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1.
J Am Vet Med Assoc ; 262(1): 100-108, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37863100

ABSTRACT

OBJECTIVE: To explore pet owners' use of information and communication technologies (ICTs) during virtual veterinarian-client-patient consultations and to examine pet owners' attitudes toward virtual consultations. SAMPLE: 714 pet owners. METHODS: In an anonymous online survey distributed using snowball sampling, all participants were asked about utilization of ICTs, preferred method of interaction (face-to-face and 5 ICTs), opinion on virtual communication, and demographics. Sentiment toward virtual veterinarian consultations was measured for participants who had experienced a "virtual only" or "combination virtual and face-to-face" consultation in the previous 6 months using the Net Promoter Score. For these participants, multivariable logistic regression was used to explore factors associated with recommending virtual consultations. RESULTS: 92% (583/632) of participants resided in Ontario, Canada. Most (85.6% [611/714]) participants had experience using the telephone for veterinary care, while only 5.2% (37/714) had used live videoconferencing. Participants ranked face-to-face interactions as most preferred (P < .001), followed by telephone and then live videoconferencing. Participants were significantly (P < .001) less confident communicating during virtual consultations, particularly for building rapport. For participants experiencing a virtual consultation in the previous 6 months (n = 348), the overall Net Promoter Score was neutral at -1.43. Participants were divided about recommending virtual consultations, with 33.3% (116/348) being promoters and 34.8% (121/348) being detractors. Age of participant and comfort using videoconferencing were positively associated (P < .05) with recommending virtual consultations. CLINICAL RELEVANCE: Although participating pet owners significantly preferred face-to-face consultations with veterinarians, many appear willing to consider virtual consultations. Further exploration of pet owners' preferences and concerns around virtual care, including communication, is needed.


Subject(s)
Veterinarians , Animals , Humans , Ownership , Interpersonal Relations , Communication , Surveys and Questionnaires , Ontario
2.
J Am Vet Med Assoc ; 261(12): 1820-1828, 2023 12 01.
Article in English | MEDLINE | ID: mdl-37562777

ABSTRACT

OBJECTIVE: To explore veterinarians' use of virtual veterinarian-client-patient consultations before and during the coronavirus disease 2019 (COVID-19) pandemic and examine veterinarians' attitudes toward virtual consultations. SAMPLE: 135 companion animal veterinarians in Canada, the US, and Europe. METHODS: An anonymous online survey was distributed to gather participating veterinarians' use of information and communication technologies and their perception of virtual consultations' effect on patient care, client communication, and their own well-being. Willingness to recommend virtual consultations was evaluated using the Net Promoter Score. Multivariable logistic regression explored factors associated with willingness to recommend virtual consultations. RESULTS: Percentage of participating veterinarians using the telephone and videoconferencing increased significantly (P < .001) from before (83.6% and 3.0%, respectively) to during the COVID-19 pandemic (97.0% and 22.4%, respectively). Participants were significantly less confident (P < .001) about their ability to reach a diagnosis using a virtual consultation as compared to a hands-on patient examination. Participants perceived client communication to be more challenging during virtual as compared to face-to-face consultations, particularly for building rapport and expressing empathy. Participants were extremely unwilling to recommend virtual consultations (Net Promoter Score = -41.4) with 21.6% (24/111) promoters and 63.1% (70/111) detractors. Confidence doing a virtual patient examination and comfort using videoconferencing technology were both positively associated (P < .05) with willingness to recommend virtual consultations. CLINICAL RELEVANCE: Veterinary practices and organizations interested in encouraging virtual veterinarian-client-patient consultations likely need to prioritize veterinarians' acceptance as an initial focus. The veterinary profession would benefit from further research and education to inform virtual veterinary care.


