assigned them separately were advised to consume less than or equal to one tea- and randomly (1:1 ratio) to either the DASH diet group spoon of salt per day (2300 mg/d). or the legume-based DASH diet group. The recruitment To evaluate the participants’ adherence to the inter- of participants is shown in Fig. 1. ventions, the dietitian instructed them to record their The participants were randomly assigned to receive one daily dietary intake using a three-day food record (two of the two diets by a member of the TLGS staff. Using weekdays and one  weekend  day) every weeks. The dieti - sealed and sequentially numbered opaque envelopes, the tian called the participants every week to gather their Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 4 of 10 Fig. 1 Flowchart for the participants dietary information, compared their information with rs7903146 risk allele (CT + TT) and non-risk allele (CC) the instructed diet, and reinforced their diet adherence. separately. The intake of macro- and micronutrients was also calcu - lated using NUTRITIONIST III Version 7.0 (N-Squared Computing, Salem, OR, USA), designed for Iranian Measurements foods. All participants were requested to maintain their Weight was measured using a digital scale (Seca 707; physical activity and not to change their medications range: 0–150  kg; Seca GmbH, Germany), with mini- during the 16-week interventions unless prescribed by mal clothing and without shoes; it was recorded to the their physicians. nearest 100  g. Height was also measured in a standing position, with shoulders in neutral alignment using a stadiometer (Seca 225; Seca GmbH, Germany) without shoes and recorded to the nearest 0.5 cm. The body mass Primary and secondary outcomes index (BMI) was calculated by dividing weight in kilo The primary outcome of this study was the difference in - hs-CRP change from baseline to week 16 of follow-up grams by height in meters squared. between the groups. The secondary outcome was the dif - At the beginning of the study and 16-week follow-up ference in IL-6, TNF-α, and MDA changes between the (between 7∶00 a.m. and 9∶00 a.m.), venous blood sam- groups. Another secondary outcome was assessment of ples were collected from all participants who fasted for changes in the inflammatory markers, based on TCF7L2 12–14  h overnight. The blood samples were placed in Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 5 of 10 vacutainer tubes, centrifuged within 30–45 min of collec- Differences in the changes of outcomes between the tion, and stored in a − 80 °C freezer. The serum concen - two diets in the total population and also with respect tration of hs-CRP was measured using an enzyme-linked to the TCF7L2 rs7903146 risk allele (CT + TT) and immunosorbent assay (ELISA) kit (ZellBio, Germany). non-risk allele (CC) were compared using the analysis To analyze the concentrations of TNF-α and IL-6, of covariance (ANCOVA). Model 1 was adjusted for ELISA assay was performed using a commercial kit the baseline values, and model 2 was further adjusted (Diaclone, France). Also, the serum MDA concentra- for oral antihyperglycemic Medications. The gene-diet tion was assessed based on a colorimetric method using interaction was analyzed by an ANCOVA multivariate a commercial kit (ZellBio GmbH, Ulm, Germany). The interaction model, and P-value < 0.2 indicated the sig- intra-assay coefficients of variation (CVs) for the serum nificant effect of gene-diet interaction on the outcomes. hs-CRP, IL-6, TNF-α, and MDA were 2.7%, 8.1%, 6.3%, The Benjamini–Hochberg correction method for mul - and 3.3%, respectively. tiple testing yielded critical P-values of < 0.1 for the Genomic DNA was extracted from the buffy coat of secondary outcome comparisons. Cohen’s d for effect samples, using a standard salting out method with pro- size (0.20, 0.50, and 0.80 interpreted as small, medium, teinase K. The quality of extracted DNA was determined and large treatment effects, respectively) was also cal - using the NanoDrop 1000 Spectrophotometer. Samples culated based on mean and SD [33]. All analyses were in the range of 1.7 < A260/A280 < 2 were excluded due performed in Stata Version 14.0 (StataCorp LLC, TX, to low quality and concentration. DNA samples were USA). processed on a HumanOmniExpress-24-v1-0 BeadChip (containing 649,932 SNP loci with an average mean dis- tance of 4 kb) at deCODE Genetics Company (Reykjavik, Results Iceland), according to the manufacturer’s instructions This trial was carried out between July 11, 2020 and (Illumina Inc., San Diego, CA, USA). Quality control pro- March 10, 2021. Of 563 participants screened for eligi- cedures were also performed using PLINK V. 1.07 and R bility, 300 were randomly allocated to the diet groups. Statistic V. 3.2 [31]. Sixteen participants withdrew from the study, and finally, 284 individuals completed the study (Fig.  1). The mean age and BMI of the participants were 55.4  years Assessment of other variables (SD = 7.0) and 30.4 kg/m (SD = 3.4), respectively (42.9% Medication regimen (e.g., antihypertensive, lipid-lower- female and 48.7% obese). No significant differences ing, and anti-diabetes drugs and others) and supplement were found in the baseline variables, except for the use intake were collected. Physical activity was also assessed of oral antihyperglycemic Medications, between the two using the Modifiable Activity Questionnaire (MAQ), and groups in the total population and also among rs7903146 the frequency and amount of time spent per week on risk allele (CT + TT) and non-risk allele (CC) carriers physical activity over the last year were recorded. (Table  1). Compared to the DASH diet, metformin was more commonly used for the legume-based DASH diet Statistical analysis group (46.0 vs. 36.7), while participants in the DASH diet The target sample size was measured to be 150 in each group were more treated with metformin plus sulfonylu- intervention group to detect a difference of 1  mg/dl rea (20.7 vs. 30.0). Among carriers of rs7903146 non-risk reduction in hs-CRP [32] between the two diets in the allele, metformin and metformin plus thiazolidinedione total population by assuming an α error of 0.05, a β error was used slightly more often for participants in the leg- of 0.20, power of 80%, and an attrition rate of 20%. ume-based DASH diet group, while the DASH diet group Through visual inspection of the histograms, scatter was treated more with sulfonylurea, and metformin plus plots, and Shapiro–Wilk test, the normal distribution sulfonylurea. Metformin was slightly more often used of data was assessed. Normal variables are presented as for the carriers of rs7903146 T allele in the legume- mean ± SD for demographic variables and mean ± SEM based DASH diet group, while the DASH diet group was for dietary variables. Skewed variables are also presented treated more with metformin plus sulfonylurea. as median (interquartile range) and dichotomous vari- Analysis of the subjects’ food records showed that com- ables as count (percentage). Analyses were performed pared to the DASH diet, the intake of legumes and fiber according to the per-protocol and intention-to-treat was higher, while the intake of red meat and cholesterol principles. Multiple imputation by chained equations was lower in the legume-based DASH diet group. No sig- method was also applied to impute the primary and sec- nificant difference was found regarding the total energy ondary missing outcomes. In this method, the predic- requirements, macronutrients, and dietary food groups tors included all variables presented in Table  1, TCF7L2 between the groups (Additional file 1: Table 1). rs7903146 variant, and intervention diets. Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 6 of 10 Table 1 Baseline characteristic of participants according to group of intervention diets and TCF7L2 rs7903146 gene variant Total population CC genotypes TT + CT genotypes DASH diet Legume-based DASH diet Legume-based DASH diet Legume- DASH diet DASH diet based DASH diet Participants, n 150 150 75 75 75 75 Age, years 55.5 (6.9) 55.4 (7.1) 55.1 (6.7) 55.2 (8.1) 55.6 (7.1) 55.5 (6.1) Female, n (%) 85 (56.3) 86 (57.7) 42 (56.0) 45 (60.0) 43 (56.6) 41 (55.4) hsCRP, mg/dl 3.6 (1.9–5.0) 3.7 (2.1–5.0) 3.6 (2.1–5.4) 3.7 (1.9–4.8) 3.5 (1.9–4.6) 3.8 (2.1–5.2) MDA, µM 5.1 (3.7–7.7) 5.0 (3.6–8.3) 5.0 (3.7–7.6) 5.1 (3.4–8.3) 5.1 (3.4–8.3) 4.8 (3.6–7.9) TNF‑α, pg/ml 13.0 (11.2–15.9) 11.4 (9.8–15.8) 11.4 (9.8–13.4) 11.4 (9.8–13.4) 15.2 (12.6–17.9) 11.4 (9.9–16.5) IL‑6, pg/ml 4.3 (3.7–5.4) 3.8 (3.5–4.6) 3.9 (3.6–5.2) 3.7 (3.4–4.7) 4.5 (4.1–5.7) 3.9 (3.5–4.6) Obese, n (%) 72 (48.0) 74 (49.3) 42 (56.0) 41 (54.7) 30 (40.0) 33 (44.0) Physical activity levels, Met h/week 3.5 (2.7) 3.3 (2.7) 3.6 (2.8) 3.4 (2.3) 3.3 (2.6) 3.4 (3.0) Academic degree, n (%) 18 (11.9) 22 (14.8) 6 (8.0) 6 (8.0) 12 (15.8) 16 (21.6) Medication Antihyperglycemic Medications Metformin, n (%) 55 (36.7) 69 (46.0) 32 (42.7) 39 (52.0) 23 (30.7) 30 (40.0) Sulfonylurea, n (%) 40 (26.5) 29 (19.3) 21 (28.0) 14 (18.7) 19 (25.3) 15 (20.0) Metformin + sulfonylurea, n (%) 45 (30.0) 31 (20.7) 20 (26.7) 13 (17.3) 25 (33.3) 18 (24.0) Metformin + thiazolidinedione, n (%) 5 (3.3) 11 (7.3) 2 (2.7) 9 (12.0) 3 (4.0) 2 (2.7) Others, n (%) 5 (3.3) 10 (6.7) 0 (0) 0 (0) 5 (6.7) 10 (13.3) Lipid lowering drugs Statin use, n (%) 86 (57.0) 84 (56.4) 47 (62.7) 42 (56.0) 39 (51.3) 43 (57.3) Others, n (%) 1 (0.7) 4 (2.7) 0 (0.0) 2 (2.7) 1 (1.3) 2 (2.7) Antihypertensive drugs ACE inhibitor/ARB use, n (%) 52 (34.7) 48 (32.0) 28 (37.3) 26 (34.7) 24 (32.0) 22 (29.3) Thiazide, n (%) 7 (4.7) 2 (1.3) 3 (4.0) 1 (1.3) 4 (5.3) 1 (1.3) Others, n (%) 10 (6.7) 8 (5.3) 8 (10.7) 4 (5.3) 2 (2.7) 4 (5.3) Asprin n (%) 28 (18.7) 28 (18.7) 11 (14.6) 13 (17.3) 17 (22.7) 15 (20.0) Supplement Vitamin E 1 (0.7) 0 (0%) 0 (0%) 0 (0%) 1 (1.3%) 0 (0%) Vitamin D 32 (21.3) 34 (22.7) 17 (22.7) 18 (24.0) 15 (20.0) 16 (21.3) Vitamin B complex 17 (11.3) 15 (10.0) 7 (9.3) 9 (12.0) 10 (13.3) 6 (8.0) W‑3 PUFA fatty acids 4 (2.7) 3 (2.0) 3 (4.0) 0 (0.0) 1 (1.3) 3 (4.0) Obese BMI ≥ 30 kg/m2 Data are mean (SD) or median (interquartile range) unless otherwise indicated Primary outcome Secondary outcomes The ITT and completer analyses yielded similar findings After adjustments for the baseline variables and oral (Additional file  1: Table  2); therefore, only the ITT find - antihyperglycemic Medications, TNF-α (−  0.77  pg/mL ings are reported. The hs-CRP level was reduced at week [−  1.24 to −  0.29] in the DASH diet vs. -2.04  pg/mL 16 in the legume-based DASH diet group compared [− 2.51 to − 1.56] in the legume-based DASH diet), IL-6 to the DASH diet group (mean difference of change: (−  0.51  pg/mL [−  0.68 to −  0.34] in the DASH diet vs. -0.58  mg/dL [−  0.78 to −  0.39] in the DASH diet group −  0.95  pg/mL [−  1.12 to −  0.78] in the legume-based vs. − 1.20 mg/dL [− 1.39 to −1.01] in the legume-based DASH diet), and MDA (− 1.02 µM [− 1.27 to − 0.77] in DASH diet group; Cohen’s d = 0.41 [0.64–0.18]) after the DASH diet vs. −  1.64  µM [−  1.89 to −  1.39] in the adjustment for the baseline values and oral antihyper- legume-based DASH diet) reduced after the legume- glycemic Medications (model 2). This reduction was based DASH diet intervention compared to the DASH observed in both carriers of rs7903146 risk allele and diet; this reduction was observed in both risk allele and non-risk allele (Table 2). non-risk allele carriers. However, BMI did not change Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 7 of 10 Table 2 The 16 week change in inflammatory and oxidative stress markers and anthropometric measures after the DASH diet and legume based DASH diet according to TCF7L2 rs7903146 gene variant Total population CC genotype CT + T T genotype DASH diet Legume-based P value q value DASH diet Legume-based P value q value DASH diet Legume-based P value q value P i DASH diet DASH diet DASH diet Primary outcome hsCRP (mg/dl) Model 1 − 0.57 − 1.22 < 0.001 − 0.51 − 1.08 0.001 − 0.65 − 1.33 0.002 0.421 (− 0.76 to − 0.38) (− 1.40 to − 1.02) (− 0.87 to − 0.15) (− 1.27 to − 0.88) (− 0.95 to − 0.34) (− 1.53 to − 1.14) Model 2 − 0.58 − 1.20 < 0001 − 0.51 − 1.08 0.002 − 0.65 − 1.34 0.002 0.237 (− 0.78 to − 0.39) (− 1.39 to − 1.01) (− 0.87 to − 0.15) (− 1.28 to − 0.88) (− 0.95 to − 0.35) (− 1.52 to − 1.15) Secondary outcomes MDA (µM) Model 1 − 1.03 − 1.64 < 0.001 0.016 − 0.91 − 1.58 0.016 0.040 − 1.11 − 1.73 0.021 0.040 0.455 (− 1.28 to − 0.78) (− 1.88 to − 1.38) (− 1.24 to − 0.58) (− 1.97 to − 1.18) (− 1.43 to − 0.81) (− 2.11 to − 1.35) Model 2 − 1.02 − 1.64 < 0.001 0.016 − 0.91 − 1.58 0.016 0.040 − 1.11 − 1.73 0.023 0.040 0.573 (− 1.27 to − 0.77) (− 1.89 to − 1.39) (− 1.24 to − 0.58) (− 1.97 to − 1.18) (− 1.43 to − 0.80) (− 2.11 to − 1.35) TNF− α (pg/ml) Model 1 − 0.76 − 2.04 < 0.001 0.016 − 0.68 − 1.78 0.010 0.038 − 0.87 − 2.27 0.006 0.032 0.593 (− 1.23 to − 0.29) (− 2.51 to − 1.57) (− 1.28 to − 0.08) (− 2.41 to − 1.16) (− 1.63 to − 0.11) (− 2.97 to − 1.58) Model 2 − 0.77 − 2.04 < 0.001 0.016 − 0.68 − 1.78 0.010 0.038 − 0.87 − 2.28 0.012 0.038 0.496 (− 1.24 to − 0.29) (− 2.51 to − 1.56) (− 1.45 to − 0.08) (− 2.42 to − 1.14) (− 1.60 to − 0.14) (− 2.98 to − 1.57) IL− 6 (pg/ml) Model 1 − 0.53 − 0.93 0.001 0.016 − 0.52 − 0.82 0.028 0.044 − 0.52 − 1.06 0.019 0.041 0.753 (− 0.70 to − 0.36) (− 1.10 to − 0.76) (− 0.68 to − 0.36) (− 1.05 to − 0.58) (− 0.82 to − 0.22) (− 1.28 to − 0.85) Model 2 − 0.51 − 0.95 0.004 0.032 − 0.52 − 0.81 0.012 0.038 − 0.52 − 1.06 0.019 0.040 0.793 (− 0.68 to − 0.34) (− 1.12 to − 0.78) (− 0.68 to − 0.36) (− 1.04 to − 0.58) (− 0.82 to − 0.22) (− 1.28 to − 0.85) BMI (kg/m ) Model 1 − 1.48 − 1.57 0.287 0.382 − 1.41 − 1.56 0.238 0.346 − 1.54 − 1.58 0.709 0.756 0.617 (− 1.60 to − 1.36) (− 1.69 to − 1.45) (− 1.59 to − 1.23) (− 1.73 to − 1.39) (− 1.67 to − 1.42) (− 1.79 to − 1.37) Model 2 − 1.49 − 1.56 0.424 0.492 − 1.41 − 1.56 0.431 0.492 − 1.54 − 1.58 0.859 0.859 0.859 (− 1.61 to − 1.37) (− 1.68 to − 1.44) (− 1.59 to − 1.23) (− 1.73 to − 1.39) (− 1.67 to − 1.42) (− 1.79 to − 1.37) DASH, dietary approach to stop hypertension; FPG, fasting plasma glucose; WC, waist circumference; HOMAIR, homeostatic model assessment for insulin resistance; Pi, P for interaction between TCF7L2 rs7903146 gene variant and intervention diets Data for change in primary and secondary outcomes are express