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Salimi Z, Asadi M, Mansoori A. The Effect of Whey Protein Consumption on Postprandial Glucose, Insulin and Incretin Responses in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Acute-Term Controlled Clinical Trials. JNFS 2025; 10 (1) :178-193
URL: http://jnfs.ssu.ac.ir/article-1-936-en.html
URL: http://jnfs.ssu.ac.ir/article-1-936-en.html
Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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The Effect of Whey Protein Consumption on Postprandial Glucose, Insulin and Incretin Responses in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Acute-Term Controlled Clinical Trials
Zahra Salimi; MSc 1, Maryam Asadi; PhD2 & Anahita Mansoori; PhD *3,4
Zahra Salimi; MSc 1, Maryam Asadi; PhD2 & Anahita Mansoori; PhD *3,4
1 Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 2 Department of Nutrition, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; 3 Diabetes Research Center,Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 4 Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| ARTICLE INFO | ABSTRACT | |
| SYSTEMATIC REVIEW and META-ANALYSIS | Background: Postprandial hyperglycemia is an important factor which contributes to glycemic status and complications of diabetes mellitus. This was a systematic review and meta-analysis that was conducted to evaluate the overall effect of whey protein consumption on postprandial glucose, insulin, and incretin hormone responses in patients with type 2 diabetes mellitus (T2DM). Methods: Web of Science, Cochrane Library, EMBASE, PubMed, and Scopus databases were searched to find acute-term controlled clinical trials investigating the effect of all types of whey proteins on products postprandial glucose (PPG) response as the main outcome and also insulin and incretin responses as secondary outcomes in patients with T2DM. Ten trials met the eligibility criteria. A random-effects model was used to obtain pooled effect size. Results: The pooled analysis of the included trials indicated a significant reduction in the mean of glucose in the area under the curve [standard mean difference (SMD)=-1.295, 95% CI: -1.878 to -0.712, P<0.001] and also an increase in the mean of insulin, gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (SMD=0.562, 95% CI: 0.303 to 0.822, P<0.001, SMD=0.349, 95% CI: 0.074 to 0.624, P=0.013 and SMD=0.439, 95% CI: 0.154 to 0.724, P=0.003, respectively) in participants who consumed whey protein compared with the control group. Conclusion: According to the findings, whey protein intake is effective in reducing postprandial blood glucose as well as increasing postprandial insulin and incretin levels. Thus, whey protein can be considered a strategy to improve glycemic control in patients with T2DM. | |
| Article history: Received: 23 Jul 2023 Revised: 28 Nov 2023 Accepted: 21 Dec 2023 |
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| *Corresponding author: Mansoori_anahita@yahoo.com Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Postal code: 61357-15794 Tel: +98 61 33738253 |
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| Keywords: Whey protein; Postprandial; Glucose; Insulin; Type 2 diabetes. |
As a serious and long-term metabolic disorder, Type 2 Diabetes mellitus (T2DM), leads to hyperglycemia and dyslipidemia through insulin resistance and even inadequate insulin secretion (DeFronzo, 2009). Postprandial hyperglycemia is an important factor that contributes to impaired glycemic response and progression of T2DM (Woerle et al., 2007). Since the acute effect of impaired glycemic response is notable in the metabolic and hormonal milieu, research on the postprandial period is an attraction for researchers. The postprandial hyperglycemia is related to an elevated risk of cardiovascular diseases and increased levels of hemoglobin A1C (HbA1c) in T2DM (Ceriello et al., 2008, Rizza, 2010, Standl et al., 2011). Thus, diet therapy should focus on reducing postprandial glucose (PPG) peaks during the day for patients with T2DM (Morgan et al., 2012).
Dietary strategies, such as the consumption of complex carbohydrates or low-glycemic index diets, may contribute to improving metabolic health (Raben, 2014); however, it is difficult to keep up for a long time (Brekke et al., 2004). According to the evidence, an adverse association between dairy intake and glycemia (Da Silva et al., 2014, Drehmer et al., 2015) as well as the occurrence of T2DM has been demonstrated (Aune et al., 2013, Díaz-López et al., 2016). Milk and other dairy products, which contain many bioactive compounds and essential nutrients, may play a major role in diminishing the risk of diseases (Lovegrove and Givens, 2016). Therefore, it is better to consider the effect of separated compounds in randomized controlled trials. It seems the intake of dairy proteins in particular whey protein has a protective role in metabolic consequences (Mignone et al., 2015, Pal and Radavelli‐Bagatini, 2013, Zhang et al., 2016). The bovine milk protein contains two different protein types, namely casein (about 80%) and whey (about 20%). However, compared to casein, whey is richer in branched-chain amino acids including isoleucine, leucine, and valine (Hall et al., 2003), which may contribute to major metabolic outcomes. unlike casein, which is passed slowly out of the stomach, whey protein has quick gastric emptying and enters the small intestine, causing further increases in plasma amino acids due to its acidic solubility (Pal and Radavelli‐Bagatini, 2013).
Several randomized controlled trials (RCTs) have been conducted regarding the effects of whey protein on PPG, insulin, and incretin responses with inconsistent findings (Bjørnshave et al., 2018, Frid et al., 2005, Goudarzi and Madadlou, 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Tessari et al., 2007, Wu et al., 2016). Some studies have revealed significant reductions in PPG (Frid et al., 2005, Jakubowicz et al., 2017, King et al., 2018, Watson et al., 2019, Wu et al., 2016), increases in plasma insulin (Bjørnshave et al., 2018, Frid et al., 2005, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Tessari et al., 2007, Wu et al., 2016), glucagon (Bjørnshave et al., 2018, Tessari et al., 2007), and incretin hormones (total and intact) (Bjørnshave et al., 2018, Frid et al., 2005, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016), while other studies have found no change in PPG (Tessari et al., 2007), plasma insulin, glucagon, and incretin hormones (Frid et al., 2005, King et al., 2018). Because of the conflicting results and the lack of a meta-analysis on this topic to date, the authors decided to carry out a systematic review and meta-analysis on acute-term RCTs to assess the overall effects of the whey protein on PPG, insulin, and gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP-1) responses in patients with T2DM.
Materials and Methods
The present systematic review was accomplished according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009). The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (http://www.crd.york.ac.uk/PROSPERO; registration no.: CRD42018110161).
Search strategy
A systematic search was performed for relevant studies in five major databases PubMed, Scopus, Web of Science, Embase, and Cochrane Library, and manually reviewed lists of published studies and articles in English from 2000 up to 2023 using the following search terms and MeSH terms in titles and abstracts of human studies: (hyperglycemia OR glucose intolerance OR diabetes OR diabetes mellitus) AND (whey OR milk OR dairy OR Whey Proteins)).
