Review Article | Open Access
Diet, Inflammation, and Glycemic Control in Type 2 Diabetes: An Integrative Review of the Literature
Type 2 diabetes (T2D) is a growing national health problem affecting 35% of adults ≥20 years of age in the United States. Recently, diabetes has been categorized as an inflammatory disease, sharing many of the adverse outcomes as those reported from cardiovascular disease. Medical nutrition therapy is recommended for the treatment of diabetes; however, these recommendations have not been updated to target the inflammatory component, which can be affected by diet and lifestyle. To assess the current state of evidence for which dietary programs contain the most anti-inflammatory and glycemic control properties for patients with T2D, we conducted an integrative review of the literature. A comprehensive search of the PubMed, CINAHL, Scopus, and Web of Science databases from January 2000 to May 2012 yielded 786 articles. The final 16 studies met the selection criteria including randomized control trials, quasiexperimental, or cross-sectional studies that compared varying diets and measured inflammatory markers. The Mediterranean and DASH diets along with several low-fat diets were associated with lower inflammatory markers. The Mediterranean diet demonstrated the most clinically significant reduction in glycosylated hemoglobin (HbA1c). Information on best dietary guidelines for inflammation and glycemic control in individuals with T2D is lacking. Continued research is warranted.
Thirty-five percent of Americans who are aged 20 years and older have type 2 diabetes (T2D) . The etiology behind such impressive statistics is complex but can be attributed in part to recent changes in the lifestyle choices of Americans, including changes in habitual diet. The What We Eat in America (WWEIA) report, based on data obtained from the National Health and Nutrition Examination Survey (NHANES), demonstrated that grains (mainly refined) have contributed to the bulk of the rise in caloric intake in the US in the last 60 years . Increased consumption of added sugars, processed grains, and saturated fat contributed to excess weight gain, which is an influential risk factor in the development of T2D [3, 4]. In fact, results from implementation of the Diabetes Prevention Program (DPP) illuminated that up to 58% of diabetes can be prevented through lifestyle changes alone, including changes in diet .
One underlying pathophysiological process resulting from poor lifestyle habits is inflammation. Inflammation is present prior to the development of T2D and cardiovascular disease (CVD), contributing to evidence to support the “common soil” hypothesis, which is a reference to the common risk factors for the development of these two diseases . CVD is one of the major complications and causes of death in persons with T2D, supporting this hypothesis . The Multi-Ethnic Study of Atherosclerosis (MESA) showed that higher levels of the inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6, were associated with an increased risk of developing T2D . Chronic inflammation in T2D initiates with states of obesity, hyperglycemia, insulin resistance, and the overexpression of proinflammatory proteins like CRP and cytokines (IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)) . These proinflammatory molecules activate the cells of innate immunity, which cause damage to tissues in the vasculature, adipose tissue, and pancreas. Acute responses through this proinflammatory pathway are needed for tissue damage repair and can improve function in tissues such as the pancreas, for example; however, chronic expression can lead to pathological changes which result in disease . These changes clinically manifest as CVD, nephropathy, and symptomatic T2D, as the innate immune system attempts to repair the damaged tissue. Moreover, inflammation is stimulated in times of stress, which can be induced by environmental, behavioral, individual, and psychosocial factors  and diet-induced hyperglycemia and hypertriglyceridemia . Hyperglycemia and hypertriglyceridemia are significant stressors that have also been shown to cause chronic inflammation and contribute to the pathogenesis of T2D .
2. Problem and Research Aims
Although the published literature is populated with articles and systematic reviews demonstrating the relationship between dietary patterns, individual dietary factors, and incidence of diabetes [11, 12], the primary literature linking inflammation to diet and T2D is minimal. One of the few reported areas is with the Mediterranean-style diet, which has been associated with lower inflammatory markers and decreased incidence of T2D [12, 13]. Although several reviews have investigated the effects of diet for T2D control, few disclosed the association with underlying inflammatory responses. Therefore, the aim of this study was to present an integrative review of the published literature on the associations between dietary intake and markers of chronic inflammation in patients with T2D. This review and synthesis of the relevant literature seeks to answer the following research question: what is the current state of the science regarding the association between diet and inflammation in established T2D?
