nutrients Article

Dietary Protein Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies Shuang Tian 1,2 , Qian Xu 2 , Ruyue Jiang 2 , Tianshu Han 2 , Changhao Sun 2, * and Lixin Na 2, * 1 2

*

Nutrition Department, Longgang Hospital of Traditional Chinese Medicine, Shenzhen 518000, Guangdong, China; [email protected] National Discipline, Department of Nutrition and Food Hygiene, School of Public Health Harbin Medical University, Harbin 150081, China; [email protected] (Q.X.); [email protected] (R.J.); [email protected] (T.H.) Correspondence: [email protected] (C.S.); [email protected] (L.N.)

Received: 28 June 2017; Accepted: 29 August 2017; Published: 6 September 2017

Abstract: Recently, some studies have focused on the relationship between dietary protein intake and the risk of type 2 diabetes mellitus (T2DM), but the conclusions have been inconsistent. Therefore, in this paper, a systematic review and meta-analysis of cohort studies regarding protein consumption and T2DM risk are conducted in order to present the association between them. We searched the PubMed and Embase databases for cohort studies on dietary protein, high-protein food consumption and risk of T2DM, up to July 2017. A summary of relative risks was compiled by the fixed-effect model or random-effect model. Eleven cohort studies regarded protein intake and T2DM (52,637 cases among 483,174 participants). The summary RR and 95% CI (Confidence Interval) of T2DM was 1.12 (1.08–1.17) in all subjects, 1.13 (1.04–1.24) in men, and 1.09 (1.04–1.15) in women for total protein; 1.14 (1.09–1.19) in all subjects, 1.23 (1.09–1.38) in men, and 1.11 (1.03–1.19) in women for animal protein; 0.96 (0.88–1.06) in all subjects, 0.98 (0.72–1.34) in men, and 0.92 (0.86–0.98) in women for plant protein. We also compared the association between different food sources of protein and the risk of T2DM. The summary RR (Relative Risk) and 95% CI of T2DM was 1.22 (1.09–1.36) for red meat, 1.39 (1.29–1.49) for processed meat, 1.03 (0.89–1.17) for fish, 1.03 (0.64–1.67) for egg, 0.89 (0.84–0.94) for total dairy products, 0.87 (0.78–0.96) for whole milk, 0.83 (0.70–0.98) for yogurt, 0.74 (0.59–0.93) in women for soy. This meta-analysis shows that total protein and animal protein could increase the risk of T2DM in both males and females, and plant protein decreases the risk of T2DM in females. The association between high-protein food types and T2DM are also different. Red meat and processed meat are risk factors of T2DM, and soy, dairy and dairy products are the protective factors of T2DM. Egg and fish intake are not associated with a decreased risk of T2DM. This research indicates the type of dietary protein and food sources of protein that should be considered for the prevention of diabetes. Keywords: protein; diabetes; systematic review; meta-analysis

1. Introduction Type 2 diabetes is rapidly increasing in the world. Ninety percent of patients with diabetes have type 2 diabetes [1]. Type 2 diabetes patients are at increased risk of cardiovascular disease, neuropathies, nephropathies, gangrene, and leg ulcers [2]. From the date of diagnosis, patients with T2DM have to face at least eight years of economic burden [3]. Evidence suggests that dietary factors may influence the risk of T2DM [4]. Many previous studies have focused on dietary macronutrient intake associated with diabetes risk [5,6], but the main content of those studies was carbohydrates and fats. Recently, some studies focused on the relationship