Eligibility criteria
Original studies were included in meta-analysis if they were randomized parallel or crossover acute-term trials that investigated the effect of all types of whey protein including isolated form (90-95% protein; contains less lactose and fat), concentrated form (About 70–80% protein; lactose and fat) or hydrolyzed form (variable protein, lactose and fat concentrations) on PPG, insulin and incretins in patients with T2DM. The incremental area under the curve (IAUC)/area under the curve (AUC) of serum glucose levels was considered primary and insulin, GIP ,and GLP-1 were considered secondary outcomes (Brouns et al., 2005). The exclusion criteria were as follows: Non-clinical trial design, no measuring PPG, non-diabetic participants, studies without a control group, prescription of the mixture of whey protein with other nutrients, insufficient data on postprandial glucose, insulin, incretin levels, and study duration. Study selection was performed by two independent authors (Z Salimi, A Mansoori) in a two-step process. First, to identify the eligibility of all found studies, the authors observed the titles and the abstracts. In the second step, the full-text versions of eligible trials in the first screening were independently evaluated for inclusion criteria by Z Salimi and A Mansoori.
Data extraction
Two researchers (Z Salimi and A Mansoori) extracted data from the eligible studies separately. The extracted information was as follows: 1) first author’s name; 2) year of publication; 3) region and country; 4) the number of participants in the intervention and control groups; 5) gender, body mass index, and age of study participants; 6) study characteristics (study design, randomization method, and blindness); 7) reported data of iAUC/AUC for serum level of glucose, insulin, and incretin in the intervention and placebo groups. Any disagreement was resolved by discussion among the authors.
Quality assessment
The quality of the studies was independently evaluated by two of the authors using instructions described in the Handbook of Cochrane for Systematic Reviews and meta-analysis of interventions (Higgins and Green, 2011). Evaluation of each study was performed using the following items: sufficiency of sequence generation, adequacy of allocations concealment, blinding of participants and personnel, selective outcome reporting, defective outcome data, and other possible biases. Cochrane Handbook recommendations indicated that “yes”, “no” and “unclear” items respectively demonstrated low, high, and unknown risk of bias. The overall quality of individual trials was classified into three categories: good (low risk for more than two items), fair (low risk for two items), or weak (low risk for less than two items).
Data analysis
The endpoints were the mean difference and standard deviation of PPG, insulin, GIP, and GLP-1 in the intervention/control group. When the exact value of iAUC/AUC was not mentioned in eligible studies, the authors used reported data in the charts and tables to obtain iAUC/AUC (Brouns et al., 2005). The iAUC of Glucose levels in three studies (Bjørnshave et al., 2018, Jakubowicz et al., 2017, Watson et al., 2019), insulin levels in two studies (Bjørnshave et al., 2018, Jakubowicz et al., 2017), GIP levels in two studies (Bjørnshave et al., 2018, King et al., 2018), and GLP-1 levels in two studies (Bjørnshave et al., 2018, King et al., 2018) were calculated using reported data in the charts of eligible studies. Also, the AUC of Glucose levels in three studies (Frid et al., 2005, Goudarzi and Madadlou, 2013, Wu et al., 2016), insulin levels in four studies (Frid et al., 2005, Goudarzi and Madadlou, 2013, King et al., 2018, Wu et al., 2016), GIP levels in two studies (Frid et al., 2005, Wu et al., 2016), and GLP-1 levels in two studies (Frid et al., 2005, Wu et al., 2016) were calculated using reported data in the tables of these studies. Unit conversion was done in two studies for glucose (mol/l and mg/dl into mmol/l) (Jakubowicz et al., 2013, Tessari et al., 2007) and in four studies for insulin (nmol/l and pmol/l into mU/l) (Bjørnshave et al., 2018, Frid et al., 2005, Goudarzi and Madadlou, 2013, Jakubowicz et al., 2014) and in three studies for GIP (pmol/l into pg/ml) (Bjørnshave et al., 2018, Frid et al., 2005, Tessari et al., 2007).
The pooled estimation of the standard mean difference (SMD) between the whey protein supplementation group and the control group was calculated using a random effect model. Between-study heterogeneity was tested using the χ² test or the same Cochran's Q test and I² and subgroup analyses were also performed to detect sources of heterogeneity (Lau et al., 1997). Sensitivity analysis was performed using the leave -one -study out (one-study removed) approach. Thus, the authors were able to explore the effect of each study on the overall effect size. For an investigation of possible publication bias, the visual funnel plot and Egger’s test was used (Egger et al., 1997).
Results
Literature search
The initial search yielded 1472 potentially relevant citations, to which 127 articles were added following manual search, which was done on initial studies. 392 duplicated articles were removed. Toweny one eligible studies were selected for full-text review based on title and abstract analysis. Eventually, after careful assessment, 10 articles were included in the present systematic review. Reasons for non-admission of the other articles were as follows: not being postprandial (Daly et al., 2014, Flaim et al., 2017, Gaffney et al., 2018), having no control group (Mortensen et al., 2012, Mortensen et al., 2009), prescription of the mixture of whey protein with other nutrients (Ang et al., 2012), participants without T2DM (Akhavan et al., 2010), lack of clarity of blood glucose curve and iAUC/AUC measurement for glucose (King et al., 2018), having unusable results (Almario et al., 2017) and unclear study time (Jakubowicz et al., 2016). The steps of the study selection process are illustrated in Figure 1.
Characteristics of included studies
Ten clinical trial studies included in the meta-analysis involved 271 participants. The largest trial had 22 participants and the smallest trial had 10 participants. Three trials used whey protein isolate (WPI) (Goudarzi and Madadlou, 2013, Tessari et al., 2007, Wu et al., 2016), two studies used whey protein hydrolysate (WPH) (Goudarzi and Madadlou, 2013, King et al., 2018), and three studies used whey protein concentrate (WPC) (Jakubowicz et al., 2013, Jakubowicz et al., 2014, King et al., 2018). Whey protein was consumed in the rest of the trials. The iAUC/AUC of Glucose, insulin, and incretin were assessed ranging from 180 min to 360 min. Ranges of whey protein dose were from 0.1 g/kg body weight to 50 g which was served with meal or pre-meal in the intervention group vs. meal without whey protein in the control group. The characteristics and results of the studies are given in Table 1.
Assessment of risk of bias
The quality of studies was assessed based on the domains of the Cochrane Collaboration’s tool applied, including random sequence generation, allocation concealment, participants and personnel blinding, incomplete outcome data, selective reporting, and other sources of bias. The results were divided into three groups: high, low, and unclear risk of bias. The interpretation of the quality assessment results was as follows: fair (low risk for 2 items), weak (low risk for less than 2 items), or good (low risk for more than 2 items). Among 10 studies investigated in this systematic review, one was classified to have a good quality (Goudarzi and Madadlou, 2013), 3 were considered to have a fair quality (Bjørnshave et al., 2018, Tessari et al., 2007, Wu et al., 2016), and 6 were of rather poor quality (Frid et al., 2005, Jakubowicz et al., 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Watson et al., 2019)
Findings from the meta-analysis
The consumption of whey protein compared with control demonstrated a significant reduction in glucose AUC mean (SMD=-1.29, 95% CI: -1.87 to -0.71, P=0.001), and with significant heterogeneity (P for heterogeneity <0.001, I2=85.7%, Figure 2) in the pooled analysis of 9 studies (15 comparisons). According to the Glucose Influence Analysis, the deletion of any of the studies did not change the result of the analysis and they were in a range from -1.40 (95% CI: -2 to -0.79) to -1.19 (95% CI:-1.77 t0 -0.60). The Pooled data of 9 studies (16 comparisons) that reported insulin showed a significant increase in insulin AUC mean in participants who consumed whey protein compared with control (SMD=0.562, 95% CI: 0.303 to 0.822, P<0.001) (P for heterogeneity=0.050, I2=40.0%, Figure 3). Five studies (7 comparisons) described data on GIP AUC pooled data and showed a significant increase in GIP AUC mean in participants who consumed whey protein compared with control (SMD=0.34, 95% CI: 0.07 to 0.62, P=0.013) (P for heterogeneity= 0.81, I2=0.0%, Figure 4). The pooled data of 5 studies (7 comparisons) that reported GLP-1 showed a significant increase in GLP-1 AUC mean in participants who consumed whey protein compared with control (SMD=0.43, 95% CI: 0.15 to 0.72, P=0.003) (P for heterogeneity=0.39, I2=4.7%, Figure 5).