Subject(s)
Veterinarians , Animals , Humans , Pandemics , Communication , Interpersonal Relations , Referral and Consultation
3.
Intern Med J ; 51(6): 923-929, 2021 06.
Article in English | MEDLINE | ID: mdl-32237099

ABSTRACT

BACKGROUND: Cough is a common symptom in interstitial lung disease (ILD), often leading to treatment dissatisfaction for patients and physicians. AIM: To identify the prevalence and subjective adequacy of control of cough in patients with ILD. METHODS: A cross-sectional study of patients with ILD attending a tertiary ILD clinic in Perth was undertaken using a pre-designed questionnaire that patients were invited to complete when attending clinic. Cough severity and impact on quality of life were assessed using a visual analogue scale and the validated Leicester cough questionnaire. Participants were asked to list triggers of their cough and strategies or medications trialled to control cough. RESULTS: Of 164 respondents, 118 (72%) had cough, with prevalence common in all ILD subtypes. A lower forced vital capacity (FVC) was found in the cough group versus non-cough group (74.6 ± 18.7 vs 87.0 ± 15.9, P-value < 0.0001). Common reported triggers were lung irritants, exertion and doing routine daily activities. Avoidance of triggers was a common strategy to control cough. A high prevalence of non-ILD causes of cough was recorded in both groups. A variety of medications had been trialled, including anti-fibrotics, immunosuppression drugs, inhalers and proton pump inhibitors, with moderate benefit reported by 18% of participants. CONCLUSIONS: Cough is prevalent in ILD but is not adequately suppressed. Cough has a significant impact on quality of life, leading patients to adopt their own strategies to control their cough. More research is needed to understand cough mechanisms in ILD and the interplay of other potential co-pathologies.


Subject(s)
Cough , Lung Diseases, Interstitial , Cough/epidemiology , Cross-Sectional Studies , Humans , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/epidemiology , Quality of Life , Vital Capacity
4.
BMC Pulm Med ; 20(1): 257, 2020 Oct 02.
Article in English | MEDLINE | ID: mdl-33008362

ABSTRACT

BACKGROUND: Interstitial Lung Disease (ILD) is a group of respiratory conditions affecting the lung interstitium often associated with progressive respiratory failure. There is increasing recognition of the need for improved epidemiological data to help determine best practice and improve standardisation of care. The Australasian ILD Registry (AILDR) is a bi-national registry of patients with all ILD subtypes designed to establish a clinically meaningful database reflecting real world practice in Australasia with an objective to improve diagnostic and treatment pathways through research and collaboration. METHODS: AILDR is a prospective observational registry recruiting patients attending ILD clinics at centres around Australia and New Zealand. Core and non-core data are stored on a secure server. The pilot phase was launched in 2016 consisting of four sites in Australia. Currently in its second phase a further 16 sites have been recruited, including three in New Zealand. RESULTS: A total of 1061 participants were consented during the pilot phase. Baseline data demonstrated a mean age 68.3 ± 12.5 (SD) years, mean FVC (%predicted) 79.1 ± 20.4 (SD), mean DLCO (%predicted) 58.5 ± 17.9 (SD) and nadir exertional SpO2 (%) 91 ± 6.9 (SD). Idiopathic pulmonary fibrosis (31%) and connective-tissue disease related ILD (21.7%) were the two most common subtypes. Baseline demographics and physiology were not significantly different across the four centres. CONCLUSION: AILDR is an important clinical and research tool providing a platform for epidemiological data that will prove essential in promoting understanding of a rare cohort of lung disease and provide foundations for our aspiration to standardise investigation and treatment pathways of ILD across Australasia.


