A5043699942- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Cellular transport and secretion
- Cancer, Hypoxia, and Metabolism
- Exercise and Physiological Responses
- Genetic Mapping and Diversity in Plants and Animals
- Diabetes Treatment and Management
- Diet and metabolism studies
- Cardiovascular Function and Risk Factors
- Diabetes and associated disorders
- Peroxisome Proliferator-Activated Receptors
- Adipokines, Inflammation, and Metabolic Diseases
- Mitochondrial Function and Pathology
- Advanced Proteomics Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Muscle Physiology and Disorders
- Liver Disease Diagnosis and Treatment
- Lipid metabolism and biosynthesis
- Ubiquitin and proteasome pathways
- Genetic Associations and Epidemiology
- Muscle metabolism and nutrition
- Genetic and phenotypic traits in livestock
- RNA modifications and cancer
- Cardiac Imaging and Diagnostics
Deutsches Diabetes-Zentrum e.V.
2016-2025
Heinrich Heine University Düsseldorf
2016-2025
German Center for Diabetes Research
2016-2025
German Institute of Human Nutrition
2008-2013
Critical illness myopathy (CIM) has no known cause and treatment. Immobilization impaired glucose metabolism are implicated.We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects evoked contraction.In a prospective observational interventional pilot study, we screened 874 mechanically ventilated with sepsis-related organ-failure assessment score greater than or equal to 8 3 consecutive days first 5 intensive care unit stay. Thirty CIM...
Exercise increases glucose uptake in skeletal muscle independently of insulin signaling. This makes exercise an effective stimulus to increase insulin-resistant muscle. AMPK has been suggested regulate during exercise/contraction, but findings from studies various transgenic animals have not reached consensus on this matter. Comparing methods used these reveals a hitherto unappreciated difference between those reporting role and that do not. led us test the hypothesis downstream target...
The Rab-GTPase–activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response activation of AKT AMP-dependent kinase. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake fat muscle tissue. aim this study was determine the impact combined inactivation on metabolism double-deficient (D1/4KO) mice. D1/4KO normal fasting concentrations but had reduced tolerance...
The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether is insulin well energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJL)) and wild-type littermates were studied. Glucose tolerance, glucose utilization, hepatic production, tissue-specific insulin-mediated uptake determined. effect of insulin, AICAR, or contraction on transport studied...
In the obesity-resistant SJL mouse strain, we previously identified a naturally occurring loss-of-function mutation in gene for Tbc1d1. Characterization of recombinant inbred mice that carried Tbc1d1(SJL) allele on C57BL/6J background indicated loss TBC1D1 protects from obesity, presumably by increasing use fat as energy source. To provide direct functional evidence an involvement substrate metabolism, generated and characterized conventional Tbc1d1 knockout mice. TBC1D1-deficient showed...
Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK necessary AICAR, contraction, and exercise to enhance muscle whole-body mice. Correlative observations from both human rodent skeletal suggest regulation phosphorylation status TBC1D4 may relay this sensitization. However, necessity phenomenon has not been proven. Thus, purpose study was determine whether enhancing response AICAR contraction....
Currently, only a few genetic variants explain the heritability of fatty liver disease. Quantitative trait loci (QTL) analysis mouse strains has identified susceptibility locus Ltg/NZO (liver triglycerides from New Zealand obese [NZO] alleles) on chromosome 18 as associating with increased hepatic triglycerides. Herein, we aimed to identify genomic responsible for this association.
Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal can be enhanced by variety different stimuli, including contraction as most prominent. In contrast to clearance from bloodstream response stimulation, exercise-induced into unaffected during progression resistance, placing physical activity at center prevention treatment metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 TBC1D4, represent...
Myokines released by skeletal muscle in response to contraction may contribute the health-promoting effects of exercise. Previous studies with cultured rodent and human myotubes have revealed highly complex patterns myokine secretion. However, commonalities differences secretory different cell models not been explored, limiting interpretation these results. In present study, we performed a comprehensive analysis contraction-regulated secretomes using most commonly used models, murine C2C12...
Insulin regulates glucose uptake into fat and muscle by modulating the subcellular distribution of GLUT4 between cell surface intracellular compartments. However, quantification these translocation processes in classical fractionation techniques is confounded contaminating microfibrillar protein; dynamic studies at molecular level are almost impossible. In this study, we introduce a muscle-specific transgenic mouse model which HA-GLUT4-GFP expressed under control MCK promoter. was found to...
Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before onset disease. It well accepted that physical activity improves glycemic control, but knowledge on underlying mechanisms mediating beneficial effects remains incomplete. Exercise accompanied by a decrease in intramuscular oxygen levels, resulting induction HIF-1α. HIF-1α master regulator gene expression might play an important role skeletal function metabolism. Here we show for glucose metabolism...
Abstract Background Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates lipids as energy source, disturbed. The RabGTPase-activating protein TBC1D4 represents crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling transporter GLUT4 translocation. A human loss-of-function mutation...
ADP-ribosylation factor (ARF)-related protein 1 (ARFRP1) is a GTPase regulating trafficking between intracellular organelles.Here we show that mice lacking Arfrp1 in adipocytes (Arfrp1 ad؊/؊ ) are lipodystrophic due to defective lipid droplet formation adipose cells.Ratios of mono-, di-, and triacylglycerol, as well the fatty acid composition triglycerides, were unaltered.Lipid droplets brown considerably smaller exhibited ultrastructural alterations, such disturbed interaction small...
Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well oxidative stress damage and antioxidant defense SM low-fat- high-fat-fed mice. showed an increased phosphorylated AMP-activated kinase, markers lipid turnover (p-ACC, FAT/CD36), ex vivo fatty acid oxidation. Surprisingly, elevated...
Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, survival several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation vesicles containing internalized microbes. However, how early endosome or phagosome identity is maintained incompletely understood. We show that Toll-like receptor 4 (TLR4) Fc ligation induces interaction the GTPase Rab14 with kinesin KIF16b mediating plus-end-directed...
The Rab-GTPase–activating protein (RabGAP) TBC1D4 (AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) is therefore crucial during development insulin resistance type 2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia allele carriers loss-of-function variant human gene. Using conventional Tbc1d4-deficient mice (D4KO) fed high-fat diet, we show that moderate...
In skeletal muscle, the Rab GTPase-activating (GAP) protein TBC1D1 is phosphorylated by AKT and AMP-activated kinase (AMPK) in response to insulin muscle contraction. Genetic ablation of Tbc1d1 or mutation distinct phosphorylation sites impairs intracellular GLUT4 retention traffic, presumably through alterations activation state downstream GTPases. Previous studies have focused on characterizing C-terminal GAP domain that lacks known sites, as well putative regulatory domains. As a result,...
The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4 play a crucial role in the regulation of GLUT4 translocation response to insulin contraction skeletal muscle. In mice, deficiency one or both RabGAPs leads reduced insulin- contraction-stimulated glucose uptake elevated fatty acid (FA) oxidation glycolytic oxidative muscle fibers without altering mitochondrial copy number abundance for phosphorylation. Here we present evidence novel mechanism lipid utilization...