Discussion
The present systematic review and meta-analysis of acute-term RCTs suggested that whey protein consumption significantly decreased PPG and increased post-meal insulin and incretin levels.
The number of acute-term studies published on the effects of whey protein intake on postprandial glycemic responses has increased in recent years. Several human studies have reported that whey protein intake significantly reduced PPG and increased postprandial insulin after food intake (Goudarzi and Madadlou, 2013, Jakubowicz et al., 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Wu et al., 2016). Nevertheless, according to the results of the study conducted by Tessari et al, following the ingestion of whey protein and free amino acid and casein amino acids, postprandial insulinemia was higher during whey protein consumption (Tessari et al., 2007). Inversely, PPG levels were lower during free amino acid intake compared with whey protein. Besides, the findings of Frid (Frid et al., 2005) suggested that replacing lean ham and lactose with an equal amount (18·2 g) of whey protein in high GI meals, significantly increased the insulin response but did not have any significant effects on glucose response following the breakfast meal. Furthermore, studies accomplished by Almario et al. and Bjørnshave et al showed similar results in PPG and insulin response (Almario et al., 2017, Bjørnshave et al., 2018). It is possible that using a low dosage of whey protein because of insufficient increase in post-breakfast circulating insulin to overcome insulin resistance in the post-absorptive state, and also higher levels of insulin resistance after the nocturnal fasting (Plat et al., 1996), were the causes of less-reported PPG after whey protein intake in a breakfast meal.
Studies have also shown that taking whey protein increased GLP-1 (Almario et al., 2017, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016) and GIP levels (Bjørnshave et al., 2018, Frid et al., 2005, Tessari et al., 2007, Wu et al., 2016). Interestingly, in some studies, whey protein intake did not have a significant effect on postprandial GLP-1 (Bjørnshave et al., 2018, Frid et al., 2005, King et al., 2018) and GIP levels (King et al., 2018). The reason for the discrepancy could be related to the different doses of whey protein. Studies showed that administration of larger doses of whey protein, from 25 to 50 g, significantly increased incretin response (Almario et al., 2017, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016), whereas administration of smaller doses, from 15 g to 20 g, showed no difference in incretin responses (Bjørnshave et al., 2018, Frid et al., 2005, King et al., 2018).
According to the available evidence, whey protein reduces blood glucose through insulin-dependent and insulin-independent mechanisms (Akhavan et al., 2014). Although not fully determined, whey protein consumption seems to either directly or indirectly increase postprandial insulin (Floyd et al., 1966). Due to rapid digestion and high solubility of whey protein, plasma amino acids specifically leucine, isoleucine, and valine, rapidly increase (Pal and Radavelli‐Bagatini, 2013) and directly induce the insulinotropic/β-cell-stimulating effects (Bosscher et al., 2009). In addition, amino acids and bioactive peptides obtained from gastrointestinal digestion of whey protein stimulate L cell activity enhance their proliferation, and secrete GLP-1 and other incretin hormones (Jakubowicz and Froy, 2013). Also, whey protein may serve as an endogenous inhibitor of dipeptidyl peptidase-4 in the intestine, and as a result, prevent the local GLP-1 degradation after its release from the enteroendocrine cells (Jakubowicz and Froy, 2013, Power-Grant et al., 2015). In addition, whey protein and its digested peptides and amino acids, increase glucose uptake by an enhancement in the Akt phosphorylation in the muscle cells, and finally, the GLUT4 transmission to the plasma membrane. Furthermore, Whey protein intake decreases PPG through an insulin-independent reduction in the speed of gastric emptying (Marathe et al., 2013).
Nevertheless, Smedegaard et al investigated the effect of pre-meal iso-nitrogenous amounts of whey protein isolate and β-lactoglobulin (the main component of whey protein) in T2DM patients on postprandial level of insulin and glucagon that were increased after intake of β-lactoglobulin compared with the whey protein isolate (Smedegaard et al., 2021). Some components of whey protein could stimulate glucagon secretion along with insulin secretion, which should be considered in future studies.
Dietary strategies, such as the consumption of complex carbohydrates or low-glycemic index diets, may contribute to improving metabolic health (Raben, 2014); however, it is difficult to keep up for a long time (Brekke et al., 2004). According to the evidence, an adverse association between dairy intake and glycemia (Da Silva et al., 2014, Drehmer et al., 2015) as well as the occurrence of T2DM has been demonstrated (Aune et al., 2013, Díaz-López et al., 2016). Milk and other dairy products, which contain many bioactive compounds and essential nutrients, may play a major role in diminishing the risk of diseases (Lovegrove and Givens, 2016). Therefore, it is better to consider the effect of separated compounds in randomized controlled trials. It seems the intake of dairy proteins in particular whey protein has a protective role in metabolic consequences (Mignone et al., 2015, Pal and Radavelli‐Bagatini, 2013, Zhang et al., 2016). The bovine milk protein contains two different protein types, namely casein (about 80%) and whey (about 20%). However, compared to casein, whey is richer in branched-chain amino acids including isoleucine, leucine, and valine (Hall et al., 2003), which may contribute to major metabolic outcomes. unlike casein, which is passed slowly out of the stomach, whey protein has quick gastric emptying and enters the small intestine, causing further increases in plasma amino acids due to its acidic solubility (Pal and Radavelli‐Bagatini, 2013).
Several randomized controlled trials (RCTs) have been conducted regarding the effects of whey protein on PPG, insulin, and incretin responses with inconsistent findings (Bjørnshave et al., 2018, Frid et al., 2005, Goudarzi and Madadlou, 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Tessari et al., 2007, Wu et al., 2016). Some studies have revealed significant reductions in PPG (Frid et al., 2005, Jakubowicz et al., 2017, King et al., 2018, Watson et al., 2019, Wu et al., 2016), increases in plasma insulin (Bjørnshave et al., 2018, Frid et al., 2005, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Tessari et al., 2007, Wu et al., 2016), glucagon (Bjørnshave et al., 2018, Tessari et al., 2007), and incretin hormones (total and intact) (Bjørnshave et al., 2018, Frid et al., 2005, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016), while other studies have found no change in PPG (Tessari et al., 2007), plasma insulin, glucagon, and incretin hormones (Frid et al., 2005, King et al., 2018). Because of the conflicting results and the lack of a meta-analysis on this topic to date, the authors decided to carry out a systematic review and meta-analysis on acute-term RCTs to assess the overall effects of the whey protein on PPG, insulin, and gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP-1) responses in patients with T2DM.
