A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.

Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance (HIR); however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum (ER), mitochondria, plasma membrane (PM), lipid droplets, and cytosol. Acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced HIR in rats. This was due to PM sn-1,2-DAG accumulation, which promoted PKCϵ activation and insulin receptor kinase (IRK)-T1160 phosphorylation, resulting in decreased IRK-Y1162 phosphorylation. Liver PM sn-1,2-DAG content and IRK-T1160 phosphorylation were also higher in humans with HIR. In rats, liver-specific PKCϵ KD ameliorated high-fat diet-induced HIR by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKCϵ-induced HIR by promoting IRK-T1160 phosphorylation. These data identify PM sn-1,2-DAGs as the key pool of lipids that activate PKCϵ and that hepatic PKCϵ is both necessary and sufficient in mediating HIR.

Effects of Aerobic Training Versus Breathing Exercises on Asthma Control: A Randomized Trial.

BACKGROUND: Aerobic training and breathing exercises are interventions that improve asthma control. However, the outcomes of these 2 interventions have not been compared. OBJECTIVE: To compare the effects of aerobic training versus breathing exercises on clinical control (primary outcome), quality of life, exercise capacity, and airway inflammation in outpatients with moderate-to-severe asthma. METHODS: Fifty-four asthmatics were randomized into either the aerobic training group (AG, n = 29) or the breathing exercise group (BG, n = 25). Both interventions lasted for 24 sessions (2/week, 40 minutes/session). Asthma clinical control (Asthma Control Questionnaire [ACQ]), quality of life (Asthma Quality of Life Questionnaire), asthma symptom-free days (ASFD), airway inflammation, exercise capacity, psychological distress (Hospital Anxiety and Depression Scale), daily-life physical activity (DLPA), and pulmonary function were evaluated before, immediately after, and 3 months after the intervention. RESULTS: Both interventions presented similar results regarding the ACQ score, psychological distress, ASFD, DLPA, and airway inflammation (P > .05). However, participants in the AG were 2.6 times more likely to experience clinical improvement at the 3-month follow-up than participants in the BG (P = .02). A greater proportion of participants in the AG also presented a reduction in the number of days without rescue medication use compared with BG (34% vs 8%; P = .04). CONCLUSIONS: Outpatients with moderate-to-severe asthma who participated in aerobic training or breathing exercise programs presented similar results in asthma control, quality of life, asthma symptoms, psychological distress, physical activity, and airway inflammation. However, a greater proportion of participants in the AG presented improvement in asthma control and reduced use of rescue medication.

SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia.

BACKGROUND: Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking. METHODS: E0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni's multiple comparisons test. RESULTS: Dapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth. CONCLUSIONS: Taken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation.

Obesity is associated with increased incidence and worse prognosis of more than one dozen tumor types; however, the molecular mechanisms for this association remain under debate. We hypothesized that insulin, which is elevated in obesity-driven insulin resistance, would increase tumor glucose oxidation in obesity-associated tumors. To test this hypothesis, we applied and validated a stable isotope method to measure the ratio of pyruvate dehydrogenase flux to citrate synthase flux (VPDH/VCS, i.e. the percent of total mitochondrial oxidation fueled by glucose) in tumor cells. Using this method, we found that three tumor cell lines associated with obesity (colon cancer [MC38], breast cancer [4T1], and prostate cancer [TRAMP-C3] cells) increase VPDH/VCS in response to physiologic concentrations of insulin. In contrast, three tumor cell lines that are not associated with obesity (melanoma [YUMM1.7], B cell lymphoma [BCL1 clone 5B1b], and small cell lung cancer [NCI-H69] cells) exhibited no oxidative response to insulin. The observed increase in glucose oxidation in response to insulin correlated with a dose-dependent increase in cell division in obesity-associated tumor cell lines when grown in insulin, whereas no alteration in cell division was seen in tumor types not associated with obesity. These data reveal that a shift in substrate preference in the setting of physiologic insulin may comprise a metabolic signature of obesity-associated tumors that differs from that of those not associated with obesity.

Upper Limb Coordination in Individuals With Stroke: Poorly Defined and Poorly Quantified.