3. The Literature Search
This review targeted adults (≥18 years) diagnosed with T2D. All studies that included a dietary intervention, either exclusively or as part of an intervention, were included. Eligibility criteria included diet, inflammatory markers, and T2D evaluated in randomized clinical trial (RCT), quasiexperimental, or cross-sectional studies. The following databases were searched: PubMed, CINAHL, Scopus, and Web of Science. Keywords used in the search were combinations of the “diet,” “chronic inflammation,” “type 2 diabetes,” “C-reactive protein,” “interleukins,” and “tumor necrosis factor” (TNF). A health sciences librarian was consulted on the selection of these search terms. The search was conducted on articles published between January 2000 (the year of the first appearance of diet, inflammation, and T2D in the literature) and May 2012. Studies were limited to only those written in the English language. Studies that focused on prevention of T2D were excluded, as they did not offer data to assist in the exploration of how diet relates to the inflammatory process within the pathogenesis of T2D. Other exclusion criteria were studies that focused on supplements alone or exercise without an evaluation of, or comparison to, diet.
4. Search Outcomes
The search produced 371 studies in PubMed, 265 studies in Web of Science, and 150 studies in CINAHL (see Figure 1). Titles and abstracts were initially screened. Among these, 19 studies met the full inclusion criteria. The full text from these articles was carefully reviewed. Six more studies were discarded. Two were eliminated because they included predominantly healthy subjects in a cross-sectional study; one was eliminated because it included exercise only, one was eliminated due to its focus on prevention of T2D, and two were eliminated because they focused on acute responses to dietary interventions. Three additional studies were identified by hand-searching reference lists of the selected articles. A final total of 16 papers were included for critical analysis with synthesis of findings. Experimental and nonexperimental studies were included in the analysis. In this integrative review, two studies were cross-sectional [14, 15], two were experimental [16, 17], and twelve were quasiexperimental, as follows: three were crossover experimental designs [18–20], three were pretest-posttest designs with only one group [21–23], and six were pretest-posttest designs with two or more comparison groups [24–29]. More than half of the studies were international with one from the Middle East, one from Canada, three from Australia, and six from Europe. The other five were from the US. All were published in English. All subjects in the cross-sectional studies had a diagnosis of T2D, while several experimental studies utilized healthy and/or obese controls. Acceptable measures for inflammation included serum evaluations of CRP, IL-6, TNF, or a combination of one or more of these with other markers of inflammation.
Each study was read twice to ensure identification of salient topics for analysis. Three tables were created to aid synthesis of the data. Table 1 is an overview of information for broad topics created to aid in abstracting those aspects that were definitive in interpreting the implications of the findings. From this table, it became clear that each study reported inflammatory markers at different time points (e.g., some studies did not report baseline values), which was informative for the data reduction process. Quality assessment ratings were established, and each article was scored based on these criteria (Table 2). Tables 3 and 4 contain the results of data abstraction and synthesis, respectively.
|Note. Ad: adherence; Diet: dietary intervention defined; Read: readability; Repr: reproducibility; TO: appropriate use of temporal ordering.|
|Note: CRP: C-reactive protein; HbA1c: glycosylated hemoglobin; F: females; M: males; : mean; age: mean age; Δ: change in; HOMA: homeostatic model assessment; DPP: Diabetes Prevention Program; DASH: Dietary Approaches to Stop Hypertension; GI: Glycemic Index; MUFA: monounsaturated fatty acid; ns: not significant; C: energy from carbohydrates; F: energy from fat; *: Significance of between group differences.|
|Note: CRP: C-reactive protein; IL-6: interleukin-6; TNF: tumor necrosis factor-alpha; F: females; M: males; age: mean age; Semiquant: semiquantitative; FFQ: food frequency questionnaire; BMI: body mass index.|
5.1. Quality Assessment
Articles retrieved for review were assessed for quality of study conduct and reporting . Quality assessment scores were assigned based on 11 questions designed to capture the essence of the study design, methods, and analyses (Table 2). The quality score for each question was assigned based on how well the article fulfilled the expectations. A score of 0 represented absence of the criteria in question, and a score of 1 designated fulfillment of each criterion. These categories included aims, methods (3 questions), diet (3 questions), inflammatory measures, and analysis (2 questions). There was also one question related to results and conclusions with a rating of 0–2, with 2 being of highest quality, which was weighted more heavily due to its importance in interpretation of the study findings. The highest achievable score was 12.
5.2. Data Reduction
Studies were grouped by design method to differentiate results sections for accurate synthesis . Studies were first grouped into experimental () and correlational (). Studies were then further delineated by diet categories of association with inflammation and those with a focus on diabetes control (glycemic control). Tables 3 and 4 detail these findings.