as mean (95% confidence interval) Model 1 adjusted for baseline values Model 2 adjusted for baseline values and oral anti diabetic medications P values were calculated by ANCOVA q value were calculated by Benjamini–Hochberg correction and Q < 0.2 is significant Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 8 of 10 significantly after adherence to the legume-based DASH [43]. Although the role of insulin resistance in induc- diet as compared to the DASH diet (Table 2). ing inflammation has been identified [25], the effect of TCF7L2 gene on inflammation has been less investigated Discussion [26, 27, 44]. There was no significant difference in the In this weight-loss interventional trial among individual inflammatory markers among TCF7L2 genotypes after with type 2 diabetes, the inflammatory and oxidative treatment with fenofibrate [26]. Also, dietary patterns stress status improved by replacing one serving of red rich in functional foods did not modify the effects on meat with legumes in the DASH diet at least five days CRP [28]. a week, regardless of having rs7903146 risk or non-risk Although few studies have examined the modulatory allele. effect of TCF7L2 rs7903146 variant on the relation - Generally, low-grade inflammation occurs in the insu - ship between diet and inflammation, some studies have lin resistance stage of type 2 diabetes. Therefore, identi - reported that the detrimental effects of TCF7L2 gene on fying dietary determinants that increase inflammation cardiometabolic risk factors may be improved by anti- and replacing them with dietary food groups that reduce inflammatory dietary patterns, such as the Mediterra - inflammation are important. In many observational stud - nean diet [45, 46]. The DASH dietary pattern is another ies, but not all [9, 13], a positive association has been anti-inflammatory diet. Although the beneficial effect of observed between biomarkers of inflammation and red DASH diet on the management of cardiovascular risk meat consumption or red meat-rich dietary patterns [8, factors, such as inflammation, has been documented 10–12]. Also, substitution of a serving of total red meat [47–49], to the best of our knowledge, no study has yet with high-quality plant protein sources, such as leg- investigated the effect of interaction between the DASH umes, was associated with lower CRP concentrations diet and TCF7L2 gene on these risk factors. [8]. However, there is no clear evidence on the effects of Previous studies, however, have assessed the interac- changes in red meat intake and replacement of red meat tion between the DASH diet and some genes, such as with other protein sources on inflammation biomarkers genetic predisposition to obesity, based on BMI-asso- in dietary interventions. Although substituting carbohy- ciated variants [50, 51], as well as MC4R rs17782313 drates with proteins in interventional studies has shown polymorphism [52] on cardiometabolic risk factors. In no effects on inflammatory markers [16, 17, 34, 35], the the Nurses’ Health Study and the Health Professionals results related to the substitution of red meat with other Follow-up Study, during a 20-year follow-up, the effect of protein sources are controversial. High-protein diets, interaction between adherence to DASH diet and genetic both animal and plant proteins, have been suggested to predisposition to obesity (based on 77 SNPs) on changes reduce inflammatory markers [18]. In a previous study, in body weight was reported [50]. The detrimental effect although replacement of pork with chicken and red of genetic predisposition on weight gain was reduced by meat did not change the CRP concentration [36], par- greater adherence to the DASH diet; this effect was more tial replacement of red meat with plant proteins, such pronounced among participants with a higher genetic as soy protein and legumes, improved the inflammatory risk of obesity [50]. In another study investigating three biomarkers [37, 38]. Moreover, replacement of red meat observational cohorts of US women and men, adherence with 30 g of soy was adequate in reducing the concentra- to the DASH diet accentuated the detrimental effects of tion of inflammatory markers in postmenopausal women the genetic risk score (GRS), based on 97 BMI-associated [38, 39]. In the current study, improvement of inflamma - variants, on BMI [51]. Also, in a cross-sectional study, tory markers was achieved by replacement of one serv- high adherence to the DASH diet modified the effect of ing of red meat with legumes at least five days a week; melanocortin-4 receptor (MC4R) rs17782313 polymor- this finding is consistent with previous clinical trials and phism on cardiometabolic risk factors, including tri- a systematic review and meta-analysis, documenting the glyceride concentration, blood pressure, and glucose health-promoting effects of legume intake, with a median concentration, especially among MC4R rs17782313 risk intake of 63  g/d to 150  g (~ 1½ servings/d) [37, 40–42]. allele carriers [52]. Nevertheless, in the current study, we This effect might be due to the higher consumption of did not find any effect of interaction between the diet and dietary fiber and low-glycemic-load carbohydrates in rs7903146 variant on inflammatory markers in individual diets with high-quality plant protein sources. with type 2 diabetes. Our findings must be examined in The TCF7L2 rs7903146 SNP is the most impor- other ethnic populations with different allele frequencies; tant genetic predictor of T2DM [20]. Disturbances in also, family-based investigations on a large sample size insulin sensitivity and induction of insulin resistance are needed. are among the molecular mechanisms through which Some limitations of the current study need to be TCF7L2 rs7903146 variant increases the risk of T2DM addressed. The assessment of adherence to dietary Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 9 of 10 Consent for publication interventions was based on self-report diet records, and Not applicable. because of our limited funding, we could not measure the biochemical index of adherence to dietary interventions. Competing interests On behalf of all authors, the corresponding author hereby declares that there Therefore, the dietitian called the participants once a is no conflict of interest. week and encouraged their adherence to the dietary rec- ommendations. Another limitation of this study was not Author details Nutrition and Endocrine Research Center, Research Institute for Endocrine blinding the participants to the study objectives, which Sciences, Shahid Beheshti University of Medical Sciences, No. 24, A’rabi St., might have affected the subjects’ behaviors. Finally, this Yeman Av., Velenjak, Tehran 19395‑4763, Iran. Prevention of Metabolic study was conducted in an area with a middle to high Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Cellular and Molecular socioeconomic status, and our findings cannot be extrap - Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti olated to individual with type 2 diabetes with a low socio- University of Medical Sciences, Tehran, Iran. Endocrine Research Center, economic status. Research Institute for Endocrine Sciences, Shahid Beheshti University of Medi‑ cal Sciences, Tehran, Iran. In conclusion, substituting one serving of red meat with one serving of legumes in DASH diet, at least five Received: 2 August 2021 Accepted: 2 May 2022 days a week, could improve the hs-CRP, TNF-α, IL-6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non-risk allele. References 1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Abbreviations Association of glycaemia with macrovascular and microvascular compli‑ hs‑ CRP: C‑reactive protein; CVD: Cardiovascular disease; TCF7L2: Transcription cations of type 2 diabetes (UKPDS 35): prospective observational study. factor 7‑like 2; DASH: Dietary approach to stop hypertension; TNF‑α: Tumor BMJ. 2000;321:405–12. necrosis factor‑α; IL ‑6: Interleukin‑6; MDA: Malondialdehyde; TLGS: Tehran Lipid 2. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al KJ. Epidemiol‑ and Glucose Study; ELISA: Enzyme‑linked immunosorbent assay; ANCOVA: ogy of type 2 diabetes—global burden of disease and forecasted trends. Analysis of covariance; MC4R: Melanocortin‑4 receptor. J Epidemiol Glob Health. 2020;10:107–11. 3. Ridker PM. Clinician’s guide to reducing inflammation to reduce atherothrombotic risk: JACC review topic of the week. J Am Coll Cardiol. Supplementary Information 2018;72:3320–31. The online version contains supplementary material available at https:// doi. 4. 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The effect of TCF7L2 polymorphisms on inflammatory markers after 16weeks of legume-based dietary approach to stop hypertension (DASH) diet versus a standard DASH diet: a randomised controlled trial

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Abstract

Backgrounds: This randomized controlled trial aimed to investigate the effects of replacing red meat with legumes in the dietary approach to stop hypertension (DASH) diet on inflammatory markers over 16 weeks in overweight and obese individuals with type 2 diabetes. Also, the modulatory effects of TCF7L2 rs7903146 variant on this effect were assessed. Methods: In this trial, 300 participants with type 2 diabetes, aged 30–65 years with an identified TCF7L2 rs7903146 genotype, were studied. The participants were randomly assigned to the DASH diet or the legume‑based DASH diet over 16 weeks. In the DASH diet group, the participants were instructed to follow the standard DASH diet. The legume‑based DASH diet was similar to the standard DASH diet, with the exception that one serving of red meat was replaced with one serving of legumes at least five days a week. At the beginning of the study and 16‑ week follow‑up, venous blood samples were collected from all participants who fasted for 12–14 h overnight. The serum concentration of High‑sensitivity C‑reactive protein (hs‑ CRP), tumor necrosis factor‑α ( TNF‑α) and interleukin‑6 (IL ‑6) was measured using an enzyme‑linked immunosorbent assay (ELISA) kit. Also, the serum malondialdehyde (MDA) concentration was assessed based on a colorimetric method using a commercial kit. The primary outcome was the difference in hs‑ CRP changes between the diets. A secondary outcomes was the difference in IL ‑6, TNF‑α, and MDA between the groups among total population and based on TCF7L2 rs7903146 risk allele (CT + TT ) and non‑risk allele (CC) separately. Results: The hs‑ CRP level reduced in the legume‑based DASH diet group as compared to the DASH diet group in the 16‑ week follow‑up group. The levels of TNF‑α, IL ‑6, and MDA reduced after the legume ‑based DASH diet relative to the DASH diet. Reduction of inflammatory markers was observed in both carriers of rs7903146 risk allele and non‑risk allele. *Correspondence: mirmiran@endocrine.ac.ir Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, No. 24, A’rabi St., Yeman Av., Velenjak, Tehran 19395‑4763, Iran Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 2 of 10 Conclusions: Substituting one serving of red meat with one serving of legumes in DASH diet, at least five days a week, could improve the hs‑ CRP, TNF‑α, IL ‑6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non‑risk allele. Trial registration IRCT, IRCT20090203001640N17. Keywords: Legumes, Type 2 diabetes, Inflammatory markers, Oxidative stress Introduction common comorbidity [22, 23]. Although the associa- Type 2 diabetes is a cause of long-term micro- and mac- tion between insulin resistance and abnormal secre- rovascular complications [1]. These vascular complica - tion of inflammatory markers is well established [24, tions are the main morbidities in individuals with type 25], the effect of TCF7L2 gene on inflammatory mark - 2 diabetes [2]. Despite the focus on the management of ers and also the effect of interaction between environ - conventional cardiovascular risk factors, such as dyslipi- mental factors and this gene on inflammatory markers demia, hypertension, and dysglycemia to prevent mor- have been less investigated [26, 27]. Some studies docu- bidity and mortality in these patients, inflammation plays mented that TCF7L2 gene did not modify the effect of an important role in the development and progression of medications, such as fenofibrate, or diets rich in func - these disorders [3]. High-sensitivity C-reactive protein tional foods on inflammatory biomarkers [26, 28]. (hs-CRP), as a markers of inflammation, is independently Considering the conflicting evidence on the effect of associated with cardiovascular disease (CVD) and its red meat consumption on inflammation, besides the risk factors [4, 5]. Reduction of hs-CRP leads to the risk limited number of studies on the modulatory effect of reduction of micro- and macrovascular complications TCF7L2 rs7903146 polymorphism on the relationship and decreases the mortality of CVD in patients with type between diet and inflammation, the primary outcome 2 diabetes [3, 6]. of this randomized controlled trial was to investigate The most common strategy for the management of the effect of replacing red meat with legumes in the inflammation in type 2 diabetes is a healthy diet [7]. One Dietary Approach to Stop Hypertension (DASH) diet of the most challenging aspects of dietary modification on hs-CRP over 16 weeks in overweight and obese indi- for the prevention and management of cardiovascu- vidual with type 2 diabetes. The secondary outcome of lar risk factors, such as inflammation, is the selection of this study was to assess the effect of substituting red protein sources. Red meat is a major source of protein in meat with legumes on other inflammatory markers, most diets. However, the effect of red meat consumption such as tumor necrosis factor-α (TNF-α) and inter- on inflammation is ambiguous. Epidemiological studies leukin-6 (IL-6), and oxidative stress markers including have reported a positive association between red meat malondialdehyde (MDA). Another secondary outcome consumption and dietary patterns rich in red meat and of this study was assessment of the effect of including inflammation and oxidative stress [8–12]. On the other legumes in the DASH diet on inflammatory biomarkers hand, substituting red meat with alternative