BACKGROUND: The identification of deficits in interjoint coordination is important in order to better focus upper limb rehabilitative treatment after stroke. The majority of standardized clinical measures characterize endpoint performance, such as accuracy, speed, and smoothness, based on the assumption that endpoint performance reflects interjoint coordination, without measuring the underlying temporal and spatial sequences of joint recruitment directly. However, this assumption is questioned since improvements of endpoint performance can be achieved through different degrees of restitution or compensation of upper limb motor impairments based on the available kinematic redundancy of the system. Confusion about adequate measurement may stem from a lack a definition of interjoint coordination during reaching. METHODS AND RESULTS: We suggest an operational definition of interjoint coordination during reaching as a goal-oriented process in which joint degrees of freedom are organized in both spatial and temporal domains such that the endpoint reaches a desired location in a context-dependent manner. CONCLUSIONS: In this point-of-view article, we consider how current approaches to laboratory and clinical measures of coordination comply with our definition. We propose future study directions and specific research strategies to develop clinical measures of interjoint coordination with better construct and content validity than those currently in use.

Oral insulin improves metabolic parameters in high fat diet fed rats.

INTRODUCTION/AIM: The gut has shown to have a pivotal role on the pathophysiology of metabolic disease. Food stimulation of distal intestinal segments promotes enterohormones secretion influencing insulin metabolism. In diabetic rats, oral insulin has potential to change intestinal epithelium behavior. This macromolecule promotes positive effects on laboratorial metabolic parameters and decreases diabetic intestinal hypertrophy. This study aims to test if oral insulin can influence metabolic parameters and intestinal weight in obese non-diabetic rats. METHODS: Twelve weeks old Wistar rats were divided in 3 groups: control (CTRL) standard chow group; high fat diet low carbohydrates group (HFD) and HFD plus daily oral 20U insulin gavage (HFD+INS). Weight and food consumption were weekly obtained. After eight weeks, fasting blood samples were collected for laboratorial analysis. After euthanasia gut samples were isolated. RESULTS: Rat oral insulin treatment decreased body weight gain (p<0,001), fasting glucose and triglycerides serum levels (p<0,05) an increased intestinal weight of distal ileum (P<0,05). Animal submitted to high fat diet presented higher levels of HOMA-IR although significant difference to CT was not achieved. HOMA-beta were significantly higher (p<0.05) in HFD+INS. Visceral fat was 10% lower in HFD+INS but the difference was not significant. CONCLUSIONS: In non-diabetic obese rats, oral insulin improves metabolic malfunction associated to rescue of beta-cell activity.

Oral insulin improves metabolic parameters in high fat diet fed rats

ABSTRACT Introduction/Aim: The gut has shown to have a pivotal role on the pathophysiology of metabolic disease. Food stimulation of distal intestinal segments promotes enterohormones secretion influencing insulin metabolism. In diabetic rats, oral insulin has potential to change intestinal epithelium behavior. This macromolecule promotes positive effects on laboratorial metabolic parameters and decreases diabetic intestinal hypertrophy. This study aims to test if oral insulin can influence metabolic parameters and intestinal weight in obese non-diabetic rats. Methods: Twelve weeks old Wistar rats were divided in 3 groups: control (CTRL) standard chow group; high fat diet low carbohydrates group (HFD) and HFD plus daily oral 20U insulin gavage (HFD+INS). Weight and food consumption were weekly obtained. After eight weeks, fasting blood samples were collected for laboratorial analysis. After euthanasia gut samples were isolated. Results: Rat oral insulin treatment decreased body weight gain (p<0,001), fasting glucose and triglycerides serum levels (p<0,05) an increased intestinal weight of distal ileum (P<0,05). Animal submitted to high fat diet presented higher levels of HOMA-IR although significant difference to CT was not achieved. HOMA-beta were significantly higher (p<0.05) in HFD+INS. Visceral fat was 10% lower in HFD+INS but the difference was not significant. Conclusions: In non-diabetic obese rats, oral insulin improves metabolic malfunction associated to rescue of beta-cell activity.

Does the Finger-to-Nose Test measure upper limb coordination in chronic stroke?