Materials and Methods
The present systematic review was accomplished according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009). The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (http://www.crd.york.ac.uk/PROSPERO; registration no.: CRD42018110161).
Search strategy
A systematic search was performed for relevant studies in five major databases PubMed, Scopus, Web of Science, Embase, and Cochrane Library, and manually reviewed lists of published studies and articles in English from 2000 up to 2023 using the following search terms and MeSH terms in titles and abstracts of human studies: (hyperglycemia OR glucose intolerance OR diabetes OR diabetes mellitus) AND (whey OR milk OR dairy OR Whey Proteins)).
Eligibility criteria
Original studies were included in meta-analysis if they were randomized parallel or crossover acute-term trials that investigated the effect of all types of whey protein including isolated form (90-95% protein; contains less lactose and fat), concentrated form (About 70–80% protein; lactose and fat) or hydrolyzed form (variable protein, lactose and fat concentrations) on PPG, insulin and incretins in patients with T2DM. The incremental area under the curve (IAUC)/area under the curve (AUC) of serum glucose levels was considered primary and insulin, GIP ,and GLP-1 were considered secondary outcomes (Brouns et al., 2005). The exclusion criteria were as follows: Non-clinical trial design, no measuring PPG, non-diabetic participants, studies without a control group, prescription of the mixture of whey protein with other nutrients, insufficient data on postprandial glucose, insulin, incretin levels, and study duration. Study selection was performed by two independent authors (Z Salimi, A Mansoori) in a two-step process. First, to identify the eligibility of all found studies, the authors observed the titles and the abstracts. In the second step, the full-text versions of eligible trials in the first screening were independently evaluated for inclusion criteria by Z Salimi and A Mansoori.
Data extraction
Two researchers (Z Salimi and A Mansoori) extracted data from the eligible studies separately. The extracted information was as follows: 1) first author’s name; 2) year of publication; 3) region and country; 4) the number of participants in the intervention and control groups; 5) gender, body mass index, and age of study participants; 6) study characteristics (study design, randomization method, and blindness); 7) reported data of iAUC/AUC for serum level of glucose, insulin, and incretin in the intervention and placebo groups. Any disagreement was resolved by discussion among the authors.
Quality assessment
The quality of the studies was independently evaluated by two of the authors using instructions described in the Handbook of Cochrane for Systematic Reviews and meta-analysis of interventions (Higgins and Green, 2011). Evaluation of each study was performed using the following items: sufficiency of sequence generation, adequacy of allocations concealment, blinding of participants and personnel, selective outcome reporting, defective outcome data, and other possible biases. Cochrane Handbook recommendations indicated that “yes”, “no” and “unclear” items respectively demonstrated low, high, and unknown risk of bias. The overall quality of individual trials was classified into three categories: good (low risk for more than two items), fair (low risk for two items), or weak (low risk for less than two items).
Data analysis
The endpoints were the mean difference and standard deviation of PPG, insulin, GIP, and GLP-1 in the intervention/control group. When the exact value of iAUC/AUC was not mentioned in eligible studies, the authors used reported data in the charts and tables to obtain iAUC/AUC (Brouns et al., 2005). The iAUC of Glucose levels in three studies (Bjørnshave et al., 2018, Jakubowicz et al., 2017, Watson et al., 2019), insulin levels in two studies (Bjørnshave et al., 2018, Jakubowicz et al., 2017), GIP levels in two studies (Bjørnshave et al., 2018, King et al., 2018), and GLP-1 levels in two studies (Bjørnshave et al., 2018, King et al., 2018) were calculated using reported data in the charts of eligible studies. Also, the AUC of Glucose levels in three studies (Frid et al., 2005, Goudarzi and Madadlou, 2013, Wu et al., 2016), insulin levels in four studies (Frid et al., 2005, Goudarzi and Madadlou, 2013, King et al., 2018, Wu et al., 2016), GIP levels in two studies (Frid et al., 2005, Wu et al., 2016), and GLP-1 levels in two studies (Frid et al., 2005, Wu et al., 2016) were calculated using reported data in the tables of these studies. Unit conversion was done in two studies for glucose (mol/l and mg/dl into mmol/l) (Jakubowicz et al., 2013, Tessari et al., 2007) and in four studies for insulin (nmol/l and pmol/l into mU/l) (Bjørnshave et al., 2018, Frid et al., 2005, Goudarzi and Madadlou, 2013, Jakubowicz et al., 2014) and in three studies for GIP (pmol/l into pg/ml) (Bjørnshave et al., 2018, Frid et al., 2005, Tessari et al., 2007).
The pooled estimation of the standard mean difference (SMD) between the whey protein supplementation group and the control group was calculated using a random effect model. Between-study heterogeneity was tested using the χ² test or the same Cochran's Q test and I² and subgroup analyses were also performed to detect sources of heterogeneity (Lau et al., 1997). Sensitivity analysis was performed using the leave -one -study out (one-study removed) approach. Thus, the authors were able to explore the effect of each study on the overall effect size. For an investigation of possible publication bias, the visual funnel plot and Egger’s test was used (Egger et al., 1997).
Results
Literature search
The initial search yielded 1472 potentially relevant citations, to which 127 articles were added following manual search, which was done on initial studies. 392 duplicated articles were removed. Toweny one eligible studies were selected for full-text review based on title and abstract analysis. Eventually, after careful assessment, 10 articles were included in the present systematic review. Reasons for non-admission of the other articles were as follows: not being postprandial (Daly et al., 2014, Flaim et al., 2017, Gaffney et al., 2018), having no control group (Mortensen et al., 2012, Mortensen et al., 2009), prescription of the mixture of whey protein with other nutrients (Ang et al., 2012), participants without T2DM (Akhavan et al., 2010), lack of clarity of blood glucose curve and iAUC/AUC measurement for glucose (King et al., 2018), having unusable results (Almario et al., 2017) and unclear study time (Jakubowicz et al., 2016). The steps of the study selection process are illustrated in Figure 1.
Characteristics of included studies
Ten clinical trial studies included in the meta-analysis involved 271 participants. The largest trial had 22 participants and the smallest trial had 10 participants. Three trials used whey protein isolate (WPI) (Goudarzi and Madadlou, 2013, Tessari et al., 2007, Wu et al., 2016), two studies used whey protein hydrolysate (WPH) (Goudarzi and Madadlou, 2013, King et al., 2018), and three studies used whey protein concentrate (WPC) (Jakubowicz et al., 2013, Jakubowicz et al., 2014, King et al., 2018). Whey protein was consumed in the rest of the trials. The iAUC/AUC of Glucose, insulin, and incretin were assessed ranging from 180 min to 360 min. Ranges of whey protein dose were from 0.1 g/kg body weight to 50 g which was served with meal or pre-meal in the intervention group vs. meal without whey protein in the control group. The characteristics and results of the studies are given in Table 1.
