Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance.

The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet (HFD), we show that already a moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

Impact of physical fitness and exercise training on subcutaneous adipose tissue beiging markers in humans with and without diabetes and a high-fat diet-fed mouse model.

AIMS: Exercise training induces white adipose tissue (WAT) beiging and improves glucose homeostasis and mitochondrial function in rodents. This could be relevant for type 2 diabetes in humans, but the effect of physical fitness on beiging of subcutaneous WAT (scWAT) remains unclear. This translational study investigates if beiging of scWAT associates with physical fitness in healthy humans and recent-onset type 2 diabetes and if a voluntary running wheel intervention is sufficient to induce beiging in mice. MATERIALS AND METHODS: Gene expression levels of established beiging markers were measured in scWAT biopsies of humans with (n = 28) or without type 2 diabetes (n = 28), stratified by spiroergometry into low (L-FIT; n = 14 each) and high physical fitness (H-FIT; n = 14 each). High-fat diet-fed FVB/N mice underwent voluntary wheel running, treadmill training or no training (n = 8 each group). Following the training intervention, mitochondrial respiration and content of scWAT were assessed by high-resolution respirometry and citrate synthase activity, respectively. RESULTS: Secreted CD137 antigen (Tnfrsf9/Cd137) expression was three-fold higher in glucose-tolerant H-FIT than in L-FIT, but not different between H-FIT and L-FIT with type 2 diabetes. In mice, both training modalities increased Cd137 expression and enhanced mitochondrial content without changing respiration in scWAT. Treadmill but not voluntary wheel running led to improved whole-body insulin sensitivity. CONCLUSIONS: Higher physical fitness and different exercise interventions associated with higher gene expression levels of the beiging marker CD137 in healthy humans and mice on a high-fat diet. Humans with recent-onset type 2 diabetes show an impaired adipose tissue-specific response to physical activity.

Low-cost test rig for characterization of photocatalytic planar materials using photonically sized UV-A LED light sources.

In the presented studies, a system for the characterization of planar photocatalysts was developed and tested. In the system, reference substances can be studied online with regard to their degradability and adsorption on photocatalytic materials. In order to perform accurate calculations of the quantum and photon efficiency of the catalysts, the LED arrays used were adjusted in their spacing by simulations so that a homogeneous light field is imaged on the catalysts. The system was tested with respect to measurement accuracy and reproducibility and the photocatalytic degradation of methylene blue, methyl orange and rhodamine B was investigated. Exemplarily, the reaction kinetics, photolysis and adsorption on the tested photocatalysts were determined for these compounds and the calculation was presented in detail. The exact construction plans and circuits as well as the sensors and their programming are presented in detail and should encourage other scientists to replicate the experimental setup, since especially in the field of photocatalysis research, often the results of publications cannot be compared with each other.

Degradation of chlorinated volatile organic compounds from contaminated ground water using a carrier-bound TiO2/UV/O3-system.

In the present work, a suitable experimental setup was developed to successfully apply advanced oxidation processes (AOP) to real groundwater matrices. This setup combines an O3-bubble column reactor with a carrier-bound TiO2/UV-system. The degradation of various chlorinated ethene and methane derivatives commonly found of chlorinated volatile organic compound polluted regional groundwater samples was investigated. Because of known issues within water remediation using AOP such as toxification by transformation products, this study aimed at complete mineralization of the contained organic micropollutants. Moreover, the influences of variable process parameters such as flow rate, ozone concentration, and radiation dose on process performance were statistically evaluated and discussed. Parameter optimization using a Box-Behnken experimental design resulted in very promising degradation rates. It was thus possible to achieve a degradation rate of at least 98% for cis-dichloroethene, trichloroethene and tetrachloroethene and 85% for trichloromethane without formation of transformation products. The results of this work open up the possibility of developing innovative technologies based on AOP, which can be universally applied even to challenging matrices such as groundwater.

Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1.

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for AMPK, play important roles in exercise metabolism and contraction-dependent translocation of GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK-RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK combined with knockout of either Tbc1d1, Tbc1d4, or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion of Tbc1d1 but not Tbc1d4 resulted in a further decrease in exercise capacity. In oxidative soleus muscle, AMPK deficiency reduced contraction-mediated glucose uptake, and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic extensor digitorum longus muscle, AMPK deficiency reduced contraction-stimulated glucose uptake, and deletion of Tbc1d1, but not Tbc1d4, led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase Rac1. Our results demonstrate a novel mechanistic link between glucose transport and the GTPase signaling framework in skeletal muscle in response to contraction.

Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers.

AIMS/HYPOTHESIS: The common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load. METHODS: In a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4-physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness. RESULTS: Physical activity was inversely associated with 2 h plasma glucose levels (ß[main effect of physical activity] -0.0033 [mmol/l] / [kJ kg-1 day-1], p = 6.5 × 10-5), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (ß[interaction] -0.015 [mmol/l] / [kJ kg-1 day-1], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant. CONCLUSIONS/INTERPRETATION: Physical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations. DATA REPOSITORY: The Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive ( https://www.ebi.ac.uk/ega/dacs/EGAC00001000736 ) under accession EGAD00010001428.

Hydrogen peroxide-assisted photocatalytic water treatment for the removal of anthropogenic trace substances from the effluent of wastewater treatment plants.

Supported titanium dioxide catalysts were used in a photocatalytic flat cell reactor to remove organic micropollutants from real wastewater. Catalysts based on stainless steel mesh with a porous coating made of titanium dioxide nanoparticles with predominantly anatase modification were used. The influence of the retention time, and light output, and the effect of hydrogen peroxide on the degradation were examined. The kinetics of the degradation of the parent substances was determined by liquid chromatography-tandem mass spectrometry. As a result, first-order degradation kinetics could be confirmed for all substances. The irradiance had no linear influence on the degradation of the compounds. Hydrogen peroxides were added to the wastewater to be treated, as electron acceptors and boosters, and alone had no great oxidative effect on the parent substances. The combination of photocatalysis with the addition of hydrogen peroxide as an electron acceptor had great synergetic effects which can reduce the required energy of the process through a short retention time. The process is suitable for the removal of micropollutants from wastewater.

Risking health for rental housing: Reviewing service access in the informal backyard rental sector.

Informal backyard rentals (IBRs) constitute South Africa's fastest growing housing subsector, flourishing within a relative research vacuum and without national policy intervention to address the vulnerabilities of stakeholders to the health risks potentially presented. This article reviewed the literature on IBRs, focussing on past policies and interventions, general characteristics, infrastructure and service access to inform an analysis of potential health risks from the existing literature to guide future research and policy-making. Research followed a qualitative approach to review IBR literature dating after 2004. Relevant publications were identified from bibliographic databases using Boolean search logic and by reviewing citations in and later citations of these publications. Relevant secondary sources were also included. The review evidenced that IBRs have received increasing policy, but limited research attention, and that health hazards have been particularly neglected. Although issues such as shared water and sanitation, inappropriate waste disposal, poor hygiene practices, high densities and poor quality structures have been referenced extensively - alluding to risks and health concerns - few studies have focussed directly on health, risk and vulnerability. The risk analysis completed based on the literature made potential risks explicit, exemplified by references to specific conditions, such as HIV/AIDS, tuberculosis and the coronavirus pandemic, demonstrating pathogenic pathways, contamination and transmission risks conducive to poor health, infection and potential disaster. The review captured and updated the contemporary literature on IBRs, with the subsequent analysis providing a platform for future empirical research on health, infrastructure and IBRs to address potential risks towards positive change in future policies.

Histone deacetylase 5 regulates interleukin 6 secretion and insulin action in skeletal muscle.

OBJECTIVE: Physical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. HDAC5, a class IIa histone deacetylase, has been shown to regulate transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. In this study, we analyzed the contribution of HDAC5 to the transcriptional network in muscle and the beneficial effect of muscle contraction and regular exercise on glucose metabolism. METHODS: HDAC5 knockout mice (KO) and wild-type (WT) littermates were trained for 8 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Hdac5-deficient skeletal muscle and cultured Hdac5-knockdown (KD) C2C12 myotubes were utilized for studies of gene expression and glucose metabolism. Chromatin immunoprecipitation (ChIP) studies were conducted to analyze Il6 promoter activity using H3K9ac and HDAC5 antibodies. RESULTS: Global transcriptome analysis of Hdac5 KO gastrocnemius muscle demonstrated activation of the IL-6 signaling pathway. Accordingly, knockdown of Hdac5 in C2C12 myotubes led to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT that was reversed by Il6 knockdown. Moreover, Hdac5-deficient myotubes exhibited enhanced glucose uptake, glycogen synthesis, and elevated expression levels of the glucose transporter GLUT4. Transcription of Il6 was further enhanced by electrical pulse stimulation in Hdac5-deficient C2C12 myotubes. ChIP identified a ∼1 kb fragment of the Il6 promoter that interacts with HDAC5 and demonstrated increased activation-associated histone marker AcH3K9 in Hdac5-deficient muscle cells. Exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT controls. CONCLUSIONS: We identified HDAC5 as a negative epigenetic regulator of IL-6 synthesis and release in skeletal muscle. HDAC5 may exert beneficial effects through two different mechanisms, transcriptional control of genes required for glucose disposal and utilization, and HDAC5-dependent IL-6 signaling cross-talk to improve glucose uptake in muscle in response to exercise.