6.1. Association between Diet and Inflammation
Several experimental studies demonstrated a reduction of systemic inflammation following an intervention of a prescribed diet in patients with T2D. Four of the studies with higher quality scores (≥9) demonstrated a significant association between diet and inflammation. Three of these four contained a low-fat (≤30% of energy from fat) dietary component [18, 25, 26]. Azadbakht et al.  implemented the Dietary Approaches to Stop Hypertension (DASH) diet in an eight-week crossover intervention study. The DASH diet is characterized by a high intake of whole grains, fruits, and vegetables, while limiting sodium intake (<2400 mg/day) . After controlling for weight reduction, there was a statistically significant decrease in mean CRP in the intervention group compared to the control group () . The low-fat low-protein diet implemented by Brinkworth et al.  is almost identical in macronutrient composition to the DASH diet (see Table 3). After 64 weeks of following this diet with minimal dietary counseling, participants demonstrated a drop in CRP levels, that is comparable to that which was found in the Azadbakht et al.  study group, which reached statistical significance () . The control group in this study received a high-protein, low-fat diet, which also caused a decrease in CRP, and there was not a significant difference in the mean change in CRP between groups () . Similarly, Davis et al.  demonstrated that after following an intervention of either a low-fat or low-carbohydrate diet for 24 weeks, CRP was only found to be significantly reduced in the low-fat diet arm () and not in the low-carbohydrate arm (). Wolever et al.  showed that after 52 weeks of following a low-glycemic-index, low-fat diet (~30% of energy intake from fat), CRP was reduced from baseline by 29% compared to a high-glycemic-index, low-carbohydrate diet that was also high in monounsaturated fat (MUFA) (). Wolever et al.  also examined the interaction of diet and time but found no significant effect of time or diet on CRP levels (see Table 1). Of these four studies, only Davis et al.  did not report adherence to the prescribed diet. All four studies were controlled for differences in weight loss.
Several other studies also demonstrated reductions in CRP with dietary interventions, albeit with lower quality scores, and with ranges between 4 and 8. Khoo et al.  used a crossover design and randomly assigned participants into one of two groups for 8 weeks. One group began on a low-calorie diet and the other a high-protein low-fat diet for eight weeks, then both groups continued on the high-protein low-fat diet for 44 weeks (see Table 1) . Mean-CRP levels were reduced significantly only in the high-protein, low-fat diet at 52 weeks () . Although diet diaries were collected throughout the study period, adherence to the diet was not reported. Bozzetto et al.  conducted a randomized crossover trial with only 12 participants, but the analysis revealed a decreasing mean-CRP level with fasting, 3-hour postprandial, and 6-hour postprandial following 4 weeks of a diet high in MUFAs, compared to the alternate diet which was high in carbohydrates and fiber with a low glycemic index () . A study by Giannopoulou et al.  also demonstrated the anti-inflammatory effects of a diet high in MUFAs (see Table 1). This study was 14 weeks long, and comparison groups included an exercise-only group and a group that was prescribed exercise as well as the high MUFA diet. All three groups demonstrated a significant reduction in mean-CRP at final data collection (); however, there was not a significant difference in this reduction between groups . It is interesting to note here that the diet and exercise group did not have a greater decrease in inflammatory markers than the diet-only group. These results indicate that exercise may not add benefit to improving inflammatory markers in patients with T2D. In another longitudinal study, Barnard et al.  randomized 99 participants to receive either a low-fat vegan diet or a conventional American Diabetes Association (ADA) diet for 74 weeks. Results showed a significant reduction of CRP within groups ( for each group) but a nonsignificant difference between the two diet groups , perhaps due to the similar macronutrient content of the two dietary interventions.
Following on the premise that increased fat mass in T2D contributes to inflammation, three other studies implemented diets that were low or very low in energy content [21–23]. Kozłowska et al.  implemented a diet with a 20% energy deficit and low protein for eight weeks without a comparison group. This diet did not produce a significant reduction in CRP; however, the 17 participants did exhibit significantly lower TNF-α levels () following the intervention . Additional two studies implemented two weeks of a very-low-calorie diet (VLCD) with obese subjects with T2D in highly controlled hospital environments [21, 23]. Dostlova et al.  demonstrated a significant drop in mean-CRP after two weeks of following a VLCD diet (). Mraz et al.  found that 2 weeks of a VLCD significantly decreased mean-CRP (), as well as decreased IL-6 levels (). Although significant results were found, such diets cannot be maintained, and as such the long-term effects are not known.