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between dietary protein intake and the risk of T2DM. High-protein diets have shown beneficial effects on glucose homeostasis in some short–term trials [7,8]. Subsequent longitudinal studies have evaluated the associations between dietary protein intake and risk of T2DM as well as the type of dietary protein and risk of T2DM.A study focusing on the Mediterranean islands showed that animal protein consumption was associated with a higher prevalence of diabetes among the elderly, and a recommended range of protein from plant sources appears was seen to be considerably protective [9]. Some other publications have also reported an increased risk of T2DM with a high intake of total protein [10–14] and animal protein [10,13–15], and a decreased risk of T2DM with a high intake of plant protein [14,15]. However, there have been no reports that how an association between T2DM and total protein [15–18], animal protein [16–18] and plant protein intake or a high risk of T2DM with a high intake of plant protein [10,13].The association between dietary protein and T2DM is still debated. In the present study, we conducted a systematic review and meta-analysis of cohort studies to clarify the association of protein consumption with risk of T2DM. In order to provide a better dietary instruction for the lay public, we also conducted a systematic review and meta-analysis of cohort studies to study the association between different kinds of high-protein food and the risk of T2DM. 2. Materials and Methods 2.1. Search Strategy We searched relevant studies from the Embase and PubMed electronic databases from their starting dates to July 2017. Protein: search items included: ‘dietary protein’ or ‘protein intake’ or ‘plant protein’ or ‘animal protein’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Meat: search items included: ‘red meat’ or ‘processed meat’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Fish: search items included: ‘fish’ or ‘seafood’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Egg: search items included: ‘egg’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Dairy: search items included: ‘dairy’ or ‘milk’ or ‘dairy product’ or ‘yogurt’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Soy: search items included: ‘soy’ or ‘legume’ or ‘soy product’ or ‘food’ and ‘diabetes’ or ‘diabetes mellitus’ or ‘T2DM’ and ‘population’ or ‘human’. Eligible studies are selected by further manual scanning of all included studies and relevant reference lists. 2.2. Study Selection All included studies should match the following criteria:(1) the study must have a cohort design; (2) the endpoint of the study was the incidence or mortality of the T2DM; (3) the study had to report risk ratios and the results had to be within a 95% CI in the paper (if this not clear, we requested this information from the authors); and (4) the study had to show the participants’ intake of dietary protein or other high-protein foods such as meat, fish, egg, dairy, soy. 2.3. Data Extraction We extracted the following information from each publication we selected: first the author of the publication, publication year, the country where the study was conducted, the number of the samples and cases, T2DM diagnosis and criteria, the year the study began and finished, the years of follow-up, the methods of diet exposure assessment, the RRs and 95% CI, and the adjustment factors (Tables S1–S12).

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follow-up, the methods of diet exposure assessment, the RRs and 95% CI, and the adjustment factors 3 of 17 (Tables S1–S12).

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2.4. Statistical Methods

2.4. Statistical Methods

We used effect models to calculate the summary RRs and 95% confidence to compare the

We used effectprotein modelsconsumption to calculatewith the summary and 95% confidence to[19]. compare the highest highest dietary the lowest RRs dietary protein consumption Two-sided p dietary protein consumption with the lowest dietary protein consumption [19]. Two-sided p < 0.05 < 0.05 was considered statistically significant. The black square in the forest plots represents the was considered The black square in the forest plotsofrepresents contribution weightstatistically contributionsignificant. of every study. In order to evaluate the extent variability,the theweight I2-test statistic 2 2 of every In order to evaluate the extent of variability, -testand statistic to estimate wasstudy. adapted to estimate the heterogeneity [20].When Ithe< I 50% p > was 0.05,adapted there was no heterogeneity;[20].When we used the Thethere random-effect model was selected when > 50% the heterogeneity I2 fixed-effect < 50% andmodel. p > 0.05, was no heterogeneity; we used theI2fixed-effect or pThe < 0.05. We used themodel Egger was linear regression testI2and Beggorrank test tothe search forlinear model. random-effect selected when > 50% p < correlation 0.05. We used Egger publication bias. When p > 0.05, there was no publication bias. Comprehensive Meta-Analysis regression test and Begg rank correlation test to search for publication bias. When p > 0.05, thereV2 was no was employed for data analysis. publication bias. Comprehensive Meta-Analysis V2 was employed for data analysis. 3. Results

3. Results

3.1. Dietary Protein Intake and Risk of T2DM

3.1. Dietary Protein Intake and Risk of T2DM

We included 11 cohort studies in the analysis (Figure 1, Tables S1 and S2). Six of the studies

We cohort studies in from the analysis 1, Tables S1 and Six of theone studies wereincluded from the11Unite States, three Europe, (Figure one from Asia, one fromS2). Melboume, from were from Finland. the Unite States, three from Europe, one from Asia, one from Melboume, one from Finland.

Figure1.1.Flow Flow chart chart for Figure forstudy studyselection. selection.

