Do polyphenols affect body fat and/or glucose metabolism?

Background Obesity is reaching epidemic proportions with 51% of the population expected to be obese by 2030. Recently, polyphenols have been highlighted as an effective approach to managing obesity and associated risks. Polyphenols are a large class of bioactive plant compounds classified into two major categories: flavonoids which are distinguished by the fundamental C6-C3-C6 skeleton and non-flavonoids. Objective This systematic review evaluated the effect of different polyphenol sources in overweight and obese people with and without type 2 diabetes. The primary outcome was lipid profile and the secondary outcomes were blood glucose, HbA1c (%), HOMA-IR, weight, and body mass index. Method A search was undertaken in PubMed, Web of Science, Medline, and Wiley for randomized control trials that assessed different sources of polyphenols in overweight and obese people with or without type 2 diabetes. The quality of the included studies was assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tool. Result The search yielded 935 studies, of which six randomized control trials met the inclusion criteria. Five studies found no significant difference in lipid profile between the control and intervention groups in triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol. However, one study showed significant differences in triglycerides (p = 0.04) and HDL cholesterol (p = 0.05) between the two groups with no significant difference in total cholesterol and LDL cholesterol. There were no significant changes in blood glucose observed in the included studies, with only two studies reporting a significant difference in A1c between the groups. Four studies found no difference in HOMA-IR, while one study showed a significant decrease in HOMA-IR in the intervention group compared to the control group. Three studies reported no difference in BMI or weight between the two groups. Conclusion The data associated with the specific health benefits of polyphenols and their sources in people with overweight, obese, and type 2 diabetes are still limited, so further research is required to support their use and prove their benefits.


Introduction
Obesity has reached epidemic proportions, with the World Health Organization (WHO) estimating that there are more than 1.9 billion overweight adults worldwide, of which 650 million are obese (1).In addition, there are more than 340 million overweight or obese children and adolescents between the ages of 5 and 19 (1).By 2030, 51% of the population is expected to be obese (2).Excess weight is associated with a range of metabolic complications such as hypertension, insulin resistance, dyslipidaemia, and type 2 diabetes (3-5), as well as a significant economic burden.The direct costs include healthcare costs for treating related diseases, while indirect costs include lost productivity due to disability or premature death (2,6).Altering lifestyles to reduce calorie consumption and increase physical activity are difficult to preserve in the long term, therefore, it is necessary to find methods to lower the prevalence of obesity and its associated diseases.
Recently, polyphenols have been highlighted as a practical approach to managing obesity and associated risks.Polyphenols are an enormous class of bioactive plant compounds classified into two major categories: flavonoids which are distinguished by the fundamental C6-C3-C6 skeleton, and non-flavonoids (particularly phenolic acids, stilbenes, and lignans) (7) as shown in Table 1.Flavones, flavonols, isoflavones, flavanones, anthocyanins, and flavanols, commonly known as catechins, are the subclasses that result from the heterocyclic ring connecting the two aromatic rings (7), the primary forms are either conjugated with acid-alcohol or with glycosides in plant food items (7,8).In addition, polyphenols exist as monomers and oligomers, which are typically referred to as tannins (8).Condensed tannins and hydrolysable tannins are derived from catechin and are usually called procyanidins (8).Phenolic compounds are challenging to quantify because of their diversity and complexity (7,8).As Polyphenols represent a diverse group of phytochemicals found abundantly in plant-based foods as shown in Table 1.

Lignans
Lignans are polyphenolic compounds abundant in seeds, whole grains, fruits, and vegetables.They are converted by intestinal bacteria into enterolignans, which have been associated with various health benefits, including hormone regulation and antioxidant activity (9,11).

Stilbenes
This subgroup includes compounds such as resveratrol, primarily found in grapes, red wine, peanuts, and berries.Resveratrol has gained attention for its potential health-promoting effects, including anti-inflammatory and cardioprotective properties (9,11).