protein food in TCF7L2 rs7903146 risk allele (CT + TT) and non- sources (i.e., poultry, fish, legumes, or nuts) seems to risk allele (CC) carriers separately. have beneficial effects on the cardiometabolic risk factors [8]. However, there is no clear evidence on the beneficial effects of reducing red meat consumption and replac - Materials and methods ing red meat with other protein sources in clinical trials This randomized controlled trial was registered in the [13–18]. Iranian Registry of Clinical Trials (Trial registration: The effect of genetic factors on the risk of diabetes is IRCT, IRCT20090203001640N17. Registered 20 may estimated at 30–70% [19]. Transcription factor 7-like 2 2020, https:// en. irct. ir/ trial/ 46855). Ethical approval (TCF7L2) gene  rs7903146 polymorphism is a common was obtained from the Ethics Committee of Research type 2 diabetes-associated variant [20]. This polymor - Institute for Endocrine Sciences of Shahid Beheshti phism has been also associated with the progression of University of Medical Sciences, Tehran, Iran (No. common complications of type 2 diabetes, especially IR.SBMU.ENDOCRINE.REC.1399.001). All partici- CVD [21]. Impairment of hepatic insulin sensitivity and pants provided written informed consent forms before induction of insulin resistance are among molecular recruitment. According to the principles of the Dec- mechanisms through which TCF7L2 rs7903146 vari- laration of Helsinki, the study procedures, purpose, ant increases the risk of type 2 diabetes and its most and adverse events were explained to each participant (written and orally). Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 3 of 10 Participants, randomization, and allocation concealment subject’s allocation to treatment was concealed from all This randomized controlled trial was conducted in the staff members and the principal investigator; they were framework of Tehran Lipid and Glucose Study (TLGS). only opened sequentially by the dietitian in the presence The TLGS is a large long-term community-based pro - of eligible participants in the first visit. spective study being conducted on a representative sam- ple of residents from district No. 13 of Tehran, Iran. The Blinding population of this district represents the urban popula- In the nutritional interventions, blinding of the par- tion of Tehran. The details of this study are described ticipants was practically impossible. However, the elsewhere [29]. Briefly, the first examination was initi - participants were unaware of their assignment to the ated in March 1999. Using multistage stratified clus - intervention groups before enrolment. Individuals who ter random sampling, more than 15,000 individuals, assessed the outcomes, including laboratory techni- aged ≥ 3  years, were enrolled. Overall, since 1999, the cians and staff members, were blind to the participants’ TLGS participants have undergone assessments for soci- assignment, and dietary interventions were provided by odemographic factors, lifestyle, medication use, socio- a dietitian. economic status, anthropometric indices, and medical history of cardiovascular risk factors. The information is Dietary interventions documented every three years in face-to-face visits by the First, 307 individuals participated in a two-week run-in local research team to update the previous data. Phases period when they consumed their usual diet while elimi- II, III, IV, V, and VI of this study were prospective follow- nating the legume intake. In the run-in period, seven par- ups conducted during 2002–2004, 2005–2008, 2008– ticipants were unwilling to continue the study and were 2011, 2012–2015, and 2016–2018, respectively. excluded. At the end of the run-in period, 300 partici- Of 10,927 individuals participating in phase VI of the pants, stratified based on risk and non-risk alleles, were TLGS study, TCF7L2 rs7903146 genotype was ran- randomly assigned to the DASH diet group or legume- domly determined in 8399 participants. Of these, 662 based DASH diet group over 16 weeks. participants, aged 30–65  years, had type 2 diabetes The participants’ energy requirements were esti - with available information on TCF7L2 rs7903146 geno- mated from the resting energy expenditure, based on type (CC genotype, n = 240; TT genotype, n = 128, the Mifflin-St Jeor formula and multiplied by the physi - and CT genotype, n = 294). The criteria  for  diagnos - cal activity coefficient [30]. Because the participants were ing  diabetes  included a fasting plasma glucose (FPG) overweight and obese, 500–700  kcal/d was deducted level ≥ 126  mg/dL, two-hour plasma glucose ≥ 200  mg/ from their energy requirements. Based on each partici- dL, or using antihyperglycemic medications. Other pant’s energy requirement, the dietitian determined the inclusion criteria were being overweight or obese (BMI: diet, which contained approximately 25–30% fat, 15% 25–40  kg/m ); no weight changes in the last three protein, and 55–60% carbohydrate. In the DASH diet months before enrollment; consumption of red meat ≥ 1 group, the participants were instructed to follow the serving/d; and willingness to consume legumes in the DASH diet (2000–3000  kcal based on the participant’s diet. On the other hand, participants with pregnancy or energy requirement), composed of 8–12 servings/day of lactation, cardiac, hepatic, or renal impairment (creati- fruits and vegetables, 7–15 servings of whole grains, 2–3 nine ≥ 1.4  mg/dL in men and ≥ 1.3  mg/dL in women), servings of low-fat dairy products, two servings of red and insulin use were excluded. meat, one serving of nuts and seeds, and limited intake of Randomization was carried out to generate the ran- sweets (five servings per week). The legume-based DASH domization sequence using the randomization website diet was similar to the standard DASH diet, with the (www. rando mizat ion. com). The randomization sequence exception that one serving of red meat was replaced with was separately generated for participants with TCF7L2 one serving of legumes at least five days a week. Also, rs7903146 risk allele (CT + TT) and non-risk allele (CC). because legumes are equivalent to one serving of whole Among participants eligible for this study, we selected grains, one serving of bread was also deducted from the 150 participants with genotype CC and 150 participants legume-based DASH diet. In both diets, the participants with genotype TT + CT and assigned them separately were advised to consume less than or equal to one tea- and randomly (1:1 ratio) to either the DASH diet group spoon of salt per day (2300 mg/d). or the legume-based DASH diet group. The recruitment To evaluate the participants’ adherence to the inter- of participants is shown in Fig. 1. ventions, the dietitian instructed them to record their The participants were randomly assigned to receive one daily dietary intake using a three-day food record (two of the two diets by a member of the TLGS staff. Using weekdays and one  weekend  day) every weeks. The dieti - sealed and sequentially numbered opaque envelopes, the tian called the participants every week to gather their Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 