Assessment of risk of bias
The quality of studies was assessed based on the domains of the Cochrane Collaboration’s tool applied, including random sequence generation, allocation concealment, participants and personnel blinding, incomplete outcome data, selective reporting, and other sources of bias. The results were divided into three groups: high, low, and unclear risk of bias. The interpretation of the quality assessment results was as follows: fair (low risk for 2 items), weak (low risk for less than 2 items), or good (low risk for more than 2 items). Among 10 studies investigated in this systematic review, one was classified to have a good quality (Goudarzi and Madadlou, 2013), 3 were considered to have a fair quality (Bjørnshave et al., 2018, Tessari et al., 2007, Wu et al., 2016), and 6 were of rather poor quality (Frid et al., 2005, Jakubowicz et al., 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Watson et al., 2019)
Findings from the meta-analysis
The consumption of whey protein compared with control demonstrated a significant reduction in glucose AUC mean (SMD=-1.29, 95% CI: -1.87 to -0.71, P=0.001), and with significant heterogeneity (P for heterogeneity <0.001, I2=85.7%, Figure 2) in the pooled analysis of 9 studies (15 comparisons). According to the Glucose Influence Analysis, the deletion of any of the studies did not change the result of the analysis and they were in a range from -1.40 (95% CI: -2 to -0.79) to -1.19 (95% CI:-1.77 t0 -0.60). The Pooled data of 9 studies (16 comparisons) that reported insulin showed a significant increase in insulin AUC mean in participants who consumed whey protein compared with control (SMD=0.562, 95% CI: 0.303 to 0.822, P<0.001) (P for heterogeneity=0.050, I2=40.0%, Figure 3). Five studies (7 comparisons) described data on GIP AUC pooled data and showed a significant increase in GIP AUC mean in participants who consumed whey protein compared with control (SMD=0.34, 95% CI: 0.07 to 0.62, P=0.013) (P for heterogeneity= 0.81, I2=0.0%, Figure 4). The pooled data of 5 studies (7 comparisons) that reported GLP-1 showed a significant increase in GLP-1 AUC mean in participants who consumed whey protein compared with control (SMD=0.43, 95% CI: 0.15 to 0.72, P=0.003) (P for heterogeneity=0.39, I2=4.7%, Figure 5).
Discussion
The present systematic review and meta-analysis of acute-term RCTs suggested that whey protein consumption significantly decreased PPG and increased post-meal insulin and incretin levels.
The number of acute-term studies published on the effects of whey protein intake on postprandial glycemic responses has increased in recent years. Several human studies have reported that whey protein intake significantly reduced PPG and increased postprandial insulin after food intake (Goudarzi and Madadlou, 2013, Jakubowicz et al., 2013, Jakubowicz et al., 2014, Jakubowicz et al., 2017, King et al., 2018, Wu et al., 2016). Nevertheless, according to the results of the study conducted by Tessari et al, following the ingestion of whey protein and free amino acid and casein amino acids, postprandial insulinemia was higher during whey protein consumption (Tessari et al., 2007). Inversely, PPG levels were lower during free amino acid intake compared with whey protein. Besides, the findings of Frid (Frid et al., 2005) suggested that replacing lean ham and lactose with an equal amount (18·2 g) of whey protein in high GI meals, significantly increased the insulin response but did not have any significant effects on glucose response following the breakfast meal. Furthermore, studies accomplished by Almario et al. and Bjørnshave et al showed similar results in PPG and insulin response (Almario et al., 2017, Bjørnshave et al., 2018). It is possible that using a low dosage of whey protein because of insufficient increase in post-breakfast circulating insulin to overcome insulin resistance in the post-absorptive state, and also higher levels of insulin resistance after the nocturnal fasting (Plat et al., 1996), were the causes of less-reported PPG after whey protein intake in a breakfast meal.
Studies have also shown that taking whey protein increased GLP-1 (Almario et al., 2017, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016) and GIP levels (Bjørnshave et al., 2018, Frid et al., 2005, Tessari et al., 2007, Wu et al., 2016). Interestingly, in some studies, whey protein intake did not have a significant effect on postprandial GLP-1 (Bjørnshave et al., 2018, Frid et al., 2005, King et al., 2018) and GIP levels (King et al., 2018). The reason for the discrepancy could be related to the different doses of whey protein. Studies showed that administration of larger doses of whey protein, from 25 to 50 g, significantly increased incretin response (Almario et al., 2017, Jakubowicz et al., 2014, Jakubowicz et al., 2017, Tessari et al., 2007, Wu et al., 2016), whereas administration of smaller doses, from 15 g to 20 g, showed no difference in incretin responses (Bjørnshave et al., 2018, Frid et al., 2005, King et al., 2018).
According to the available evidence, whey protein reduces blood glucose through insulin-dependent and insulin-independent mechanisms (Akhavan et al., 2014). Although not fully determined, whey protein consumption seems to either directly or indirectly increase postprandial insulin (Floyd et al., 1966). Due to rapid digestion and high solubility of whey protein, plasma amino acids specifically leucine, isoleucine, and valine, rapidly increase (Pal and Radavelli‐Bagatini, 2013) and directly induce the insulinotropic/β-cell-stimulating effects (Bosscher et al., 2009). In addition, amino acids and bioactive peptides obtained from gastrointestinal digestion of whey protein stimulate L cell activity enhance their proliferation, and secrete GLP-1 and other incretin hormones (Jakubowicz and Froy, 2013). Also, whey protein may serve as an endogenous inhibitor of dipeptidyl peptidase-4 in the intestine, and as a result, prevent the local GLP-1 degradation after its release from the enteroendocrine cells (Jakubowicz and Froy, 2013, Power-Grant et al., 2015). In addition, whey protein and its digested peptides and amino acids, increase glucose uptake by an enhancement in the Akt phosphorylation in the muscle cells, and finally, the GLUT4 transmission to the plasma membrane. Furthermore, Whey protein intake decreases PPG through an insulin-independent reduction in the speed of gastric emptying (Marathe et al., 2013).
Nevertheless, Smedegaard et al investigated the effect of pre-meal iso-nitrogenous amounts of whey protein isolate and β-lactoglobulin (the main component of whey protein) in T2DM patients on postprandial level of insulin and glucagon that were increased after intake of β-lactoglobulin compared with the whey protein isolate (Smedegaard et al., 2021). Some components of whey protein could stimulate glucagon secretion along with insulin secretion, which should be considered in future studies.
Although the present study was the first
meta-analysis on this topic so far, there were some limitations. 1) AUC was calculated for glucose, insulin, and incretin levels by formulas in a few studies because their data were shown in the chart which may be considered an erroneous source. 2) There was language limitation for published trials. So, only English-published trials were included. 3) postprandial glycemic status was measured in different periods, although the authors used standardized methods for the elimination of the differences. 4) The authors could not perform subgroup analysis based on dose and type of whey protein due to the small number of studies. 5) And most of the studies showed low quality because in such studies blinding and allocation concealment is difficult or sometimes unlikely. In the design of future studies, consideration of an efficacious dose to reduce postprandial hyperglycemia, avoiding overconsumption of energy, and ensuring palatability is recommended. In addition, since regular consumption of whey protein in high doses may hurt energy balance, the calorie of prescribed whey protein should be considered as a part of the total calorie.
