The state of the science on the health benefits of blueberries: a perspective.

Mounting evidence indicates that blueberry consumption is associated with a variety of health benefits. It has been suggested that regular consumption of blueberries can support and/or protect against cardiovascular disease and function, pre-diabetes and type 2 diabetes, and brain and cognitive function in individuals with health conditions and age-related decline. Further, mechanistic investigations highlight the role of blueberry anthocyanins in mediating these health benefits, in part through interactions with gut microbiota. Also, nutritional interventions with blueberries have demonstrated the ability to improve recovery following exercise-induced muscle damage, attributable to anti-inflammatory effects. Despite these advancements in blueberry health research, research gaps persist which affects the generalizability of findings from clinical trials. To evaluate the current state of knowledge and research gaps, a blueberry health roundtable with scientific experts convened in Washington, DC (December 6-7, 2022). Discussions centered around five research domains: cardiovascular health, pre-diabetes and diabetes, brain health and cognitive function, gut health, and exercise recovery. This article synthesizes the outcomes of a blueberry research roundtable discussion among researchers in these domains, offering insights into the health benefits of blueberries and delineating research gaps and future research directions.

Recent Research on the Health Benefits of Blueberries and Their Anthocyanins.

Awareness of the human health benefits of blueberries is underpinned by a growing body of positive scientific evidence from human observational and clinical research, plus mechanistic research using animal and in vitro models. Blueberries contain a large number of phytochemicals, including abundant anthocyanin pigments. Of their various phytochemicals, anthocyanins probably make the greatest impact on blueberry health functionality. Epidemiological studies associate regular, moderate intake of blueberries and/or anthocyanins with reduced risk of cardiovascular disease, death, and type 2 diabetes, and with improved weight maintenance and neuroprotection. These findings are supported by biomarker-based evidence from human clinical studies. Among the more important healthful aspects of blueberries are their anti-inflammatory and antioxidant actions and their beneficial effects on vascular and glucoregulatory function. Blueberry phytochemicals may affect gastrointestinal microflora and contribute to host health. These aspects have implications in degenerative diseases and conditions as well as the aging process. More evidence, and particularly human clinical evidence, is needed to better understand the potential for anthocyanin-rich blueberries to benefit public health. However, it is widely agreed that the regular consumption of tasty, ripe blueberries can be unconditionally recommended.

Protective Effects of Anthocyanins in Obesity-Associated Inflammation and Changes in Gut Microbiome.

Obesity is a complex disease and a major public health epidemic. Chronic, low-grade inflammation is a common underlying feature of obesity and associated metabolic diseases; adipose tissue is a major contributor to this systemic inflammation. Evidence shows that obesity-associated inflammation may originate from gut dysfunction, including changes in intestinal bacteria or microbiome profiles. Increasingly, food and plant bioactive compounds with antioxidant and anti-inflammatory properties are proposed to ameliorate obesity-associated inflammation. Among these, the health-promoting effects of anthocyanin-rich foods are of interest here. Specifically, this review summarizes the reported benefits of anthocyanins in obesity-associated inflammation and underlying molecular mechanisms, including the role of gut microbiome and cell signaling pathways regulated by anthocyanins both in vivo and in vitro.

Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes.

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism's health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1ß), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

Blueberry supplementation attenuates oxidative stress within monocytes and modulates immune cell levels in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Blueberries (BB) have been shown to improve insulin sensitivity and endothelial function in obese and pre-diabetic humans, and decrease oxidative stress and inflammation, and ameliorate cardio-renal damage in rodents. This indicates that blueberries have a systemic effect and are not limited to a particular organ system. In order for blueberries to exert beneficial effects on the whole body, the mechanism would logically have to operate through modulation of cellular humoral factors. OBJECTIVE: This study investigated the role of blueberries in modulating immune cell levels and attenuating circulatory and monocyte inflammation and oxidative stress in metabolic syndrome (MetS) subjects. DESIGN: A double-blind, randomized and placebo-controlled study was conducted in adults with MetS, in which they received a blueberry (22.5 g freeze-dried) or placebo smoothie twice daily for six weeks. Free radical production in the whole blood and monocytes, dendritic cell (DC) levels, expression of cytokines in monocytes and serum inflammatory markers were assessed pre- and post-intervention. RESULTS: Baseline free radical levels in MetS subjects' samples were not different between groups. Treatment with blueberries markedly decreased superoxide and total reactive oxygen species (ROS) in whole blood and monocytes compared to the placebo (p ≤ 0.05). The baseline DC numbers in MetS subjects' samples in both groups were not different, however treatment with blueberries significantly increased myeloid DC (p ≤ 0.05) and had no effect on plasmacytoid cells. Blueberry treatment decreased monocyte gene expression of TNFα, IL-6, TLR4 and reduced serum GMCSF in MetS subjects when compared to the placebo treatment (p ≤ 0.05). CONCLUSIONS: The findings of the current study demonstrate that blueberries exert immunomodulatory effects and attenuate oxidative stress and inflammation in adults with MetS.