4 of 10 Fig. 1 Flowchart for the participants dietary information, compared their information with rs7903146 risk allele (CT + TT) and non-risk allele (CC) the instructed diet, and reinforced their diet adherence. separately. The intake of macro- and micronutrients was also calcu - lated using NUTRITIONIST III Version 7.0 (N-Squared Computing, Salem, OR, USA), designed for Iranian Measurements foods. All participants were requested to maintain their Weight was measured using a digital scale (Seca 707; physical activity and not to change their medications range: 0–150  kg; Seca GmbH, Germany), with mini- during the 16-week interventions unless prescribed by mal clothing and without shoes; it was recorded to the their physicians. nearest 100  g. Height was also measured in a standing position, with shoulders in neutral alignment using a stadiometer (Seca 225; Seca GmbH, Germany) without shoes and recorded to the nearest 0.5 cm. The body mass Primary and secondary outcomes index (BMI) was calculated by dividing weight in kilo The primary outcome of this study was the difference in - hs-CRP change from baseline to week 16 of follow-up grams by height in meters squared. between the groups. The secondary outcome was the dif - At the beginning of the study and 16-week follow-up ference in IL-6, TNF-α, and MDA changes between the (between 7∶00 a.m. and 9∶00 a.m.), venous blood sam- groups. Another secondary outcome was assessment of ples were collected from all participants who fasted for changes in the inflammatory markers, based on TCF7L2 12–14  h overnight. The blood samples were placed in Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 5 of 10 vacutainer tubes, centrifuged within 30–45 min of collec- Differences in the changes of outcomes between the tion, and stored in a − 80 °C freezer. The serum concen - two diets in the total population and also with respect tration of hs-CRP was measured using an enzyme-linked to the TCF7L2 rs7903146 risk allele (CT + TT) and immunosorbent assay (ELISA) kit (ZellBio, Germany). non-risk allele (CC) were compared using the analysis To analyze the concentrations of TNF-α and IL-6, of covariance (ANCOVA). Model 1 was adjusted for ELISA assay was performed using a commercial kit the baseline values, and model 2 was further adjusted (Diaclone, France). Also, the serum MDA concentra- for oral antihyperglycemic Medications. The gene-diet tion was assessed based on a colorimetric method using interaction was analyzed by an ANCOVA multivariate a commercial kit (ZellBio GmbH, Ulm, Germany). The interaction model, and P-value < 0.2 indicated the sig- intra-assay coefficients of variation (CVs) for the serum nificant effect of gene-diet interaction on the outcomes. hs-CRP, IL-6, TNF-α, and MDA were 2.7%, 8.1%, 6.3%, The Benjamini–Hochberg correction method for mul - and 3.3%, respectively. tiple testing yielded critical P-values of < 0.1 for the Genomic DNA was extracted from the buffy coat of secondary outcome comparisons. Cohen’s d for effect samples, using a standard salting out method with pro- size (0.20, 0.50, and 0.80 interpreted as small, medium, teinase K. The quality of extracted DNA was determined and large treatment effects, respectively) was also cal - using the NanoDrop 1000 Spectrophotometer. Samples culated based on mean and SD [33]. All analyses were in the range of 1.7 < A260/A280 < 2 were excluded due performed in Stata Version 14.0 (StataCorp LLC, TX, to low quality and concentration. DNA samples were USA). processed on a HumanOmniExpress-24-v1-0 BeadChip (containing 649,932 SNP loci with an average mean dis- tance of 4 kb) at deCODE Genetics Company (Reykjavik, Results Iceland), according to the manufacturer’s instructions This trial was carried out between July 11, 2020 and (Illumina Inc., San Diego, CA, USA). Quality control pro- March 10, 2021. Of 563 participants screened for eligi- cedures were also performed using PLINK V. 1.07 and R bility, 300 were randomly allocated to the diet groups. Statistic V. 3.2 [31]. Sixteen participants withdrew from the study, and finally, 284 individuals completed the study (Fig.  1). The mean age and BMI of the participants were 55.4  years Assessment of other variables (SD = 7.0) and 30.4 kg/m (SD = 3.4), respectively (42.9% Medication regimen (e.g., antihypertensive, lipid-lower- female and 48.7% obese). No significant differences ing, and anti-diabetes drugs and others) and supplement were found in the baseline variables, except for the use intake were collected. Physical activity was also assessed of oral antihyperglycemic Medications, between the two using the Modifiable Activity Questionnaire (MAQ), and groups in the total population and also among rs7903146 the frequency and amount of time spent per week on risk allele (CT + TT) and non-risk allele (CC) carriers physical activity over the last year were recorded. (Table  1). Compared to the DASH diet, metformin was more commonly used for the legume-based DASH diet Statistical analysis group (46.0 vs. 36.7), while participants in the DASH diet The target sample size was measured to be 150 in each group were more treated with metformin plus sulfonylu- intervention group to detect a difference of 1  mg/dl rea (20.7 vs. 30.0). Among carriers of rs7903146 non-risk reduction in hs-CRP [32] between the two diets in the allele, metformin and metformin plus thiazolidinedione total population by assuming an α error of 0.05, a β error was used slightly more often for participants in the leg- of 0.20, power of 80%, and an attrition rate of 20%. ume-based DASH diet group, while the DASH diet group Through visual inspection of the histograms, scatter was treated more with sulfonylurea, and metformin plus plots, and Shapiro–Wilk test, the normal distribution sulfonylurea. Metformin was slightly more often used of data was assessed. Normal variables are presented as for the carriers of rs7903146 T allele in the legume- mean ± SD for demographic variables and mean ± SEM based DASH diet group, while the DASH diet group was for dietary variables. Skewed variables are also presented treated more with metformin plus sulfonylurea. as median (interquartile range) and dichotomous vari- Analysis of the subjects’ food records showed that com- ables as count (percentage). Analyses were performed pared to the DASH diet, the intake of legumes and fiber according to the per-protocol and intention-to-treat was higher, while the intake of red meat and cholesterol principles. Multiple imputation by chained equations was lower in the legume-based DASH diet group. No sig- method was also applied to impute the primary and sec- nificant difference was found regarding the total energy ondary missing outcomes. In this method, the predic- requirements, macronutrients, and dietary food groups tors included all variables presented in Table  1, TCF7L2 between the groups (Additional file 1: Table 1). rs7903146 variant, and intervention diets. Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 6 of 10 Table 1 Baseline characteristic of participants according to group of intervention diets and TCF7L2 rs7903146 gene variant Total population CC genotypes TT + CT genotypes DASH diet Legume-based DASH diet Legume-based DASH diet Legume- DASH diet DASH diet based DASH diet Participants, n 150 150 75 75 75 75 Age, years 55.5 (6.9) 55.4 (7.1) 55.1 (6.7) 55.2 (8.1) 55.6 (7.1) 55.5 (6.1) Female, n (%) 85 (56.3) 86 (57.7) 42 (56.0) 45 (60.0) 43 (56.6) 41 (55.4) hsCRP, mg/dl 3.6 (1.9–5.0) 3.7 (2.1–5.0) 3.6 (2.1–5.4) 3.7 (1.9–4.8) 3.5 (1.9–4.6) 3.8 (2.1–5.2) MDA, µM 5.1 (3.7–7.7) 5.0 (3.6–8.3) 5.0 (3.7–7.6) 5.1 (3.4–8.3) 5.1 (3.4–8.3) 4.8 (3.6–7.9) TNF‑α, pg/ml 13.0 (11.2–15.9) 11.4 (9.8–15.8) 11.4 (9.8–13.4) 11.4 (9.8–13.4) 15.2 (12.6–17.9) 11.4 (9.9–16.5) IL‑6, pg/ml 4.3 (3.7–5.4) 3.8 (3.5–4.6) 3.9 (3.6–5.2) 3.7 (3.4–4.7) 4.5 (4.1–5.7) 3.9 (3.5–4.6) Obese, n (%) 72 (48.0) 74 (49.3) 42 (56.0) 41 (54.7) 30 (40.0) 33 (44.0) Physical activity levels, Met h/week 3.5 (2.7) 3.3 (2.7) 3.6 (2.8) 3.4 (2.3) 3.3 (2.6) 3.4 (3.0) Academic degree, n (%) 18 (11.9) 22 (14.8) 6 (8.0) 6 (8.0) 12 (15.8) 16 (21.6) Medication Antihyperglycemic Medications Metformin, n (%) 55 (36.7) 69 (46.0) 32 (42.7) 39 (52.0) 23 (30.7) 30 (40.0) Sulfonylurea, n (%) 40 (26.5) 29 (19.3) 21 (28.0) 14 (18.7) 19 (25.3) 15 (20.0) Metformin + sulfonylurea, n (%) 45 (30.0) 31 (20.7) 20 (26.7) 13 (17.3) 25 (33.3) 18 (24.0) Metformin + thiazolidinedione, n (%) 5 (3.3) 11 (7.3) 2 (2.7) 9 (12.0) 3 (4.0) 2 (2.7) Others, n (%) 5 (3.3) 10 (6.7) 0 (0) 0 (0) 5 (6.7) 10 (13.3) Lipid lowering drugs Statin use, n (%) 86 (57.0) 84 (56.4) 47 (62.7) 42 (56.0) 39 (51.3) 43 (57.3) Others, n (%) 1 (0.7) 4 (2.7) 0 (0.0) 2 (2.7) 1 (1.3) 2 (2.7) Antihypertensive drugs ACE inhibitor/ARB use, n (%) 52 (34.7) 48 (32.0) 28 (37.3) 26 (34.7) 24 (32.0) 22 (29.3) Thiazide, n (%) 7 (4.7) 2 (1.3) 3 (4.0) 1 (1.3) 4 (5.3) 1 (1.3) Others, n (%) 10 (6.7) 8 (5.3) 8 (10.7) 4 (5.3) 2 (2.7) 4 (5.3) Asprin n (%) 28 (18.7) 28 (18.7) 11 (14.6) 13 (17.3) 17 (22.7) 15 (20.0) Supplement Vitamin E 1 (0.7) 0 (0%) 0 (0%) 0 (0%) 1 (1.3%) 0 (0%) Vitamin D 32 (21.3) 34 (22.7) 17 (22.7) 18 (24.0) 15 (20.0) 16 (21.3) Vitamin B complex 17 (11.3) 15 (10.0) 7 (9.3) 9 (12.0) 10 (13.3) 6 (8.0) W‑3 PUFA fatty acids 4 (2.7) 3 (2.0) 3 (4.0) 0 (0.0) 1 (1.3) 3 (4.0) Obese BMI ≥ 30 kg/m2 Data are mean (SD) or median (interquartile range) unless otherwise indicated Primary outcome Secondary outcomes The ITT and completer analyses yielded similar findings After adjustments for the baseline variables and oral (Additional file  1: Table  2); therefore, only the ITT find - antihyperglycemic Medications, TNF-α (−  0.77  pg/mL ings are reported. The hs-CRP level was reduced at week [−  1.24 to −  0.29] in the DASH diet vs. -2.04  pg/mL 16 in the legume-based DASH diet group compared [− 2.51 to − 1.56] in the legume-based DASH diet), IL-6 to the DASH diet group (mean difference of change: (−  0.51  pg/mL [−  0.68 to −  0.34] in the DASH diet vs. -0.58  mg/dL [−  0.78 to −  0.39] in the DASH diet group −  0.95  pg/mL [−  1.12 to −  0.78] in the legume-based vs. − 1.20 mg/dL [− 1.39 to −1.01] in the legume-based DASH diet), and MDA (− 1.02 µM [− 1.27 to − 0.77] in DASH diet group; Cohen’s d = 0.41 [0.64–0.18]) after the DASH diet vs. −  1.64  µM [−  1.89 to −  1.39] in the adjustment for the baseline values and oral antihyper- legume-based DASH diet) reduced after the legume- glycemic Medications (model 2). This reduction was based DASH diet intervention compared to the DASH observed in both carriers of rs7903146 risk allele and diet; this reduction was observed in both risk allele and non-risk allele (Table 2). non-risk allele carriers. However, BMI did not change Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 7 of 10 Table 2 The 16 week change in inflammatory and oxidative stress markers and anthropometric measures after the DASH diet and legume based DASH diet according to TCF7L2 rs7903146 gene variant Total population CC genotype CT + T T genotype DASH diet Legume-based P value q value DASH diet Legume-based P value q value DASH diet Legume-based P value q value P i DASH diet DASH diet DASH diet Primary outcome hsCRP (mg/dl) Model 1 − 0.57 − 1.22 < 0.001 − 0.51 − 1.08 0.001 − 0.65 − 1.33 0.002 0.421 (− 0.76 to − 0.38) (− 1.40 to − 1.02) (− 0.87 to − 0.15) (− 1.27 to − 0.88) (− 0.95 to − 0.34) (− 1.53 to − 1.14) Model 2 − 0.58 − 1.20 < 0001 − 0.51 − 1.08 0.002 − 0.65 − 1.34 0.002 0.237 (− 0.78 to − 0.39) (− 1.39 to − 1.01) (− 0.87 to − 0.15) (− 1.28 to − 0.88) (− 0.95 to − 0.35) (− 1.52 to − 1.15) Secondary outcomes MDA (µM) Model 1 − 1.03 − 1.64 < 0.001 0.016 − 0.91 − 1.58 0.016 0.040 − 1.11 − 1.73 0.021 0.040 0.455 (− 1.28 to − 0.78) (− 1.88 to − 1.38) (− 1.24 to − 0.58) (− 1.97 to − 1.18) (− 1.43 to − 0.81) (− 2.11 to − 1.35) Model 2 − 1.02 − 1.64 < 0.001 0.016 − 0.91 − 1.58 0.016 0.040 − 1.11 − 1.73 0.023 0.040 0.573 (− 1.27 to − 0.77) (− 1.89 to − 1.39) (− 1.24 to − 0.58) (− 1.97 to − 1.18) (− 1.43 to − 0.80) (− 2.11 to − 1.35) TNF− α (pg/ml) Model 1 − 0.76 − 2.04 < 0.001 0.016 − 0.68 − 1.78 0.010 0.038 − 0.87 − 2.27 0.006 0.032 0.593 (− 1.23 to − 0.29) (− 2.51 to − 1.57) (− 1.28 to − 0.08) (− 2.41 to − 1.16) (− 1.63 to − 0.11) (− 2.97 to − 1.58) Model 2 − 0.77 − 2.04 < 0.001 0.016 − 0.68 − 1.78 0.010 0.038 − 0.87 − 2.28 0.012 0.038 0.496 (− 1.24 to − 0.29) (− 2.51 to − 1.56) (− 1.45 to − 0.08) (− 2.42 to − 1.14) (− 1.60 to − 0.14) (− 2.98 to − 1.57) IL− 6 (pg/ml) Model 1 − 0.53 − 0.93 0.001 0.016 − 0.52 − 0.82 0.028 0.044 − 0.52 − 1.06 0.019 0.041 0.753 (− 0.70 to − 0.36) (− 1.10 to − 0.76) (− 0.68 to − 0.36) (− 1.05 to − 0.58) (− 0.82 to − 0.22) (− 1.28 to − 0.85) Model 2 − 0.51 − 0.95 0.004 0.032 − 0.52 − 0.81 0.012 0.038 − 0.52 − 1.06 0.019 0.040 0.793 (− 0.68 to − 0.34) (− 1.12 to − 0.78) (− 0.68 to − 0.36) (− 1.04 to − 0.58) (− 0.82 to − 0.22) (− 1.28 to − 0.85) BMI (kg/m ) Model 1 − 1.48 − 1.57 0.287 0.382 − 1.41 − 1.56 0.238 0.346 − 1.54 − 1.58 0.709 0.756 0.617 (− 1.60 to − 1.36) (− 1.69 to − 1.45) (− 1.59 to − 1.23) (− 1.73 to − 1.39) (− 1.67 to − 1.42) (− 1.79 to − 1.37) Model 2 − 1.49 − 1.56 0.424 0.492 − 1.41 − 1.56 0.431 0.492 − 1.54 − 1.58 0.859 0.859 0.859 (− 1.61 to − 1.37) (− 1.68 to − 1.44) (− 1.59 to − 1.23) (− 1.73 to − 1.39) (− 1.67 to − 1.42) (− 1.79 to − 1.37) DASH, dietary approach to stop hypertension; FPG, fasting plasma glucose; WC, waist circumference; HOMAIR, homeostatic model assessment for insulin resistance; Pi, P for interaction between TCF7L2 rs7903146 gene variant and intervention diets Data for change in primary and secondary outcomes are express as mean (95% confidence interval) Model 1 adjusted for baseline values Model 2 adjusted for baseline values and oral anti diabetic medications P values were calculated by ANCOVA q value were calculated by Benjamini–Hochberg correction and Q < 0.2 is significant Hosseinpour‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 8 of 10 significantly after adherence to the legume-based DASH [43]. Although the role of insulin resistance in induc- diet as compared to the DASH diet (Table 2). ing inflammation has been identified [25], the effect of TCF7L2 gene on inflammation has been less investigated Discussion [26, 27, 44]. There was no significant difference in the In this weight-loss interventional trial among individual inflammatory