Subject(s)
Lung Diseases, Interstitial , Outcome Assessment, Health Care , Registries , Aged , Aged, 80 and over , Australia , Connective Tissue Diseases/complications , Databases, Factual , Female , Humans , Idiopathic Pulmonary Fibrosis/complications , Male , Middle Aged , New Zealand , Prospective Studies
5.
Clin Transl Immunology ; 8(11): e1086, 2019.
Article in English | MEDLINE | ID: mdl-31709050

ABSTRACT

Interstitial lung disease (ILD) encompasses a large group of pulmonary conditions sharing common clinical, radiological and histopathological features as a consequence of fibrosis of the lung interstitium. The majority of ILDs are idiopathic in nature with possible genetic predisposition, but is also well recognised as a complication of connective tissue disease or with certain environmental, occupational or drug exposures. In recent years, a concerted international effort has been made to standardise the diagnostic criteria in ILD subtypes, formalise multidisciplinary pathways and standardise treatment recommendations. In this review, we discuss some of the current challenges around ILD diagnostics, the role of serological testing, especially, in light of the new classification of Interstitial Pneumonia with Autoimmune Features (IPAF) and discuss the evidence for therapies targeted at idiopathic and immune-related pulmonary fibrosis.

6.
Contemp Clin Trials Commun ; 11: 50-54, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30003168

ABSTRACT

INTRODUCTION: This article describes a retrospective review of participant follow-up and retention strategies in the Partnership for Research on the Ebola Virus in Liberia (PREVAIL) I Vaccine Trial. It illustrates and analyzes strategies used to retain participants in an emergency clinical research response vaccine trial conducted during the 2014 Ebola outbreak in Liberia. METHODS: An anecdotal review of participant retention strategies developed and employed during the PREVAIL I vaccine trial. RESULTS: Though other factors likely contributed to the high retention rate of trial participants, the unique PREVAIL I follow-up process described resulted in an exceptionally high participant retention rate (97.8%) through 12 months of follow-up, increased the ability to obtain meaningful trial results, and provided a platform through which to respond to social issues in an emergency clinical research response setting. CONCLUSION: Successful strategies were developed and employed in the PREVAIL I vaccine trial that resulted in extraordinarily high participant retention and follow-up rates during an infectious disease outbreak. This review illustrates that employing host country social mobilization concepts within a modified clinical research management framework is highly correlated to elevated rates of retention and minimal loss to follow-up. These strategies also contributed to increased data quality and enhanced adherence to protocol requirements. The increased ability to respond to social issues such as stigma, job retention and relationship conflicts was an additional and significant benefit of this follow-up methodology.

7.
Front Vet Sci ; 2: 78, 2015.
Article in English | MEDLINE | ID: mdl-26779492

ABSTRACT

The objective of this qualitative study was to compare veterinarians' and Registered Veterinary Technicians' (RVT's) perceptions of the veterinary healthcare team with respect to the impact of toxic attitudes and a toxic environment. Focus group interviews using a semi-structured interview guide and follow up probes were held with four veterinarian groups (23 companion animal veterinarians) and four Registered Veterinary Technician groups (26 RVTs). Thematic analysis of the discussions indicated both veterinarian and RVT participants felt team members with manifestations of toxic attitudes negatively impacted veterinary team function. These manifestations included people being disrespectful, being resistant to change, always wanting to be the "go to person," avoiding conflict, and lacking motivation. When conflict was ignored, or when people with toxic attitudes were not addressed, a toxic environment often resulted. A toxic environment sometimes manifested when "broken communication and tension between staff members" occurred as a result of employees lacking confidence, skills, or knowledge not being managed properly. It also occurred when employees did not feel appreciated, when there was difficulty coping with turnover, and when there were conflicting demands. The presence of people manifesting a toxic attitude was a source of frustration for both veterinarian and RVT participants. Prompt and consistent attention to negative behaviors is recommended to reduce the development of a toxic environment.

8.
Consult Pharm ; 29(6): 369-74, 2014 Jun.
Article in English | MEDLINE | ID: mdl-25202890

ABSTRACT

Transitioning older adults from one care setting to another is often challenging, both for the patient and the health professional. The older adult often is stressed, both physically and psychologically, and may well be overwhelmed by requests for information, including a complete list of medications from different members of the interdisciplinary team. The goals of geriatric assessment are to begin a review of a patient's lifestyle and medication therapy prior to crisis and trauma, improving the outcomes of interventions and decreasing anxiety, for both patients and caregivers.