Marfella et al.  conducted an RCT in Italy with two groups that were advised to follow a Mediterranean-style diet. The Mediterranean diet is characterized by three servings of fruits and six servings of vegetables or wild leafy greens per day . Fish is consumed 5 to 6 times per week and contributes to the main source of fat, which is monounsaturated and polyunsaturated. The intervention group consumed 4 oz. of red wine per day, while the control group abstained from alcohol. Results revealed significantly greater reductions in CRP (), TNF-α (), and IL-6 () in the intervention group compared to the control group after the 52-week study period .
In contrast, there were several diets that did not alter inflammatory marker expression significantly. These included the high-carbohydrate/high-fiber/low-glycemic index diet , the low-carbohydrate diet implemented by Davis et al. , the low-carbohydrate and DPP-style diet implemented by Vetter et al. , and the Mediterranean diet .
The two cross-sectional studies included in this analysis examined associations between two different aspects of diet and differed significantly in terms of quality in reporting. Åsgård et al.  quantified fruit and vegetable intake, while Qi et al.  categorized whole grain, germ, and bran intake into quintiles. Qi et al. demonstrated a significant association between CRP and the dietary intake of interest, showing that with increasing quintiles of cereal fiber intake, CRP was significantly lower ( for trend ) . This inverse relationship was also present between TNF-α and cereal fiber intake ( for trend ). Åsgård et al.  also demonstrated a significant inverse correlation between alpha (α) and beta (β) carotenoids (foods that contain vitamin A) and inflammation ( and , resp.).
6.2. Diet Influences Glycemic Control
The positive influence of a dietary intervention on glycemic control [16, 20, 21, 24, 27] was examined in five studies. Dostlova et al.  measured fasting blood glucose (FBG) as a proxy for glycemic control and demonstrated a significant improvement in FBG following the two-week dietary intervention of a very-low-calorie diet (). Itsiopoulos et al.  also demonstrated an improvement in glycemic control following a 24-week crossover intervention with a Cretan Mediterranean diet as evidenced by a significantly reduced mean glycosylated hemoglobin (HbA1c) (), compared to the control diet which was the participants’ normal eating pattern. Both studies also demonstrated improvement in the homeostatic model assessment (HOMA) score, a measure of insulin resistance (see Table 1), although this change was not statistically significant following the Mediterranean diet [20, 21]. A third study by Barnard et al.  found that after following a vegan diet for 72 weeks, subjects had significantly improved HbA1c levels compared to those who followed a conventional diet as recommended by the ADA () (see Table 3). A Mediterranean diet was also implemented by Marfella et al. , along with either four ounces per day of red wine or no alcohol. HbA1c levels were not significantly different between the two groups; however, the mean change in HbA1c was greater than in all other studies included in this review (−1.1% for the intervention group and −1.2% for the control group) . The clinical significance of such a large change in HbA1c will be discussed later. Finally, Giannopoulou et al.  reported that although none of the intervention groups demonstrated a significant improvement in HbA1c, both the diet-only and diet and exercise groups had a significant reduction in fasting glucose levels ( for both groups). Interestingly, only the two interventions with exercise produced a significant reduction in insulin resistance .
The great variability between studies decreases the ability to draw definitive conclusions about associations between diet, inflammation, and T2D; however, particular themes emerged that are worth noting both from this review and in light of previous research. First, of the ten different diets prescribed that were low in fat, both within and across studies, eight of those diets led to significant reductions in inflammatory markers. These included the DASH diet , the low-fat DPP-style diet , the low-energy low-protein diet , the vegan and ADA diets , the high-protein low-fat diet , and both the high-protein and low-protein diets . However, this review also supported the hypothesis that the high-MUFA diet decreased inflammation.
Previous reports from the Whitehall and PREDIMED studies indicated that diets high in MUFA and polyunsaturated fatty acids (PUFAs) were correlated with decreased CRP [32, 33] and IL-6 , while diets high in saturated fatty acids were positively correlated with CRP . High intake of PUFA was also inversely correlated with incidence of T2D in the Nurse’s Health Study . Therefore, it was not surprising that the High-MUFA diet showed anti-inflammatory effects in the diabetic population [16, 19, 20, 29]. Bozzetto et al.  lacked baseline values for participants; therefore, it is not appropriate to infer causality for a change in CRP over the 4 weeks of the study period, but rather only in the acute postprandial response. Unfortunately, glycemic control was not concurrently assessed.