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway.

Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α. HIF-1α is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1α is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified RAB20 and TXNIP as two novel exercise/HIF-1α-regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1α downregulates the expression of TXNIP, a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1α is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of RAB20 and TXNIP These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.

"Deletion of both Rab-GTPase­activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport [corrected].

The Rab-GTPase­activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMP-dependent kinase [corrected]. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.

Energy efficiency of substance and energy recovery of selected waste fractions.

In order to reduce the ecological impact of resource exploitation, the EU calls for sustainable options to increase the efficiency and productivity of the utilization of natural resources. This target can only be achieved by considering resource recovery from waste comprehensively. However, waste management measures have to be investigated critically and all aspects of substance-related recycling and energy recovery have to be carefully balanced. This article compares recovery methods for selected waste fractions with regard to their energy efficiency. Whether material recycling or energy recovery is the most energy efficient solution, is a question of particular relevance with regard to the following waste fractions: paper and cardboard, plastics and biowaste and also indirectly metals. For the described material categories material recycling has advantages compared to energy recovery. In accordance with the improved energy efficiency of substance opposed to energy recovery, substance-related recycling causes lower emissions of green house gases. For the fractions paper and cardboard, plastics, biowaste and metals it becomes apparent, that intensification of the separate collection systems in combination with a more intensive use of sorting technologies can increase the extent of material recycling. Collection and sorting systems must be coordinated. The objective of the overall system must be to achieve an optimum of the highest possible recovery rates in combination with a high quality of recyclables. The energy efficiency of substance related recycling of biowaste can be increased by intensifying the use of anaerobic technologies. In order to increase the energy efficiency of the overall system, the energy efficiencies of energy recovery plants must be increased so that the waste unsuitable for substance recycling is recycled or treated with the highest possible energy yield.

Increased laser Doppler flow in skin tumors corresponds to elevated vessel density and reactive hyperemia.

BACKGROUND/PURPOSE: Tumor angiogenesis plays a key role in tumor growth and formation of metastasis. Quantitative analysis of tumor blood flow is a prerequisite for developing novel treatment strategies such as antiangiogenic and antivascular treatment options. Laser Doppler flow in malignant melanomas has been shown to be increased compared with normal skin and melanocytic nevi. This study investigated whether this phenomenon is originated by elevated blood vessel density or by reactive hyperemia. METHODS: Laser Doppler flow was studied in 35 melanocytic nevi, 22 malignant melanomas and three basal cell carcinomas. After excision digital imaging analysis was performed in microtome sections (factor VIII-associated antigen and CD 31 labelled). The ratio of vessel area in histological sections from tumor tissue and in non-lesional skin was calculated and related to Doppler flow values. RESULTS: Malignant melanomas demonstrated an enlargement of vessel cross-sectional area by factor 3.7+/-1.9 and of Doppler flow by factor 10.56+/-10.7, and melanocytic nevi accomplished increase of vessel cross-sectional area by factor 1.7+/-0.9 and of Doppler flow by factor 2.7+/-3.5. CONCLUSION: The laser Doppler flow is influenced by the number and the velocity of erythrocytes in the tissue. The greater increase of laser Doppler flow than of vessel density in histological sections demonstrates that the flow signal in skin tumors is caused by neovascularization as well as by functional hyperemia. Laser Doppler perfusion imaging is a useful method for non-invasive, repeated and quantitative assessment of tumor vascular network and effects of antiangiogenic treatment directed vs. tumor vasculature in vivo, but it cannot distinguish between increased vessel density and reactive hyperemia.