Subject(s)
Geriatric Assessment , Transitional Care , Aged , Humans , Patient Care Team
9.
J Am Vet Med Assoc ; 245(5): 513-24, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25148093

ABSTRACT

OBJECTIVE: To determine the role of veterinary team effectiveness regarding job satisfaction and burnout in companion animal veterinary practice. DESIGN: Cross-sectional observational study. SAMPLE: 48 companion animal veterinary health-care teams. PROCEDURES: 274 team members participated in an online survey. Overall job satisfaction was evaluated with a 1-item measure, and the 3 dimensions of burnout (exhaustion, cynicism, and professional efficacy) were measured with the Maslach Burnout Inventory-General Survey. Team effectiveness was assessed with a survey developed for this study. Demographic and team effectiveness factors (coordinated team environment, toxic team environment, team engagement, and individual engagement) associated with job satisfaction and burnout were evaluated. RESULTS: Overall mean job satisfaction score was 5.46 of 7 (median, 6.00); veterinary technicians and kennel attendants had the lowest scores. According to the Maslach survey results, 22.4% of participants were in the high-risk category for exhaustion, 23.2% were in the high-risk category for cynicism, and 9.3% were in the high-risk category for professional efficacy. A coordinated team environment was associated with increased professional efficacy and decreased cynicism. A toxic team environment was negatively associated with job satisfaction and positively associated with exhaustion and cynicism. Individual engagement was positively associated with job satisfaction and professional efficacy and negatively associated with exhaustion and cynicism. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested the effectiveness of a veterinary team can significantly influence individual team members' job satisfaction and burnout. Practices should pay specific attention to the effectiveness with which their veterinary team operates.


Subject(s)
Burnout, Professional , Hospitals, Animal/standards , Job Satisfaction , Veterinarians , Animals , Cross-Sectional Studies
10.
J Grad Med Educ ; 5(3): 468-75, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24404312

ABSTRACT

BACKGROUND: Education for all physicians should include specialty-specific geriatrics-related and chronic disease-related topics. OBJECTIVE: We describe the development, implementation, and evaluation of a chronic disease/geriatric medicine curriculum designed to teach Accreditation Council for Graduate Medical Education core competencies and geriatric medicine competencies to residents by using longitudinal encounters with a standardized dementia patient and her caregiver daughter. INTERVENTION: Over 3 half-day sessions, the unfolding standardized patient (SP) case portrays the progressive course of dementia and simulates a 10-year longitudinal clinical experience between residents and a patient with dementia and her daughter. A total of 134 residents participated in the University of Cincinnati-based curriculum during 2007-2010, 72% of whom were from internal medicine (79) or family medicine (17) residency programs. Seventy-five percent of participants (100) said they intended to provide primary care to older adults in future practice, yet 54% (73) had little or no experience providing medical care to older adults with dementia. RESULTS: Significant improvements in resident proficiency were observed for all self-reported skill items. SPs' evaluations revealed that residents' use of patient-centered language and professionalism significantly improved over the 3 weekly visits. Nearly all participants agreed that the experience enhanced clinical competency in the care of older adults and rated the program as "excellent" or "above average" compared to other learning activities. CONCLUSIONS: Residents found this SP-based curriculum using a longitudinal dementia case realistic and valuable. Residents improved in both self-perceived knowledge of dementia and the use of patient-centered language and professionalism.