Dietary patterns, as opposed to specific aspects of diet, have also been shown to correlate with levels of chronic inflammatory markers, but this concept was not adequately examined in the selected studies. For example, the western dietary pattern, characterized by a high consumption of sugary drinks, red meat, and poultry and a low consumption of fruits, vegetables, and fiber, was correlated with higher levels of CRP in two large cross-sectional studies conducted in the US [34, 35].
The impact of diet on the metabolic milieu of T2D is evident from the results of this integrative review and others. However, statistical significance does not necessarily translate into clinical significance or meaningfulness. For example, of the two studies that were able to demonstrate a significantly reduced HbA1c following the prescribed diet, one failed to report baseline values of glycemic control,  and the other only demonstrated a mean reduction of 0.4% . While this result is statistically significant, it might not result in improvement in long-term outcomes of T2D, as demonstrated by findings from the United Kingdom Prospective Diabetes Study , which showed that a 1% reduction in HbA1c levels can lead to improvements in long-term outcomes and decreased mortality . The implementation of a Mediterranean-style diet and a glass of red wine per day produced a mean decrease in HbA1c of 1.1% (0.06) . The control group that did not receive the red wine intervention but did follow a Mediterranean diet had a similar decrease in HbA1c, as well as CRP, TNF-α, and IL-6 . The reductions in HbA1c were not found to be significantly different between intervention and control groups, though the drop in this important glycemic marker is clinically relevant, as it points to decreased incidence of diabetes-related complications and decreased mortality .
To further increase their clinical relevance, it is important for studies implementing dietary changes to examine sustainability of the prescribed diet. Although both studies of VLCD reported significant decreases in inflammatory markers, such a diet is not sustainable and is likely harmful for the individuals as evidenced by the significant increase in TNF-α following the 2-week VLCD implemented by Mraz et al. . The rationale behind this intensive diet is rapid improvement in metabolic parameters. The lack of long-term followup of the selected patients prevents us from extrapolating from these findings that patients will have sustained results. In fact, the crossover experimental study by Khoo et al.  illuminates that after 52 weeks of the prescribed diets, the group that initially received a low-calorie diet did not show a significant decrease in CRP, while the group that was prescribed the high-protein, low-fat diet for all 52 weeks did achieve significant reductions in CRP. This highlights that there may not be merit behind the rapid weight-loss from calorie-restricted programs in the aforementioned studies.
7.1. Gaps in Knowledge in the State of the Science
Due to the limited availability of data for analysis on this topic and the suboptimal quality of reporting within the studies, the results of this integrative review are inconclusive. Many of the studies reviewed suffered from significant methodological shortcomings. First, most of the studies had small sample sizes, with a range between 12 and 162 (mean sample size of 53, and median of 32), limiting the power of the intervention to detect an effect. The two studies with the largest sample sizes implemented the low-glycemic-index diet and Mediterranean diet with wine and showed significant reduction in inflammatory marker expression [16, 29]. Only three studies included in this integrative review conducted a power analysis [18, 24, 29], and one conducted a retrospective power analysis , which is paramount in substantiating findings or validating the need for further research if the findings were insignificant.
Second, several studies did not include transparent definitions of the dietary intervention, rendering it difficult to infer specific dietary factors that decrease inflammation from the results. In previous studies with healthy volunteers, decreased inflammation was correlated with several individual dietary factors including fiber, antioxidant vitamins such as vitamin C and carotenoids, and fruit and vegetable intake. For example, in large prospective studies, whole grain intake has been associated with both decreased inflammatory markers  and decreased incidence of T2D . Of the three experimental studies in the current review that indicated whole grains as an aspect of the diet, only one demonstrated decreased CRP levels following the intervention . Similarly, the cross-sectional study examining intake of whole grains showed an inverse association between increasing intake of cereal fiber and CRP levels . However, one study that implemented a high-carbohydrate, high-fiber diet and another that implemented a Cretan-Mediterranean diet, both of which are high in fiber, failed to demonstrate a decrease in CRP following the intervention [19, 20].
A third and final gap in knowledge related to this topic is adherence and change over time. Though several studies included in this study were longitudinal, the longest study was 74 weeks, which does not necessarily indicate that benefits obtained will be sustained in the long-term. This issue was highlighted in the study by Brinkworth et al.  in which two low-fat diets, one low-protein, and one high-protein were prescribed to 38 participants with regular dietary counseling for the first 12 weeks. At 12 weeks, HbA1c had decreased by 9.4% () in both groups . Results in glycemic control were attenuated, however, at 64 weeks due to the fact that participants had not received regular dietary counseling between weeks 12 and 64 . Recidivism such as this will likely be experienced in other long-term studies, underscoring the need for consistent counseling as well as followup in long-term studies that require behavior change .