Total Protein Eleven cohort studies [10–18] researched the association between total protein intake and the risk of T2DM, included 52,637 cases among 483,174 participants. The summary RR and 95% CI for high vs. low values of all studies was 1.12 (1.08–1.17) (Figure 2a), (I2 = 18.72, p = 0.25) in all subjects, 1.13 (1.04–1.24) (Figure 2b) (I2 = 11.78, p = 0.34) in men, and 1.09(1.04–1.15) (Figure 2c) (I2 = 43.39, p = 0.10) in women.

Total Protein Eleven cohort studies [10–18] researched the association between total protein intake and the risk of T2DM, included 52,637 cases among 483,174 participants. The summary RR and 95% CI for high vs. low values of all studies was 1.12 (1.08–1.17) (Figure 2a), (I2 = 18.72, p = 0.25) in all subjects, 1.13 (1.04–1.24) (Figure 2b) (I2 = 11.78, p = 0.34) in men, and 1.09(1.04–1.15) (Figure Nutrients 2017, 9, 982 4 of2c) 17 2 (I = 43.39, p = 0.10) in women.

Figure 2. relative risks(RRs) for (a) vs. thevs. lowest intake Figure 2. Total Total protein proteinand andtype type2 diabetes 2 diabetes relative risks(RRs) forthe (a)highest the highest the lowest in all subjects and (b)and the highest vs. the lowest men (c) the lowest intake in intake in all subjects (b) the highest vs. theintake lowestinintake in the menhighest (c) thevs. highest vs. the lowest women. RR ofThe each is represented by a square, CI are95% represented by the horizontal intake in The women. RRstudy of each study is represented by 95% a square, CI are represented by the lines, and the diamond the estimate and its 95%and CI. its 95% CI. horizontal lines, and therepresents diamond represents the estimate

Animal Protein Nine Ninecohort cohort studies [10,13–18] researched the association between Animal Protein studies [10,13–18] researched the association between animal animal protein protein intake and the risk of T2DM. This included 31,557 cases among 380,689 participants. intake and the risk of T2DM. This included 31,557 cases among 380,689 participants. The summaryThe RR summary RRfor and 95% forvalues high vs. lowstudies valueswas of all studies was 1.14 (1.09–1.19) (I2 = and 95% CI high vs.CI low of all 1.14 (1.09–1.19) (Figure 3a), (I2 (Figure = 43.39, 3a), p = 0.30) 43.39, p = 0.30)1.23 in (1.09–1.38) all subjects,(Figure 1.23 (1.09–1.38) (Figure 3b), in (I2men, = 0.00, = 0.44) in men,(Figure and 1.11 in all subjects, 3b), (I2 = 0.00, p = 0.44) andp 1.11 (1.03–1.19) 3c), 2 2 (1.03–1.19) (I = 32.04, p = 0.21) in women. (I = 32.04, (Figure p = 0.21)3c), in women. Plant Plant Protein Nine cohort studies [10,13–18] researched the association between between plant plant protein protein and the risk of T2DM, included 31,817 cases among 381,879 participants. The summary RR and 95% and T2DM, included 31,817 cases among 381,879 participants. The summary RR and 95% CI 2 2 CI high vs. low values all studies was(0.88–1.06) 0.96 (0.88–1.06) (I =p59.01, = 0.07) in all for for high vs. low values of allofstudies was 0.96 (Figure(Figure 4a), (I 4a), = 59.01, = 0.07)p in all subjects. subjects. used a sensitivity to the exclude most influential the summary We used We a sensitivity analysis analysis to exclude mostthe influential studies: studies: the summary RR and RR 95%and CI 95% CI ranged from 0.92 (0.87–0.98) when the European men’s study [10] was excluded to 0.98 ranged from 0.92 (0.87–0.98) when the European men’s study [10] was excluded to 0.98 (0.87–1.10) (0.87–1.10) when the USA study [14] was excluded. The heterogeneity was partly of when the USA men’s studymen’s [14] was excluded. The heterogeneity was partly because of thebecause European the European men’s study [10] when we this study, there washeterogeneity moderate heterogeneity men’s study [10] and when weand excluded thisexcluded study, there was moderate (I2 = 14.85, 2 = 78.57, p = (I 14.85,The p =summary 0.31). TheRR summary CI was 0.98(Figure (0.72–1.34) p 2==0.31). and 95%RR CI and was 95% 0.98 (0.72–1.34) 4b) (I2(Figure = 78.57,4b) p =(I0.003) in men. 0.003) in men.analysis A sensitivity analysis was used to exclude the most influential studies:RR theand summary A sensitivity was used to exclude the most influential studies: the summary 95% CI RR and 95% CI ranged from 0.88 (0.76–1.02) when the European study [10] was excluded to 1.07 ranged from 0.88 (0.76–1.02) when the European study [10] was excluded to 1.07 (0.75–1.52) when the (0.75–1.52) when the[18] Finnish men’s study was excluded. Thestill heterogeneity men stillanalysis, existed Finnish men’s study was excluded. The[18] heterogeneity in men existed afterin sensitivity partly because there were only four cohort studies about the association between plant protein intake and the risk of T2DM in men. The summary RR and 95% CI was 0.92 (0.86–0.97) (Figure 4c) (I2 = 45.72, p = 0.12) in women.