11.
J Mol Biol ; 420(1-2): 8-16, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22472421

ABSTRACT

The substrate for the proteins that express genetic information in the cell is not naked DNA but an assembly of nucleosomes, where the DNA is wrapped around histone proteins. The organization of these nucleosomes on genomic DNA is influenced by the DNA sequence. Here, we present a structure-based computational approach that translates sequence information into the energy required to bend DNA into a nucleosome-bound conformation. The calculations establish the relationship between DNA sequence and histone octamer binding affinity. In silico selection using this model identified several new DNA sequences, which were experimentally found to have histone octamer affinities comparable to the highest-affinity sequences known. The results provide insights into the molecular mechanism through which DNA sequence information encodes its organization. A quantitative appreciation of the thermodynamics of nucleosome positioning and rearrangement will be one of the key factors in understanding the regulation of transcription and in the design of new promoter architectures for the purposes of tuning gene expression dynamics.


Subject(s)
DNA/chemistry , Histones/metabolism , Nucleosomes/chemistry , Base Sequence , Binding Sites , Computational Biology , Computer Simulation , DNA/metabolism , Humans , Molecular Sequence Data , Nucleic Acid Conformation , Nucleosomes/genetics , Protein Binding
12.
J Am Geriatr Soc ; 58(9): 1780-5, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20863337

ABSTRACT

Providing practicing physicians with effective education that leads to better patient outcomes remains challenging. In 2003, the University of Cincinnati College of Medicine developed a comprehensive program to enhance practicing physician geriatric medicine education based on the Assessing the Care of Vulnerable Elders model. The program was implemented with a large, multisite primary care group based in the greater Cincinnati area and was designed to increase physicians' clinical skills and assist them in implementing new office and system strategies that could improve the quality of care for their older patients. Four topic areas were chosen: medication management, falls and mobility, urinary incontinence, and dementia. A multifaceted physician education program was developed for each topic area, with lunch-time, in-office, geriatrician-led presentations as the primary intervention. Over a 4-year period (2004-2007), more than 60 physicians in 16 primary care practices attended 107 teaching sessions. The value of the presentation content, quality of the presentations, and perception of meeting the primary care physicians' (PCPs') educational needs were each rated at 3.8 or above (4=excellent). Between 80% and 92% of the PCPs planned to make a change in their practice behavior as a result of the training, but only two offices initiated formal quality improvement projects. During the teaching sessions, the PCPs were provided with screening tools to identify "at risk" patients, assessment chart templates, and community resource and patient education materials. The application of a modified version of the ACOVE model to reach a large group of primary care physicians is possible and may be one strategy to improve the assessment and management of geriatric syndromes.


Subject(s)
Education, Medical, Continuing/methods , Geriatric Assessment/methods , Geriatrics/education , Physicians, Family/education , Primary Health Care/organization & administration , Quality Assurance, Health Care/methods , Vulnerable Populations , Aged , Humans , Ohio , Retrospective Studies , Workforce
14.
PLoS One ; 5(2): e9129, 2010 Feb 09.
Article in English | MEDLINE | ID: mdl-20161746

ABSTRACT

Active eukaryotic regulatory sites are characterized by open chromatin, and yeast promoters and transcription factor binding sites (TFBSs) typically have low intrinsic nucleosome occupancy. Here, we show that in contrast to yeast, DNA at human promoters, enhancers, and TFBSs generally encodes high intrinsic nucleosome occupancy. In most cases we examined, these elements also have high experimentally measured nucleosome occupancy in vivo. These regions typically have high G+C content, which correlates positively with intrinsic nucleosome occupancy, and are depleted for nucleosome-excluding poly-A sequences. We propose that high nucleosome preference is directly encoded at regulatory sequences in the human genome to restrict access to regulatory information that will ultimately be utilized in only a subset of differentiated cells.