Conclusion
In conclusion, the intake of whey protein exactly before or along with a meal reduced postprandial glucose and increased insulin, GIP, and GLP-1 in patients with T2DM. Since long-term treatment with a pre-meal low-dose whey/guar preload in patients with T2DM is associated with a clinically modest reduction in Hba1c, whey protein supplementation may be a new approach to improve glycemic control in patients with T2DM. However, long-term studies focusing on glycemic control are needed to achieve stronger results.
Acknowledgments
Nothing to declare
Authors’ contributions
Z Salimi conceived the study and performed the literature search, data extraction, independent reviewing and carried out the quality evaluation of the included studies. A Mansoori conducted data analysis, interpretation and oversaw the methods. Z Salimi and M Asadi wrote the manuscript. All authors read and confirmed the manuscript. All authors read and approved the final manuscript.
Conflict of interest
The authors declared no conflict of interest.
Funding
This review did not receive any funding from the public and commercial agencies.
References
Akhavan T, Luhovyy BL, Brown PH, Cho CE & Anderson GH 2010. Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults–. The American journal of clinical nutrition. 91 (4): 966-975.
Akhavan T, et al. 2014. Mechanism of action of pre-meal consumption of whey protein on glycemic control in young adults. The Journal of nutritional biochemistry. 25 (1): 36-43.
Almario RU, Buchan WM, Rocke DM & Karakas SE 2017. Glucose-lowering effect of whey protein depends upon clinical characteristics of patients with type 2 diabetes. BMJ Open diabetes research and care. 5 (1): e000420.
Ang M, Müller AS, Wagenlehner F, Pilatz A & Linn T 2012. Combining protein and carbohydrate increases postprandial insulin levels but does not improve glucose response in patients with type 2 diabetes. Metabolism. 61 (12): 1696-1702.
Aune D, Norat T, Romundstad P & Vatten LJ 2013. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. The American journal of clinical nutrition. 98 (4): 1066-1083.
Bjørnshave A, Hermansen K & Holst JJ 2018. Pre-meal effect of whey proteins on metabolic parameters in subjects with and without type 2 diabetes: a randomized, crossover trial. Nutrients. 10 (2): 122.
Bosscher D, et al. 2009. Dairy peptides in effective blood glucose management. Australian journal of dairy technology. 64 (1): 54.
Brekke H, Sunesson Å, Axelsen M & Lenner R 2004. Attitudes and barriers to dietary advice aimed at reducing risk of type 2 diabetes in first‐degree relatives of patients with type 2 diabetes. Journal of human nutrition and dietetics. 17 (6): 513-521.
Brouns F, et al. 2005. Glycaemic index methodology. Nutrition research reviews. 18 (1): 145-171.
Ceriello A, Colagiuri S, Gerich J & Tuomilehto J 2008. Guideline for management of postmeal glucose. Nutrition, metabolism and cardiovascular diseases. 18 (4): S17-S33.
Da Silva MS, et al. 2014. Associations between dairy intake and metabolic risk parameters in a healthy French-Canadian population. Applied physiology, nutrition, and metabolism. 39 (12): 1323-1331.
Daly RM, et al. 2014. The effects of progressive resistance training combined with a whey-protein drink and vitamin D supplementation on glycaemic control, body composition and cardiometabolic risk factors in older adults with type 2 diabetes: study protocol for a randomized controlled trial. Trials. 15 (1): 431.
DeFronzo RA 2009. From the triumvirate to the „ominous octet”: a new paradigm for the treatment of type 2 diabetes mellitus. Clinical diabetology. 10 (3): 101-128.
Díaz-López A, et al. 2016. Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. European journal of nutrition. 55 (1): 349-360.
Drehmer M, et al. 2015. Associations of dairy intake with glycemia and insulinemia, independent of obesity, in Brazilian adults: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The American journal of clinical nutrition. 101 (4): 775-782.
Egger M, Smith GD, Schneider M & Minder C 1997. Bias in meta-analysis detected by a simple, graphical test. Bmj. 315 (7109): 629-634.
Flaim C, Kob M, Di Pierro AM, Herrmann M & Lucchin L 2017. Effects of a whey protein supplementation on oxidative stress, body composition and glucose metabolism among overweight people affected by diabetes mellitus or impaired fasting glucose: A pilot study. The Journal of nutritional biochemistry. 50: 95-102.
Floyd J, Fajans SS, Conn JW, Knopf RF & Rull J 1966. Stimulation of insulin secretion by amino acids. The Journal of clinical investigation. 45 (9): 1487-1502.
Frid AH, Nilsson M, Holst JJ & Björck IM 2005. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects–. American journal of clinical nutrition. 82 (1): 69-75.
Gaffney KA, et al. 2018. Nil Whey Protein Effect on Glycemic Control after Intense Mixed-Mode Training in Type 2 Diabetes. Medicine and science in sports and exercise. 50 (1): 11-17.
Goudarzi M & Madadlou A 2013. Influence of whey protein and its hydrolysate on prehypertension and postprandial hyperglycaemia in adult men. International dairy journal. 33 (1): 62-66.
Hall W, Millward D, Long S & Morgan L 2003. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. British journal of nutrition. 89 (2): 239-248.
Higgins J & Green S 2011. Handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. The Cochrane Collaboration.
Jakubowicz D, et al. 2013. Effect of whey protein concentrate on blood glucose, insulin and C-peptide serum levels following a high glycaemic index breakfast in patients with type 2 diabetes. In Diabetologia.
Jakubowicz D & Froy O 2013. Biochemical and metabolic mechanisms by which dietary whey protein may combat obesity and Type 2 diabetes. The Journal of nutritional biochemistry. 24 (1): 1-5.
Jakubowicz D, et al. 2014. Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial. Diabetologia. 57 (9): 1807-1811.
Jakubowicz D, Landau Z, Wainstein J, Bar-Dayan Y & Froy O 2016. Whey Protein Induces Greater Reduction of Postprandial Glycemia and HbA1c. Weight Loss and Satiety Compared to Other Protein Sources in Type. 2.
Jakubowicz D, et al. 2017. High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA1C in Type 2 diabetes. Journal of nutritional biochemistry. 49: 1-7.
King DG, et al. 2018. A small dose of whey protein co-ingested with mixed-macronutrient breakfast and lunch meals improves postprandial glycemia and suppresses appetite in men with type 2 diabetes: a randomized controlled trial. The American journal of clinical nutrition. 107 (4): 550-557.
Lau J, Ioannidis JP & Schmid CH 1997. Quantitative synthesis in systematic reviews. Annals of internal medicine. 127 (9): 820-826.
Lovegrove JA & Givens DI 2016. Dairy food products: good or bad for cardiometabolic disease? Nutrition research reviews. 29 (2):
249-267.
Marathe CS, Rayner CK, Jones KL & Horowitz M 2013. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes care. 36 (5): 1396-1405.
