April J. Stull

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.

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.

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.

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 (rs = 0.39; P = 0.03; adjusted for age and insulin sensitivity) and negatively related to insulin sensitivity (rs = −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.

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.

Effects of acute pinitol supplementation on plasma pinitol concentration, whole body glucose tolerance, and activation of the skeletal muscle insulin receptor in older humans.

Limited research with rodents and humans suggests that oral ingestion of pinitol (3- O-methyl- D- CHIRO-inositol) might positively influence glucose tolerance. This double-blinded, placebo-controlled, and cross-over study assessed the effects of acute pinitol supplementation on plasma pinitol concentration, glucose tolerance, insulin sensitivity, and activation of the skeletal muscle insulin receptor. Fifteen older, nondiabetic subjects (62+/-1 years, mean+/-SEM) completed four, 1-day trials. Subjects consumed a non-nutritive beverage with nothing (placebo) or 1,000 mg pinitol. Sixty minutes later, the subjects consumed beverages that were either energy- and carbohydrate-free (Sham) or contained 75 g glucose (OGTT). Blood samples were collected frequently over the 240-min testing period. For the OGTT trials only, vastus lateralis samples were obtained before the placebo and pinitol supplementation and 60 min after consuming the 75 g glucose beverage. Plasma pinitol concentration increased and was maintained for 240 min. Pinitol did not influence the fasting state and 180-min area under the curves for plasma glucose and insulin during the Sham and OGTT trials or hepatic (placebo 0.83+/-0.08; pinitol 0.80+/-0.08) and whole-body (placebo 6.10+/-0.54; pinitol 6.22+/-0.52) insulin sensitivities. Activation of the muscle insulin receptor was increased by 140% with glucose ingestion (Pre 0.62+/-0.12; Post 1.49+/-0.35), but pinitol did not influence this response. These results show that the pinitol supplement was quickly absorbed, but did not acutely influence indices of whole-body glucose tolerance and insulin sensitivity, or the activation of the skeletal muscle insulin receptor in older, nondiabetic humans.

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-1β), 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.

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.

Successful Scientist: What’s the Winning Formula?

What does it take to become a successful scientist? This question is usually asked or thought about at some point in a young scientists career. The early stages of a scientific career are fraught with many hardships, and achieving success can seem impossible and daunting. After encountering many obstacles, it becomes easy to focus on failures and lose sight of career goals. The journey to success can seem so simple when looked upon from the outside, but even the best scientists have endured many hardships, which are often not communicated. This educational symposium featured a diverse panel of 5 accomplished scientists representing different work environments, such as government, industry, and academia. They discussed tips on how to have a successful career journey and the key qualities of a successful scientist. Also, they revealed the secret to whats in the winning formula for success.