markers among TCF7L2 genotypes after with type 2 diabetes, the inflammatory and oxidative treatment with fenofibrate [26]. Also, dietary patterns stress status improved by replacing one serving of red rich in functional foods did not modify the effects on meat with legumes in the DASH diet at least five days CRP [28]. a week, regardless of having rs7903146 risk or non-risk Although few studies have examined the modulatory allele. effect of TCF7L2 rs7903146 variant on the relation - Generally, low-grade inflammation occurs in the insu - ship between diet and inflammation, some studies have lin resistance stage of type 2 diabetes. Therefore, identi - reported that the detrimental effects of TCF7L2 gene on fying dietary determinants that increase inflammation cardiometabolic risk factors may be improved by anti- and replacing them with dietary food groups that reduce inflammatory dietary patterns, such as the Mediterra - inflammation are important. In many observational stud - nean diet [45, 46]. The DASH dietary pattern is another ies, but not all [9, 13], a positive association has been anti-inflammatory diet. Although the beneficial effect of observed between biomarkers of inflammation and red DASH diet on the management of cardiovascular risk meat consumption or red meat-rich dietary patterns [8, factors, such as inflammation, has been documented 10–12]. Also, substitution of a serving of total red meat [47–49], to the best of our knowledge, no study has yet with high-quality plant protein sources, such as leg- investigated the effect of interaction between the DASH umes, was associated with lower CRP concentrations diet and TCF7L2 gene on these risk factors. [8]. However, there is no clear evidence on the effects of Previous studies, however, have assessed the interac- changes in red meat intake and replacement of red meat tion between the DASH diet and some genes, such as with other protein sources on inflammation biomarkers genetic predisposition to obesity, based on BMI-asso- in dietary interventions. Although substituting carbohy- ciated variants [50, 51], as well as MC4R rs17782313 drates with proteins in interventional studies has shown polymorphism [52] on cardiometabolic risk factors. In no effects on inflammatory markers [16, 17, 34, 35], the the Nurses’ Health Study and the Health Professionals results related to the substitution of red meat with other Follow-up Study, during a 20-year follow-up, the effect of protein sources are controversial. High-protein diets, interaction between adherence to DASH diet and genetic both animal and plant proteins, have been suggested to predisposition to obesity (based on 77 SNPs) on changes reduce inflammatory markers [18]. In a previous study, in body weight was reported [50]. The detrimental effect although replacement of pork with chicken and red of genetic predisposition on weight gain was reduced by meat did not change the CRP concentration [36], par- greater adherence to the DASH diet; this effect was more tial replacement of red meat with plant proteins, such pronounced among participants with a higher genetic as soy protein and legumes, improved the inflammatory risk of obesity [50]. In another study investigating three biomarkers [37, 38]. Moreover, replacement of red meat observational cohorts of US women and men, adherence with 30 g of soy was adequate in reducing the concentra- to the DASH diet accentuated the detrimental effects of tion of inflammatory markers in postmenopausal women the genetic risk score (GRS), based on 97 BMI-associated [38, 39]. In the current study, improvement of inflamma - variants, on BMI [51]. Also, in a cross-sectional study, tory markers was achieved by replacement of one serv- high adherence to the DASH diet modified the effect of ing of red meat with legumes at least five days a week; melanocortin-4 receptor (MC4R) rs17782313 polymor- this finding is consistent with previous clinical trials and phism on cardiometabolic risk factors, including tri- a systematic review and meta-analysis, documenting the glyceride concentration, blood pressure, and glucose health-promoting effects of legume intake, with a median concentration, especially among MC4R rs17782313 risk intake of 63  g/d to 150  g (~ 1½ servings/d) [37, 40–42]. allele carriers [52]. Nevertheless, in the current study, we This effect might be due to the higher consumption of did not find any effect of interaction between the diet and dietary fiber and low-glycemic-load carbohydrates in rs7903146 variant on inflammatory markers in individual diets with high-quality plant protein sources. with type 2 diabetes. Our findings must be examined in The TCF7L2 rs7903146 SNP is the most impor- other ethnic populations with different allele frequencies; tant genetic predictor of T2DM [20]. Disturbances in also, family-based investigations on a large sample size insulin sensitivity and induction of insulin resistance are needed. are among the molecular mechanisms through which Some limitations of the current study need to be TCF7L2 rs7903146 variant increases the risk of T2DM addressed. The assessment of adherence to dietary Hosseinpour ‑Niazi et al. Nutrition & Metabolism (2022) 19:35 Page 9 of 10 Consent for publication interventions was based on self-report diet records, and Not applicable. because of our limited funding, we could not measure the biochemical index of adherence to dietary interventions. Competing interests On behalf of all authors, the corresponding author hereby declares that there Therefore, the dietitian called the participants once a is no conflict of interest. week and encouraged their adherence to the dietary rec- ommendations. Another limitation of this study was not Author details Nutrition and Endocrine Research Center, Research Institute for Endocrine blinding the participants to the study objectives, which Sciences, Shahid Beheshti University of Medical Sciences, No. 24, A’rabi St., might have affected the subjects’ behaviors. Finally, this Yeman Av., Velenjak, Tehran 19395‑4763, Iran. Prevention of Metabolic study was conducted in an area with a middle to high Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Cellular and Molecular socioeconomic status, and our findings cannot be extrap - Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti olated to individual with type 2 diabetes with a low socio- University of Medical Sciences, Tehran, Iran. Endocrine Research Center, economic status. Research Institute for Endocrine Sciences, Shahid Beheshti University of Medi‑ cal Sciences, Tehran, Iran. In conclusion, substituting one serving of red meat with one serving of legumes in DASH diet, at least five Received: 2 August 2021 Accepted: 2 May 2022 days a week, could improve the hs-CRP, TNF-α, IL-6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non-risk allele. References 1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. 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Journal

Nutrition & Metabolism – Springer Journals

Published: May 18, 2022

Keywords: Legumes; Type 2 diabetes; Inflammatory markers; Oxidative stress

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