Mignone L, et al. 2016. A whey/guar" preload" improves postprandial glycaemia and HbA (1c) in type 2 diabetes: a 12-week, single-blind, randomised and placebo controlled trial. Diabetologia. 59 (Suppl. 1): S9-S9.
Mignone LE, Wu T, Horowitz M & Rayner CK 2015. Whey protein: The “whey” forward for treatment of type 2 diabetes? World journal of diabetes. 6 (14): 1274.
Moher D, Liberati A, Tetzlaff J & Altman DG 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of internal medicine. 151 (4): 264-269.
Morgan LM, Shi J-W, Hampton SM & Frost G 2012. Effect of meal timing and glycaemic index on glucose control and insulin secretion in healthy volunteers. British journal of nutrition. 108 (7): 1286-1291.
Mortensen L, et al. 2012. Effects of different fractions of whey protein on postprandial lipid and hormone responses in type 2 diabetes. European journal of clinical nutrition. 66 (7): 799.
Mortensen LS, et al. 2009. Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein–. The American journal of clinical nutrition. 90 (1): 41-48.
Pal S & Radavelli‐Bagatini S 2013. The effects of whey protein on cardiometabolic risk factors. Obesity reviews. 14 (4): 324-343.
Plat L, et al. 1996. Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans. American journal of physiology-endocrinology and metabolism. 270 (1): E36-E42.
Power-Grant O, et al. 2015. In vitro bioactive properties of intact and enzymatically hydrolysed whey protein: targeting the enteroinsular axis. Food & function. 6 (3): 972-980.
Raben A 2014. Glycemic index and metabolic risks: how strong is the evidence? Oxford University Press.
Rizza RA 2010. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes. 59 (11): 2697-2707.
Smedegaard SB, et al. 2021. β-Lactoglobulin Elevates Insulin and Glucagon Concentrations Compared with Whey Protein—A Randomized Double-Blinded Crossover Trial in Patients with Type Two Diabetes Mellitus. Nutrients. 13 (2): 308.
Standl E, Schnell O & Ceriello A 2011. Postprandial hyperglycemia and glycemic variability: should we care? Diabetes care. 34 (Supplement 2): S120-S127.
Tessari P, et al. 2007. Slow versus fast proteins in the stimulation of beta‐cell response and the activation of the entero‐insular axis in type 2 diabetes. Diabetes/metabolism research and reviews. 23 (5): 378-385.
Watson LE, et al. 2019. A whey/guar "preload" improves postprandial glycaemia and glycated haemoglobin levels in type 2 diabetes: A 12-week, single-blind, randomized, placebo-controlled trial. Diabetes, obesity and metabolism. 21 (4): 930-938.
Woerle HJ, et al. 2007. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance of postprandial glycemia to achieve target HbA1c levels. Diabetes research and clinical practice. 77 (2): 280-285.
Wu T, et al. 2016. A protein preload enhances the glucose-lowering efficacy of vildagliptin in type 2 diabetes. Diabetes care. 39 (4): 511-517.
Zhang J, et al. 2016. Effect of whey protein on blood lipid profiles: a meta-analysis of randomized controlled trials. European journal of clinical nutrition. 70 (8): 879.
meta-analysis on this topic so far, there were some limitations. 1) AUC was calculated for glucose, insulin, and incretin levels by formulas in a few studies because their data were shown in the chart which may be considered an erroneous source. 2) There was language limitation for published trials. So, only English-published trials were included. 3) postprandial glycemic status was measured in different periods, although the authors used standardized methods for the elimination of the differences. 4) The authors could not perform subgroup analysis based on dose and type of whey protein due to the small number of studies. 5) And most of the studies showed low quality because in such studies blinding and allocation concealment is difficult or sometimes unlikely. In the design of future studies, consideration of an efficacious dose to reduce postprandial hyperglycemia, avoiding overconsumption of energy, and ensuring palatability is recommended. In addition, since regular consumption of whey protein in high doses may hurt energy balance, the calorie of prescribed whey protein should be considered as a part of the total calorie.
Conclusion
In conclusion, the intake of whey protein exactly before or along with a meal reduced postprandial glucose and increased insulin, GIP, and GLP-1 in patients with T2DM. Since long-term treatment with a pre-meal low-dose whey/guar preload in patients with T2DM is associated with a clinically modest reduction in Hba1c, whey protein supplementation may be a new approach to improve glycemic control in patients with T2DM. However, long-term studies focusing on glycemic control are needed to achieve stronger results.
Acknowledgments
Nothing to declare
Authors’ contributions
Z Salimi conceived the study and performed the literature search, data extraction, independent reviewing and carried out the quality evaluation of the included studies. A Mansoori conducted data analysis, interpretation and oversaw the methods. Z Salimi and M Asadi wrote the manuscript. All authors read and confirmed the manuscript. All authors read and approved the final manuscript.
Conflict of interest
The authors declared no conflict of interest.
Funding
This review did not receive any funding from the public and commercial agencies.
References
Akhavan T, Luhovyy BL, Brown PH, Cho CE & Anderson GH 2010. Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults–. The American journal of clinical nutrition. 91 (4): 966-975.
Akhavan T, et al. 2014. Mechanism of action of pre-meal consumption of whey protein on glycemic control in young adults. The Journal of nutritional biochemistry. 25 (1): 36-43.
Almario RU, Buchan WM, Rocke DM & Karakas SE 2017. Glucose-lowering effect of whey protein depends upon clinical characteristics of patients with type 2 diabetes. BMJ Open diabetes research and care. 5 (1): e000420.
Ang M, Müller AS, Wagenlehner F, Pilatz A & Linn T 2012. Combining protein and carbohydrate increases postprandial insulin levels but does not improve glucose response in patients with type 2 diabetes. Metabolism. 61 (12): 1696-1702.
Aune D, Norat T, Romundstad P & Vatten LJ 2013. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. The American journal of clinical nutrition. 98 (4): 1066-1083.
Bjørnshave A, Hermansen K & Holst JJ 2018. Pre-meal effect of whey proteins on metabolic parameters in subjects with and without type 2 diabetes: a randomized, crossover trial. Nutrients. 10 (2): 122.
Bosscher D, et al. 2009. Dairy peptides in effective blood glucose management. Australian journal of dairy technology. 64 (1): 54.
Brekke H, Sunesson Å, Axelsen M & Lenner R 2004. Attitudes and barriers to dietary advice aimed at reducing risk of type 2 diabetes in first‐degree relatives of patients with type 2 diabetes. Journal of human nutrition and dietetics. 17 (6): 513-521.
Brouns F, et al. 2005. Glycaemic index methodology. Nutrition research reviews. 18 (1): 145-171.
Ceriello A, Colagiuri S, Gerich J & Tuomilehto J 2008. Guideline for management of postmeal glucose. Nutrition, metabolism and cardiovascular diseases. 18 (4): S17-S33.
Da Silva MS, et al. 2014. Associations between dairy intake and metabolic risk parameters in a healthy French-Canadian population. Applied physiology, nutrition, and metabolism. 39 (12): 1323-1331.