Others
This category encompasses a wide range of polyphenolic compounds, including tannins, stilbenoids, and curcuminoids.Tannins are commonly found in tea, wine, and certain fruits, and they contribute to the astringent taste of these foods.Stilbenoids, besides resveratrol, include pterostilbene, found in blueberries and grapes (9,11).Curcuminoids are derived from turmeric and exhibit various biological activities, including antioxidant and antiinflammatory properties.
There are several possible mechanisms for the positive effect of polyphenols in obesity and associated risks as shown in Figure 1 including the inhibition of fat absorption from the gastrointestinal tract, glucose uptake by skeletal muscles, the regulation of fat production, appetite suppression, the modulation of the gut microbiota, and reduced chronic inflammation associated with obesity (12, 13).
Numerous epidemiological and clinical studies have investigated the effect of different polyphenols on obesity and associated risks.For example, Shrime et al. (14), revealed that consuming cocoa, which is high in flavanol, reduced insulin resistance.Also, insulin resistance was improved in healthy individuals who consumed pure-epicatechin for a month by alterations in fasting insulin levels without affecting fasting glucose levels (15).In a systematic analysis of six studies, the green coffee extract reduced fasting blood glucose, while only larger dosages helped enhance insulin resistance (16).Following a 12-week olive leaf polyphenols supplementation in middle-aged, overweight men had increased insulin action and secretion (17).A systematic review and meta-analysis of six studies reported that pistachio nut consumption enhanced insulin resistance (18).Pecan and almond eating appear to improve insulin resistance (19,20).However, a systematic review of walnuts found no impact on fasting blood glucose or other measures of insulin resistance (21).
Habitual consumption of tea was linked to lower body fat in a cross-sectional human study in Taiwan (22).In addition, a longitudinal investigation from the Netherlands showed a lower body mass index among women with higher dietary flavone, flavonol, and catechin consumption (23).Furthermore, clinical trials have shown a positive effect of high doses of catechins in tea drinks, effectively reducing body fat and body weight, especially when combined with an exercise regimen (24,25).Moreover, a recent meta-analysis showed that consuming resveratrol significantly reduces weight, body mass index, and fat mass (26).However, a systematic review and meta-analysis of 19 RCTs focusing on the effect of anthocyanin on cardiometabolic biomarkers showed that there is no significant effect Inconsistencies in the findings and methodological limitations of individual studies, as well as inconsistencies in the results of previous systematic reviews and meta-analyses, justify the need for a comprehensive systematic review to assess the impact of polyphenols on obesity and its associated risks.In contrast to previous systematic reviews, different types of polyphenols were included and compared.In addition to the increasing volume of new studies, an updated systematic review is needed.Therefore, this systematic review compared different sources of polyphenols in overweight and obese individuals with or without type 2 diabetes.The primary outcome was lipid profile and the secondary outcomes were blood glucose, HbA1c (%), HOMA-IR, weight, and body mass index.
The criterion for selecting the types of foods presented in the search terms was based on their known richness in polyphenols, as documented in scientific literature.We considered foods that are commonly recognized for their high polyphenol content and relevance to human consumption.Additionally, we aimed to include a diverse range of food sources to provide a comprehensive overview of polyphenol intake.However, there are many other sources of polyphenol not included in our search terms, including olives oil and that should be considered in future research.

Eligibility criteria
The current systematic review examined study eligibility using a population comparison and outcome as shown in

Data extraction and synthesis
The following data were extracted from the studies: the author's name, the year of publication, the study location, the study design, the target population, the sample size, the baseline characteristics of participants, and the primary outcome lipid profile.The secondary outcomes were blood glucose, weight, and body mass index.A metaanalysis was not performed due to the heterogeneity of the data.

Quality assessment
The study quality was evaluated using the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for randomized controlled trials (29).The tool comprises 14 questions answered using the following options: yes, no, not reported, or not applicable.

Eligibility of studies
The literature search retrieved 935 studies, of which 97 were duplicate studies.Further screening of the title and abstract led to the exclusion of 811 studies, leaving 27 studies to be assessed against the inclusion/exclusion criteria and finally, six studies were included in this review (Figure 2).

Quality assessment
The quality of each study was evaluated using the NHLBI Quality Assessment Tool for randomized controlled trials (Table 3).Overall, the studies reported on the effect of different sources of polyphenols in overweight and obese people with and without type 2 diabetes seem convergent and reliable to indicate the effect of polyphenols.

Study characteristics
The six included studies, which involved a total of 301 adults, were published between 2010 and 2019.Four studies were conducted on people who were obese or overweight (30)(31)(32)(33), and two studies were conducted on people with type 2 diabetes (34, 35).

Primary outcomes Polyphenols and lipid profile
Six studies evaluated the lipid profile, five of which found no significant difference in triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol between the control and the intervention groups (30-34).However, Asadi et al. (35) showed significant differences in TG (p = 0.04) and HDL-c (p = 0.05) between the two groups at the end of the study.

Polyphenols and A1c
Only two studies assessed cumulative glucose and found significant differences between groups (34, 35).Was the study described as randomised, a randomised trial, a randomised clinical trial, or an RCT? 2.
Was the method of randomization adequate (i.e., use of randomly generated assignment)? 3.
Was the treatment allocation concealed (so that assignments could not be predicted)? 4.
Were study participants and providers blinded to treatment group assignment?

5.
Were the people assessing the outcomes blinded to the participants' group assignments?Were outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)? 14.
Were all randomszed participants analysed in the group to which they were originally assigned, i.e., did they use an intention-to-treat analysis?Five studies evaluated HOMA-IR, four of which found no difference between the two groups (30,32,33,35) while Aghasi et al. (34) showed that there is a significant decrease in HOMA-IR (−1.7) in the intervention group compared to the control group.