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after after sensitivity sensitivity analysis, analysis, partly partly because because there there were were only only four four cohort cohort studies studies about about the the association association between plant protein intake and the risk of T2DM in men. The summary RR and 95% between CI was was 0.92 0.925 of 17 Nutrients 2017, 9,plant 982 protein intake and the risk of T2DM in men. The summary RR and 95% CI 22 = 45.72, p = 0.12) in women. (0.86–0.97) (Figure 4c) (I (0.86–0.97) (Figure 4c) (I = 45.72, p = 0.12) in women.

Figure 3. Animal protein and and typetype 2 diabetes RRsRRs for (a) vs. the lowest intake in all Figure 3. protein 22 diabetes for (a) the vs. lowest intake in all Figure 3. Animal Animal protein and type diabetes RRs for the (a) highest the highest highest vs. the the lowest intake in subjects all subjects and (b) the highest vs. the lowest intake in men (c) the highest vs. the lowest intake in and (b) the highest vs. the lowest intake in men (c) the highest vs. the lowest intake in women. subjects and (b) the highest vs. the lowest intake in men (c) the highest vs. the lowest intake The in RR women. The RR of each study is represented by a square, 95% CI are represented by the horizontal of each study is represented by a square, 95% CI are represented by the horizontal lines, and women. The RR of each study is represented by a square, 95% CI are represented by the horizontal the lines, and represents lines,represents and the the diamond diamond represents the estimate and its its 95% 95% CI. CI. diamond the estimate andthe itsestimate 95% CI.and

Figure 4. Plant protein and type 2 diabetes RRs for (a) the highest vs. the lowest intake in all subjects and (b) the highest vs. the lowest intake in men (c) the highest vs. the lowest intake in women. The RR of each study is represented by a square, 95% CI are represented by the horizontal lines, and the diamond represents the estimate and its 95% CI.

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Figure 4. Plant protein and type 2 diabetes RRs for (a) the highest vs. the lowest intake in all subjects and (b) the highest vs. the lowest intake in men (c) the highest vs. the lowest intake in women. The RR 2017, of each study is represented by a square, 95% CI are represented by the horizontal lines, and the6 of 17 Nutrients 9, 982 diamond represents the estimate and its 95% CI.

High-Protein Food and Risk of T2DM 3.2. High-Protein

We also conducted a systematic review and meta-analysis of cohort studies to clarify the association with high dietary protein food consumption and the risk of T2DM. T2DM. researched the the association association between between red meat Red Meat Thirteen Thirteen cohort cohort studies studies [6,18,21–31] [6,18,21–31]researched consumption and and the the risk risk of of T2DM T2DM (Figure (Figure 1, Tables S3 and S4).The summary RR and 95% CI for consumption 2 2= = high vs. low low red red meat meat consumption consumption was was 1.22 1.22 (1.09–1.36) (1.09–1.36) (Figure5a) (Figure 5a)(I(I 51.11,p p= = 0.01). We used 51.11, 0.01). We used a a sensitivity analysistotoexclude excludethe themost mostinfluential influentialstudies: studies:the thesummary summaryRR RR and and 95% 95% CI ranged sensitivity analysis (1.07–1.35) when when the the U.S. U.S. Study Study [24] was excluded excluded to to 1.26 1.26 (1.15–1.38) (1.15–1.38) when the Chinese from1.20 (1.07–1.35) study [25] was excluded. The heterogeneity was partly because of the Chinese study study [25], and when 2 0.17). we excluded this study, study, there there was was moderate moderate heterogeneity heterogeneity(I(I2 = 27.68, p == 0.17).