Blueberries' Impact on Insulin Resistance and Glucose Intolerance.

Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM). These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity) after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by homeostatic model assessment-estimated insulin resistance (HOMA-IR), insulin tolerance tests, and hyperinsulinemic-euglycemic clamps. Additionally, the improvements in glucose tolerance after blueberry consumption were assessed by glucose tolerance tests. However, firm conclusions regarding the anti-diabetic effect of blueberries cannot be drawn due to the small number of existing clinical studies. Although the current evidence is promising, more long-term, randomized, and placebo-controlled trials are needed to establish the role of blueberries in preventing or delaying T2DM.

Lifestyle Approaches and Glucose Intolerance.

Glucose intolerance is a global health concern that encompasses glucose metabolism abnormalities such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). There is an urgent need to focus on the prediabetes (ie, IGT and IFG) stage before the disease actually occurs. The progression from IGT to T2D can be prevented or delayed by modifying the lifestyles in high-risk individuals, and these health benefits are well documented in various ethnicities with prediabetes across the world. Specifically, consuming a healthy diet (high in polyunsaturated fatty acids, monounsaturated fatty acids, fiber, and whole grains), losing weight, quitting smoking, consuming alcohol in moderation, and increasing physical activity can improve glucose tolerance and reduce the risk of T2D. Also, pharmacological agents and botanicals can be used to manage glucose intolerance if the implementation of lifestyle changes is challenging. Pharmacological treatments have been successful in managing glucose intolerance; however, they have adverse effects. Also, more research on botanicals is warranted before a definitive recommendation can be made for their use in managing glucose intolerance. To make progress on this worldwide problem, efforts are needed to improve the awareness of prediabetes, increase promotion of healthy behaviors, and improve the availability of evidence-based lifestyle intervention programs to the community.

Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial.

Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post-intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 ± 0.13 versus -0.33 ± 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome.

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Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabetes.

AIMS: To elucidate if endothelial dysfunction is an early CV risk marker in obese men and women with prediabetes. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Clinical Research Unit, Pennington Biomedical Research Center, Baton Rouge, LA. United States. METHODOLOGY: Overweight and obese status denotes an increasing adipose tissue burden which spills over into ectopic locations, including the visceral compartment, muscle and liver. Associated co-morbidities enhance cardiovascular (CV) risk. Endothelium which is the largest receptor-effector end-organ in our bodies, while responding to numerous physical and chemical stimuli maintains vascular homeostasis. Endothelial dysfunction (ED) is the initial perturbation, which precedes fatty streak known to initiate atherosclerosis: insidious process which often culminates as sudden catastrophic CV adverse event. Asymptomatic men and women; [n=42] coming in after an overnight fast had demographic, anthropometric, clinical chemistry and resting endothelial function [EF: increased test finger peripheral arterial tone (PAT) relative to control; expressed as relative hyperemia index (RHI)] assessments. RESULTS: Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) µU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg]. Obese adults [n=22] had prediabetes [FPG, 106.5(3.5) mg/dL], hyperinsulinemia [INS 18.0(5.2) µU/ml], insulin resistance [HOMA-IR 4.59(2.3)], prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and endothelial dysfunction [ED; reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05]. Age-adjusted RHI correlated with BMI [r=-0.53; p<0.001]; however, BMI-adjusted RHI was not correlated with age [r=-0.01; p=0.89]. CONCLUSION: Endothelial dysfunction reflective of cardiometabolic changes in obese adults can be an early risk marker for catastrophic CV events.