Polyphenols and BMI
Three studies assessed BMI and found no difference between the two groups (30,32,34).

Polyphenols and weight
Three studies measured weight and showed that there is no difference between the two groups (30,32,33).

Discussion
This systematic review compared the effects of different sources of polyphenols in overweight and obese people with or without type 2 diabetes.The primary outcome was lipid profile and the secondary outcomes were blood glucose, HbA1c (%), HOMA-IR, weight, and body mass index.However, the effects of different sources of polyphenols for obese or overweight adults with or without type 2 diabetes remain unclear.

Epicatechin
Epicatechin is a polyphenol found in various plant-based foods and beverages such as cocoa, grapes, apples, berries, hazelnuts, walnuts, and tea.Kirch (30) investigated whether regular consumption of 25 mg of pure epicatechin can affect glucose, HOMA-IR, LDL, HDL, total cholesterol, and triglycerides in overweight or obese people, showing that 2 weeks of epicatechin supplementation did not reduce cardiometabolic risk factors with no significant changes in glucose metabolism (glucose, HOMA-IR).Similarly, both Dower et al. (15) and Gutiérrez-Salmeán et al. (36) showed that regular intake of pure epicatechin (25-100 mg/ day) was not effective or less effective on cardiovascular disease risk factors than comparative cocoa intake.Meta-analyses of randomized controlled trials found positive effects of cocoa consumption on glucose and lipid metabolism (14,37) that could be predicted by epicatechin intake from cocoa (38).However, the results are inconsistent due to different dosing duration and may be due to adherence.

Strawberry and cranberry
There are several different types of phenolic compounds in strawberries and cranberries including phenolic acids, flavonoids, and polymerized molecules (39).Several vitro and animal studies have suggested that polyphenols may enhance peripheral glucose absorption in insulin-sensitive areas by enhancing GLUT4 translocation and activity and lowering oxidative stress and inflammation (40,41).For example, Paquette et al. (31) evaluated the effectiveness of berries and strawberries on insulin sensitivity and lipid profile in overweight, obese, and non-diabetic subjects showing that a six-week intervention with 333 mg of polyphenols from strawberries and cranberries improved insulin sensitivity but was ineffective in improving cardiac risk factors.
However, other studies have shown that eating freeze-dried strawberry powder or cranberry extract has a positive influence on lowering total cholesterol and LDL cholesterol (42,43).This discrepancy may be due to the delivery of strawberries and cranberries in different forms (juice, dried strawberries, and powder) and the different quantities consumed, which makes it difficult to determine their effect.

Green tea
Epidemiologic and animal research supports the positive effect of regular green tea consumption in decreasing the risk of cardiovascular disease (44) and obesity (45).There are several hypothesized methods by which green tea and its naturally occurring polyphenolic catechins may modify body weight.For instance, green tea and its derivatives cause glucose malabsorption and downregulate fatty acid synthase (46, 47).Individuals with visceral obesity who consumed 583 mg of catechins daily for 12 weeks saw significant reductions in body weight and LDL cholesterol compared to the control group (48).However, Stendell-Hollis et al. (32) evaluated the effect of green tea consumption on weight, body mass index, triglycerides, total cholesterol, HDL and LDL cholesterol, glucose, and HOMA-IR in weight gain showing no significant differences between the participants who consumed 960 mL of decaffeinated green tea or placebo daily for 6 months.

Red wine
It has been reported that a moderate wine intake might inhibit metabolic syndrome and related medical consequences (49).According to preclinical research, red wine polyphenols are beneficial and improve insulin sensitivity in obese animal models.However, the effect of red wine on humans is minimal.Only one randomized control trial was conducted by Woerdeman et al. (33) to assess the effection of red wine consumption on total cholesterol, HDL and LDL cholesterol, glucose, and HOMA-IR.The participants were randomized to 600 mg/day of red wine polyphenols or placebo daily for 8 weeks and there were no significant changes in either total, LDL or HDL cholesterol or triglyceride levels, glucose, and HOMA-IR after red wine supplementation between groups (p > 0.5).