Daly RM, et al. 2014. The effects of progressive resistance training combined with a whey-protein drink and vitamin D supplementation on glycaemic control, body composition and cardiometabolic risk factors in older adults with type 2 diabetes: study protocol for a randomized controlled trial. Trials. 15 (1): 431.
DeFronzo RA 2009. From the triumvirate to the „ominous octet”: a new paradigm for the treatment of type 2 diabetes mellitus. Clinical diabetology. 10 (3): 101-128.
Díaz-López A, et al. 2016. Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. European journal of nutrition. 55 (1): 349-360.
Drehmer M, et al. 2015. Associations of dairy intake with glycemia and insulinemia, independent of obesity, in Brazilian adults: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The American journal of clinical nutrition. 101 (4): 775-782.
Egger M, Smith GD, Schneider M & Minder C 1997. Bias in meta-analysis detected by a simple, graphical test. Bmj. 315 (7109): 629-634.
Flaim C, Kob M, Di Pierro AM, Herrmann M & Lucchin L 2017. Effects of a whey protein supplementation on oxidative stress, body composition and glucose metabolism among overweight people affected by diabetes mellitus or impaired fasting glucose: A pilot study. The Journal of nutritional biochemistry. 50: 95-102.
Floyd J, Fajans SS, Conn JW, Knopf RF & Rull J 1966. Stimulation of insulin secretion by amino acids. The Journal of clinical investigation. 45 (9): 1487-1502.
Frid AH, Nilsson M, Holst JJ & Björck IM 2005. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects–. American journal of clinical nutrition. 82 (1): 69-75.
Gaffney KA, et al. 2018. Nil Whey Protein Effect on Glycemic Control after Intense Mixed-Mode Training in Type 2 Diabetes. Medicine and science in sports and exercise. 50 (1): 11-17.
Goudarzi M & Madadlou A 2013. Influence of whey protein and its hydrolysate on prehypertension and postprandial hyperglycaemia in adult men. International dairy journal. 33 (1): 62-66.
Hall W, Millward D, Long S & Morgan L 2003. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. British journal of nutrition. 89 (2): 239-248.
Higgins J & Green S 2011. Handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. The Cochrane Collaboration.
Jakubowicz D, et al. 2013. Effect of whey protein concentrate on blood glucose, insulin and C-peptide serum levels following a high glycaemic index breakfast in patients with type 2 diabetes. In Diabetologia.
Jakubowicz D & Froy O 2013. Biochemical and metabolic mechanisms by which dietary whey protein may combat obesity and Type 2 diabetes. The Journal of nutritional biochemistry. 24 (1): 1-5.
Jakubowicz D, et al. 2014. Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial. Diabetologia. 57 (9): 1807-1811.
Jakubowicz D, Landau Z, Wainstein J, Bar-Dayan Y & Froy O 2016. Whey Protein Induces Greater Reduction of Postprandial Glycemia and HbA1c. Weight Loss and Satiety Compared to Other Protein Sources in Type. 2.
Jakubowicz D, et al. 2017. High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA1C in Type 2 diabetes. Journal of nutritional biochemistry. 49: 1-7.
King DG, et al. 2018. A small dose of whey protein co-ingested with mixed-macronutrient breakfast and lunch meals improves postprandial glycemia and suppresses appetite in men with type 2 diabetes: a randomized controlled trial. The American journal of clinical nutrition. 107 (4): 550-557.
Lau J, Ioannidis JP & Schmid CH 1997. Quantitative synthesis in systematic reviews. Annals of internal medicine. 127 (9): 820-826.
Lovegrove JA & Givens DI 2016. Dairy food products: good or bad for cardiometabolic disease? Nutrition research reviews. 29 (2):
249-267.
Marathe CS, Rayner CK, Jones KL & Horowitz M 2013. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes care. 36 (5): 1396-1405.
Mignone L, et al. 2016. A whey/guar" preload" improves postprandial glycaemia and HbA (1c) in type 2 diabetes: a 12-week, single-blind, randomised and placebo controlled trial. Diabetologia. 59 (Suppl. 1): S9-S9.
Mignone LE, Wu T, Horowitz M & Rayner CK 2015. Whey protein: The “whey” forward for treatment of type 2 diabetes? World journal of diabetes. 6 (14): 1274.
Moher D, Liberati A, Tetzlaff J & Altman DG 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of internal medicine. 151 (4): 264-269.
Morgan LM, Shi J-W, Hampton SM & Frost G 2012. Effect of meal timing and glycaemic index on glucose control and insulin secretion in healthy volunteers. British journal of nutrition. 108 (7): 1286-1291.
Mortensen L, et al. 2012. Effects of different fractions of whey protein on postprandial lipid and hormone responses in type 2 diabetes. European journal of clinical nutrition. 66 (7): 799.
Mortensen LS, et al. 2009. Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein–. The American journal of clinical nutrition. 90 (1): 41-48.
Pal S & Radavelli‐Bagatini S 2013. The effects of whey protein on cardiometabolic risk factors. Obesity reviews. 14 (4): 324-343.
Plat L, et al. 1996. Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans. American journal of physiology-endocrinology and metabolism. 270 (1): E36-E42.
Power-Grant O, et al. 2015. In vitro bioactive properties of intact and enzymatically hydrolysed whey protein: targeting the enteroinsular axis. Food & function. 6 (3): 972-980.
Raben A 2014. Glycemic index and metabolic risks: how strong is the evidence? Oxford University Press.
Rizza RA 2010. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes. 59 (11): 2697-2707.
Smedegaard SB, et al. 2021. β-Lactoglobulin Elevates Insulin and Glucagon Concentrations Compared with Whey Protein—A Randomized Double-Blinded Crossover Trial in Patients with Type Two Diabetes Mellitus. Nutrients. 13 (2): 308.
Standl E, Schnell O & Ceriello A 2011. Postprandial hyperglycemia and glycemic variability: should we care? Diabetes care. 34 (Supplement 2): S120-S127.
Tessari P, et al. 2007. Slow versus fast proteins in the stimulation of beta‐cell response and the activation of the entero‐insular axis in type 2 diabetes. Diabetes/metabolism research and reviews. 23 (5): 378-385.
Watson LE, et al. 2019. A whey/guar "preload" improves postprandial glycaemia and glycated haemoglobin levels in type 2 diabetes: A 12-week, single-blind, randomized, placebo-controlled trial. Diabetes, obesity and metabolism. 21 (4): 930-938.
Woerle HJ, et al. 2007. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance of postprandial glycemia to achieve target HbA1c levels. Diabetes research and clinical practice. 77 (2): 280-285.
Wu T, et al. 2016. A protein preload enhances the glucose-lowering efficacy of vildagliptin in type 2 diabetes. Diabetes care. 39 (4): 511-517.
Zhang J, et al. 2016. Effect of whey protein on blood lipid profiles: a meta-analysis of randomized controlled trials. European journal of clinical nutrition. 70 (8): 879.
Type of article: review article |
Subject:
public specific
Received: 2023/07/23 | Published: 2025/02/4 | ePublished: 2025/02/4
Received: 2023/07/23 | Published: 2025/02/4 | ePublished: 2025/02/4
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