Skeletal muscle protein tyrosine phosphatase 1B regulates insulin sensitivity in African Americans.

Protein tyrosine phosphatase 1B (PTP1B) is postulated to modulate insulin action by dephosphorylating the insulin receptor signaling proteins and attenuating insulin signaling. We sought to determine the relationship of skeletal muscle PTP1B to whole-body insulin sensitivity. We studied 17 African Americans with type 2 diabetes mellitus (T2DM) and 16 without diabetes. PTP1B gene expression and protein abundance were determined in the biopsied skeletal muscles at the baseline of a hyperinsulinemic-euglycemic clamp. PTP1B gene expression was significantly higher in subjects with T2DM versus control (P < 0.0001) and remained significantly different after adjusting for age and insulin sensitivity (P = 0.05). PTP1B gene expression was positively related to protein abundance (r(s) = 0.39; P = 0.03; adjusted for age and insulin sensitivity) and negatively related to insulin sensitivity (r(s) = -0.52; P = 0.002; adjusted for age). Overexpression and interference RNA of PTP1B were performed in primary human skeletal muscle culture. PTP1B overexpression resulted in reduction of Akt phosphorylation in the control subjects. Moreover, interference RNA transfection downregulated PTP1B expression and enhanced Akt phosphorylation in subjects with T2DM. These data show that skeletal muscle PTP1B gene expression is increased in African American subjects with T2DM, is negatively associated with whole-body insulin sensitivity, and contributes to modulation of insulin signaling.

Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women.

Dietary supplementation with whole blueberries in a preclinical study resulted in a reduction in glucose concentrations over time. We sought to evaluate the effect of daily dietary supplementation with bioactives from blueberries on whole-body insulin sensitivity in men and women. A double-blinded, randomized, and placebo-controlled clinical study design was used. After screening to resolve study eligibility, baseline (wk 0) insulin sensitivity was measured on 32 obese, nondiabetic, and insulin-resistant subjects using a high-dose hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU(861 pmol)⋅m(-2)⋅min(-1)). Serum inflammatory biomarkers and adiposity were measured at baseline. At the end of the study, insulin sensitivity, inflammatory biomarkers, and adiposity were reassessed. Participants were randomized to consume either a smoothie containing 22.5 g blueberry bioactives (blueberry group, n = 15) or a smoothie of equal nutritional value without added blueberry bioactives (placebo group, n = 17) twice daily for 6 wk. Both groups were instructed to maintain their body weight by reducing ad libitum intake by an amount equal to the energy intake of the smoothies. Participants' body weights were evaluated weekly and 3-d food records were collected at baseline, the middle, and end of the study. The mean change in insulin sensitivity improved more in the blueberry group (1.7 ± 0.5 mg⋅kg FFM(-1)⋅min(-1)) than in the placebo group (0.4 ± 0.4 mg⋅kg FFM(-1)⋅min(-1)) (P = 0.04). Insulin sensitivity was enhanced in the blueberry group at the end of the study without significant changes in adiposity, energy intake, and inflammatory biomarkers. In conclusion, daily dietary supplementation with bioactives from whole blueberries improved insulin sensitivity in obese, nondiabetic, and insulin-resistant participants.

The contribution of race and diabetes status to metabolic flexibility in humans.

Factors controlling metabolic flexibility (MF), the ability of the body to switch from fat to carbohydrate oxidation in response to feeding or with insulin administration, are being actively investigated. We sought to determine the effects of race (African American vs Caucasian) and diabetes status (nondiabetic vs type 2 diabetes mellitus individuals) on MF to glucose in humans. Respiratory quotient (RQ) and macronutrient substrate utilization were evaluated by indirect calorimetry during baseline (fasting) and hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU x m(-2) x min(-1)); DeltaRQ (MF) = clamp RQ - fasting RQ. The study included 168 human subjects of different races (55 African Americans, 113 Caucasians), sex (73 men, 95 women), ages (18-73 years), body mass index (19.3-47.7 kg/m(2)), and diabetes status (89 nondiabetic, 79 type 2 diabetes mellitus subjects). Metabolic flexibility was negatively correlated (P < .01) with age (r = - 0.41), fasting RQ (r = -0.22), fasting glucose (r = -0.55), insulin (r = -0.40), and triglyceride (r = -0.44) concentrations; whereas a positive association was observed with insulin sensitivity (r = 0.69, P < .0001). Insulin sensitivity, fasting RQ, triglyceride concentrations, diabetes status, and race accounted for 71% of the variability in MF with insulin sensitivity being the main determinant factor (model R(2) = 0.48, P < .0001). After controlling for the significant predictors, MF was higher in African Americans vs Caucasians (mean +/- SEM 0.080 +/- 0.004 vs 0.069 +/- 0.002, P = .008) and in nondiabetic vs type 2 diabetes mellitus subjects (P = .003). This study confirms that insulin sensitivity is the major contributor to MF in humans, but provides the novel findings that African Americans have significantly greater MF than Caucasians even after adjusting for insulin sensitivity and diabetes status.