There are several limitations of this integrative review. First, the review is limited to the published literature, so it is subject to publication bias. Several authors were contacted via email with requests for unpublished research, but none were available. Second, the articles reviewed for analysis only included a population with diagnosed T2D. This limited the available literature on the influence of diet on inflammation and glycemic control markedly. There is merit in restriction of the search to this population, given that their inflammatory markers will be elevated relative to the general population and would, therefore, benefit from dietary changes in a more clinically significant way. However, this strength may have limited the conclusions in this paper. Finally, it should be noted that this integrative review does not address the mechanism of action underlying reduction of systemic inflammation following a dietary intervention. Discussion of such is beyond the scope of this paper. The review by Visioli et al.  concluded that antioxidants, essential fatty acids, and plant extracts have been shown to reduce systemic inflammation. Extrapolating results from this integrative review to make inferences about specific nutrient effects is not possible; however, it can be inferred that nutrient content of the Mediterranean, vegan, and ADA diets may contain more of those qualities mentioned in the review .
7.3. Implication for Future Research
Given the limitations of the findings and the inconclusive results reached by this review, it is clear that more rigorous research is needed. The present level of evidence on this topic is Level III, given that most of the studies were quasiexperimental. This paper, therefore, increases the level of evidence by providing an integrative review of the available research. However, disparate methods of reporting findings have rendered synthesis of extant findings difficult and unnecessarily labor-intensive. Studies should adhere to the transparent reporting standards outlined by the Consolidated Standards of Reporting Trials . Researchers should also focus their efforts on increasing validity and reliability in research conduct. Adherence to dietary interventions needs to be reported and included in analysis of the findings, possibly by including a measure of adherence as a regression variable. Failure to include this critical factor could explain the variability in the findings of this integrative review, for a dose response is a likely influence in the success or failure of an intervention effect. Adequately-powered, high quality studies examining the association between dietary intake and inflammation in T2D are also needed.
Medical nutrition therapy is one aspect of prevention and care of T2D recommended by the ADA. Although the DPP demonstrated a reduction in the incidence of T2D following the adaptation of lifestyle changes, there have been few studies examining the influence of dietary interventions on inflammation and glycemic control in individuals with established T2D in the US. It is important to conduct these studies domestically because of the diversity of the populations affected by this disease and the increasing rates of T2D. For example, further analysis of the results from the DPP revealed an attenuated benefit from the intervention in non-Hispanic Black women, highlighting the need for an understanding of the complex sociocultural factors influencing the African American population . Studies examining the current dietary practices of individuals diagnosed with T2D are necessary, with a particular focus on differences in culturally-bound beliefs surrounding diet, food, and health.
None of the studies included in this review used a theoretical framework to guide the research, which could have contributed to the disparate findings of the included studies. Theoretical frameworks guide research questions and facilitate the process of asking a complete question. Considering that T2D is both a metabolic and inflammatory disease, it is imperative to design studies that address both of these issues in the methods and the outcome measures. For example, if an intervention of a high MUFA diet is implemented, it may be helpful not only to address inflammatory markers in the outcome measures, but also other influences on inflammation that could confound results such as physical activity, socioeconomic status, environmental stressors, and genetic factors as suggested by Kang’s Biobehavioral Model of Stress and Inflammation . It is unclear from the aforementioned studies how exercise, stress, and genetics contributed to the metabolic and inflammatory outcomes measured, and larger, more rigorous studies are needed that control these variables. Finally, based on the results of the aforementioned studies, RCTs using participants with T2D are needed for which the nutrition content of the dietary intervention has been optimized for the treatment of T2D. This includes high intake of fruits and vegetables that are high in flavonoids, which González-Castejón and Rodriguez-Casado  report in their review on phytochemicals to have anti-inflammatory and antioxidant activities that may improve the metabolic status of individuals with T2D. The Mediterranean diet is an extremely palatable diet rich in fruits, vegetables, fiber, and olive oil which has been shown with and without the addition of alcohol to improve inflammation, prevent the onset of T2D, and improve glycemic control in established T2D [16, 41, 44]. More high-quality RCTs implementing this diet are needed to provide the evidence base for modifying clinical practice guidelines in medical nutrition therapy for patients with T2D.
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