BACKGROUND: We aimed to kinematically validate that the time to perform the Finger-to-Nose Test (FNT) assesses coordination by determining its construct, convergent and discriminant validity. METHODS: Experimental, criterion standard study. Both clinical and experimental evaluations were done at a research facility in a rehabilitation hospital. Forty individuals (20 individuals with chronic stroke and 20 healthy, age- and gender-matched individuals) participated.. Both groups performed two blocks of 10 to-and-fro pointing movements (non-dominant/affected arm) between a sagittal target and the nose (ReachIn, ReachOut) at a self-paced speed. Time to perform the test was the main outcome. Kinematics (Optotrak, 100Hz) and clinical impairment/activity levels were evaluated. Spatiotemporal coordination was assessed with slope (IJC) and cross-correlation (LAG) between elbow and shoulder movements. RESULTS: Compared to controls, individuals with stroke (Fugl-Meyer Assessment, FMA-UE: 51.9 ± 13.2; Box & Blocks, BBT: 72.1 ± 26.9%) made more curved endpoint trajectories using less shoulder horizontal-abduction. For construct validity, shoulder range (ß = 0.127), LAG (ß = 0.855) and IJC (ß = -0.191) explained 82% of FNT-time variance for ReachIn and LAG (ß = 0.971) explained 94% for ReachOut in patients with stroke. In contrast, only LAG explained 62% (ß = 0.790) and 79% (ß = 0.889) of variance for ReachIn and ReachOut respectively in controls. For convergent validity, FNT-time correlated with FMA-UE (r = -0.67, p < 0.01), FMA-Arm (r = -0.60, p = 0.005), biceps spasticity (r = 0.39, p < 0.05) and BBT (r = -0.56, p < 0.01). A cut-off time of 10.6 s discriminated between mild and moderate-to-severe impairment (discriminant validity). Each additional second represented 42% odds increase of greater impairment. CONCLUSIONS: For this version of the FNT, the time to perform the test showed construct, convergent and discriminant validity to measure UL coordination in stroke.

High postprandial triglycerides serum levels: is obesity a good predictor?

The aim of this study was to analyze the correlation between triglyceride (TG) serum levels in obese and non-obese patients in a simulated postprandial state. Both groups showed TG levels < 150 mg/dL when fasting. After 12 h fasting, the subjects ingested a lipid overload diet and blood samples were collected. The variation between fasting and the postprandial TG peak levels were analyzed. The peak of postprandial TG levels occurred 4 h after the lipid overload in both groups. When the subjects were not fasting, the majority of non-obese subjects remained within the range of normal TG values, but the values for the obese group remained elevated. There was a significant correlation between Body Mass Index (BMI) and TG at each time point until 2 h after the meal, but the data did not show a correlation after 3 h. According to the receiver-operating characteristics (ROC) curve, postprandial TG values were not a good predictor of obesity (based on BMI), but they were a predictor of non-obesity. This study reinforces the importance of measuring non-fasting TG levels in obese and non-obese subjects, because some non-obese patients probably had altered fat metabolism, indicating that this examination could be an indicator of metabolic risk.

Comparison between breathing and aerobic exercise on clinical control in patients with moderate-to-severe asthma: protocol of a randomized trial.

BACKGROUND: Asthma is a chronic inflammatory airway disease characterized by reversible obstruction, inflammation and hyperresponsiveness to different stimulus. Aerobic and breathing exercises have been demonstrated to benefit asthmatic patients; however, there is no evidence comparing the effectiveness of these treatments. METHODS/DESIGN: This is a prospective, comparative, blinded, and randomized clinical trial with 2 groups that will receive distinct interventions. Forty-eight asthmatic adults with optimized medical treatment will be randomly divided into either aerobic (AG) or breathing exercises (BG). Patients will perform breathing or aerobic exercise twice a week for 3 months, totalizing 24 sessions of 40 minutes each. Before intervention, both groups will complete an educational program consisting of 2 educational classes. Before and after interventions, the following parameters will be quantified: clinical control (main outcome), health related quality of life, levels of anxiety and depression, daily living physical activity and maximal exercise capacity (secondary outcome). Hyperventilation syndrome symptoms, autonomic nervous imbalance, thoracoabdominal kinematics, inflammatory cells in the sputum, fraction of exhaled nitric oxide (FENO) and systemic inflammatory cytokines will also be evaluated as possible mechanisms to explain the benefits of both interventions. DISCUSSION: Although the benefits of breathing and aerobic exercises have been extensively studied, the comparison between both has never been investigated. Furthermore, the findings of our results will allow us to understand its application and suitability to patients that will have more benefits for every intervention optimizing its effect. TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT02065258.