Figure 5. (a) the highest highest vs. vs. the lowest (a) Red Red meat meat (b) processed meat and type 2 diabetes RRs for the intake in all subjects. The The RR RR of of each each study study is is represented represented by by aa square, square, 95% 95% CI CI are represented by the horizontal lines, and the diamond represents the estimate and its 95% 95% CI. CI.

Processed Meat Eleven cohort studies [6,18,21–26,29–31] researched the association between Processed Meat Eleven cohort studies [6,18,21–26,29–31] researched the association between processed meat consumption and the risk of T2DM (Figure 1, Tables S3 and S4), the summary RR processed meat consumption and the risk of T2DM (Figure 1, Tables S3 and S4), the summary RR and and 95% CI for high vs. low of processed meat consumption was 1.39 (1.29–1.49) (Figure25b) (I2 = 95% CI for high vs. low of processed meat consumption was 1.39 (1.29–1.49) (Figure 5b) (I = 49.32, 49.32, p = 0.03). p = 0.03). Fish Nine cohort studies [18,29,32–38] researched the association between fish consumption Fish Nine cohort studies [18,29,32–38] researched the association between fish consumption and and the risk of T2DM (Figure 1, Tables S5 and S6), the summary RR and 95% CI for high vs. low the risk of T2DM (Figure 1, Tables S5 and S6), the summary RR and 95% CI for high vs. low values values of fish consumption was 1.03 (0.89–1.17) (Figure 26) (I2 = 79.71, p < 0.001). We used a sensitivity of fish consumption was 1.03 (0.89–1.17) (Figure 6) (I = 79.71, p < 0.001). We used a sensitivity analysis to exclude the most influential studies: the summary RR ranged from0.99 (0.89–1.10) when analysis to exclude the most influential studies: the summary RR ranged from0.99 (0.89–1.10) when the American study [33] was excluded to 1.50 (0.92–1.20) when the Japanese study [35] was the American study [33] was excluded to 1.50 (0.92–1.20) when the Japanese study [35] was excluded. excluded. The heterogeneity was partly because of the Japanese study [35], and when we excluded The heterogeneity was partly because of the Japanese study [35], and when we excluded this study, this study, there was moderate heterogeneity (I2 = 79.41, p < 0.001). there was moderate heterogeneity (I2 = 79.41, p < 0.001).

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Figure 6. Fish Fish and type type 2 diabetes RRs RRs for the the highest vs. vs. the lowest lowest intake in in all subjects. subjects. The RR of Figure Figure 6. 6. Fish and and type 22 diabetes diabetes RRs for for the highest highest vs. the the lowest intake intake in all all subjects. The The RR RR of of each studyisisrepresented represented a square, CIrepresented are represented the horizontal lines, and the each byby a square, 95%95% CI are by the by horizontal lines, and the diamond each study study is represented by a square, 95% CI are represented by the horizontal lines, and the diamond represents theand estimate and 95% CI. represents the estimate its 95% CI.its diamond represents the estimate and its 95% CI.

Egg Five cohort studies [18,39–42] researched the association between egg consumption and the Egg Five cohort studies [18,39–42] researched the association between egg consumption and the risk of T2DM (Figure 1, Tables S7 and S8), the summary RR and 95% CI for high vs. low of egg Tables S7 S7 and and S8), S8), the the summary summary RR RR and and 95% 95% CI CI for for high high vs. vs. low of egg risk of T2DM (Figure 1, Tables consumption was 1.03 (0.64–1.67) (Figure 7) (I222= 91.12, p < 0.001). We used a sensitivity analysis to used a sensitivity analysis to consumption was 1.03 1.03 (0.64–1.67) (0.64–1.67) (Figure (Figure 7) 7) (I(I ==91.12, 91.12,p p<

Dietary Protein Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies.

Recently, some studies have focused on the relationship between dietary protein intake and the risk of type 2 diabetes mellitus (T2DM), but the conclu...
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