Green cardamom
Green cardamom is a good source of polyphenols with antioxidant properties (50).Cardamom supplementation enhanced insulin sensitivity and reduced total cholesterol and LDL-cholesterol in prediabetic women (51).However, these outcomes did not differ significantly from the placebo group.According to Azimi et al. (52), the lipid profiles of type 2 diabetes people who consumed three glasses of black tea along with 3 g of cardamom were improved when compared to the control group which only consumed three glasses of black tea.Furthermore, it has been shown that 3 g of cardamom significantly decreased serum HbA1C (−0.4%),HOMA-IR (−1.7), and TG (−39.9 mg dL − 1) in the cardamom group compared to placebo (34).However, there were no significant changes in serum glucose TC, HDL-c, and LDL-c levels between the two groups after 10 weeks (34).Melissa officinalis (also known as lemon balm) Melissa officinalis is a plant that can lower blood sugar and fat levels due to its abundance of flavonoids (53).Studies have shown the lipidlowering and anti-inflammatory properties of M. officinalis (53,54).Furthermore, Asadi et al. ( 35) assessed the effect of M. officinalis intake (700 mg/d) versus placebo on HbA1c, triglycerides, total cholesterol, HDL and LDL cholesterol, glucose, and HOMA-IR in individuals with type 2 diabetes, observing significant differences in HbA1c (p = 0.002), triglycerides (p = 0.04), and HDL-c (p = 0.05) between the two groups after 12 weeks.In vitro and animal experiments also demonstrated that M. officinalis reduced blood glucose and lipids (55,56).

Potential mechanisms
Polyphenols are subject to a series of enzymatic reactions and microbial transformations upon ingestion, culminating in their absorption, distribution, metabolism, and excretion throughout various tissues and organs.
First, the chemical structure of polyphenolic compounds greatly influences their metabolic fate.For example, flavonoids, phenolic acids, and other subclasses exhibit distinct metabolic pathways, leading to the formation of diverse metabolites with different bioactivities (57).Phase I and II metabolic reactions, which are mainly facilitated by hepatic enzymes, modify the structure of the polyphenols, making them more water-soluble and leading to their elimination (58,59).
Moreover, consuming food components together can significantly affect polyphenol metabolism.Interactions with macronutrients, such as lipids and proteins, may affect the absorption kinetics and bioavailability of polyphenols (60).In addition, the presence of other bioactive compounds within food matrices can modify polyphenol metabolism, which may enhance or inhibit their bioactivity through synergistic or antagonistic effects (61).
Furthermore, individual differences in the composition of the gut microbiota contribute to interindividual differences in polyphenol metabolism.Some microbial species possess the enzymatic machinery necessary for the degradation and biotransformation of polyphenolic compounds, resulting in metabolites that may exhibit distinct physiological effects compared to their parent compounds (62).
Understanding the metabolism of polyphenolic compounds is crucial to elucidating their health effects and therapeutic potential.By revealing the complex interplay between nutritional factors, host physiology, and gut microbiota, future research endeavors can pave the way for personalized nutritional interventions aimed at improving the bioavailability of polyphenols and harnessing their beneficial properties for human health and well-being.

Strength and limitation
The quality assessment of the included studies was conducted to evaluate the methodological rigor and reliability of the evidence presented.We utilized the NHLBI Quality Assessment for Randomized Control Trials (RCTs) which assesses various aspects of study design, conduct, and reporting.
Overall, the quality of the included polyphenol studies varied.Several studies demonstrated a high level of methodological rigor, including randomized controlled trials (RCTs) with appropriate randomization and blinding procedures.However, certain limitations were observed across the studies.Common issues included small sample sizes, lack of blinding, incomplete outcome data, and potential biases.Despite these limitations, many studies provided valuable insights into the potential health effects of polyphenols.
It is important to interpret the findings of polyphenol studies with caution, considering the methodological limitations identified.Future research should prioritize high-quality study designs, including wellpowered RCTs with long-term follow-up, and systematic reviews with rigorous methodology.

Conclusion
The current systematic review discussed the effect of different sources of polyphenols in overweight and obese people with or without type 2 diabetes, showing that cardamom significantly decreased serum HbA1C, HOMA-IR, and triglyceride and M. officinalis reduced blood sugar fat levels and lipids.However, the data associated with the specific health benefits of polyphenols and their sources in people who are overweight, obese, or have type 2 diabetes are still unclear and further research is required to support their use and prove their benefits.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

6 .
Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, co-morbid conditions)?7.Was the overall drop-out rate from the study at endpoint 20% or lower of the number allocated to treatment?the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power?13.

TABLE 1
Classes of polyphenols and the principal dietary constituents.

Table 2 :
▪ Study design: randomized control trial to address the research question ▪ Population: Overweight and obese adults with or without type 2 diabetes ▪ Intervention: different sources of polyphenols ▪ Outcomes: The primary outcome is lipid profile and secondary outcomes are blood glucose, HbA1c (%), weight and body mass index.
▪ Review studies ▪ Case reports ▪ Observation study ▪ Non-English studies ▪ The full text of the study was not available.

TABLE 2
Population-intervention-comparison-outcome (PICOS) criteria for study inclusion and exclusion.

TABLE 3 NHLBI
tool for quality assessment of included studies.

TABLE 5
Type 2 diabetes mellitus and polyphenol.