Relationships between urinary inositol excretions and whole-body glucose tolerance and skeletal muscle insulin receptor phosphorylation.

This study assessed the relationships of urinary D-chiro-inositol and myo-inositol excretions to indices of whole-body glucose tolerance and total content and tyrosine phosphorylation of the insulin receptor (activation) in skeletal muscle of older nondiabetic subjects. Fifteen adults (age, 65 +/- 8 years; body mass index, 27.9 +/- 3.3 kg/m(2) [mean +/- SD]) completed duplicate assessments of oral (75-g oral glucose tolerance test [OGTT]) and intravenous (300 mg/kg body weight intravenous glucose tolerance test) glucose tolerance challenges and 24-hour urinary D-chiro-inositol and myo-inositol excretions. Skeletal muscle (vastus lateralis) biopsies were obtained at minute 60 of the OGTTs. Subjects with higher urinary D-chiro-inositol excretion had higher insulin (rho = 0.51, P < or = .05) and C-peptide (rho = 0.56, P < or = .05) area under the curves, and lower insulin sensitivity index (rho = -0.60, P < or = .05) during the intravenous glucose tolerance test. The urinary myo- to D-chiro-inositol ratio was also inversely related to insulin area under the curve (rho = -0.59, P < or = .05). Urinary D-chiro-inositol (rho = -0.60, P < or = .05) and myo-inositol (rho = -0.60, P < or = .05) were inversely related to tyrosine phosphorylation of the insulin receptor (phosphotyrosine 1162/1163), but not total content of the insulin receptor during the OGTT. The apparent relationships were modestly weakened when adjustments were made for sex. These findings support previous research linking higher urinary D-chiro-inositol excretion with a progressive decline in whole-body glucose tolerance. This is the first report to link higher urinary D-chiro-inositol excretion to a blunted activation of skeletal muscle insulin receptor signaling in older nondiabetic subjects.

Liquid and solid meal replacement products differentially affect postprandial appetite and food intake in older adults.

Liquid and solid foods are documented to elicit differential appetitive and food intake responses. This study was designed to assess the influences of liquid vs solid meal replacement products on postprandial appetite ratings and subsequent food intake in healthy older adults. This study used a randomized and crossover design with two 1-day trials (1 week between trials), and 24 adults (12 men and 12 women) aged 50 to 80 years with body mass index (calculated as kg/m2) between 22 and 30 participated. After an overnight fast, the subjects consumed meal replacement products as either a beverage (liquid) or a bar (solid). The meal replacement products provided 25% of each subject's daily estimated energy needs with comparable macronutrient compositions. Subjects rated their appetite on a 100 mm quasilogarithmic visual analog scale before and 15, 30, 45, 60, 90, 120, and 150 minutes after consuming the meal replacement product. At minute 120, each subject consumed cooked oatmeal ad libitum to a "comfortable level of fullness." Postprandial composite (area under the curve from minute 15 to minute 120) hunger was higher (P=0.04) for the liquid vs solid meal replacement products and desire to eat (P=0.15), preoccupation with thoughts of food (P=0.07), and fullness (P=0.25) did not differ for the liquid vs solid meal replacement products. On average, the subjects consumed 13.4% more oatmeal after the liquid vs solid (P=0.006) meal replacement product. These results indicate that meal replacement products in liquid and solid form do not elicit comparable appetitive and ingestive behavior responses and that meal replacement products in liquid form blunt the postprandial decline in hunger and increase subsequent food intake in older adults.