Subject(s)
Nucleosomes/metabolism , Regulatory Sequences, Nucleic Acid/genetics , Transcription Factors/metabolism , Base Composition , Base Sequence , Binding Sites/genetics , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , CpG Islands/genetics , Enhancer Elements, Genetic/genetics , Fibroblasts/cytology , Fibroblasts/metabolism , HeLa Cells , Humans , Jurkat Cells , Promoter Regions, Genetic/genetics , Protein Binding
15.
Nat Genet ; 41(4): 438-45, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19252487

ABSTRACT

Eukaryotic transcription occurs within a chromatin environment, whose organization has an important regulatory function and is partly encoded in cis by the DNA sequence itself. Here, we examine whether evolutionary changes in gene expression are linked to changes in the DNA-encoded nucleosome organization of promoters. We find that in aerobic yeast species, where cellular respiration genes are active under typical growth conditions, the promoter sequences of these genes encode a relatively open (nucleosome-depleted) chromatin organization. This nucleosome-depleted organization requires only DNA sequence information, is independent of any cofactors and of transcription, and is a general property of growth-related genes. In contrast, in anaerobic yeast species, where cellular respiration genes are relatively inactive under typical growth conditions, respiration gene promoters encode relatively closed (nucleosome-occupied) chromatin organizations. Our results suggest a previously unidentified genetic mechanism underlying phenotypic diversity, consisting of DNA sequence changes that directly alter the DNA-encoded nucleosome organization of promoters.


Subject(s)
DNA, Fungal/genetics , Gene Expression Regulation, Fungal , Genetic Variation , Nucleosomes/genetics , Yeasts/genetics , Candida albicans/genetics , Environment , Fungal Proteins/genetics , Models, Genetic , Nucleosomes/ultrastructure , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic , Ribosomal Proteins/genetics , Saccharomyces cerevisiae/genetics
16.
Nature ; 458(7236): 362-6, 2009 Mar 19.
Article in English | MEDLINE | ID: mdl-19092803

ABSTRACT

Nucleosome organization is critical for gene regulation. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers, competition with site-specific DNA-binding proteins, and the DNA sequence preferences of the nucleosomes themselves. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for approximately 40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.


Subject(s)
Eukaryotic Cells/metabolism , Genome, Fungal/genetics , Nucleosomes/genetics , Saccharomyces cerevisiae/genetics , Animals , Base Sequence , Caenorhabditis elegans/genetics , Chickens , Computational Biology , Computer Simulation , Micrococcal Nuclease/metabolism , Nucleosomes/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Saccharomyces cerevisiae/growth & development , Sequence Analysis, DNA , Transcription Factors/metabolism
17.
PLoS Comput Biol ; 4(11): e1000216, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18989395

ABSTRACT

The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence. However, less is known about the functional consequences of this encoding. Here, we address this question using a genome-wide map of approximately 380,000 yeast nucleosomes that we sequenced in their entirety. Utilizing the high resolution of our map, we refine our understanding of how nucleosome organizations are encoded by the DNA sequence and demonstrate that the genomic sequence is highly predictive of the in vivo nucleosome organization, even across new nucleosome-bound sequences that we isolated from fly and human. We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites. Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency. These distinct functions may be achieved by encoding both relatively closed (nucleosome-covered) chromatin organizations over some factor binding sites, where factors must compete with nucleosomes for DNA access, and relatively open (nucleosome-depleted) organizations over other factor sites, where factors bind without competition.


Subject(s)
DNA, Fungal/genetics , Locus Control Region , Nucleosomes/genetics , Saccharomyces cerevisiae/genetics , Transcription, Genetic/genetics , Animals , Base Sequence/genetics , Binding Sites/genetics , Chromatin Assembly and Disassembly/genetics , Drosophila melanogaster/genetics , Gene Expression Regulation, Fungal/genetics , HeLa Cells , Humans , Saccharomyces cerevisiae/metabolism , Transcription Factors/metabolism
18.
Diabetes ; 57(10): 2644-51, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18633112

ABSTRACT

OBJECTIVE: Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. RESEARCH DESIGN AND METHODS: To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Ser(307), and Ser(612) mutated to alanine (Tg IRS-1 Ser-->Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. RESULTS: Tg IRS-1 Ser-->Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser-->Ala mice displayed a significant increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. CONCLUSIONS: These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.


Subject(s)
Amino Acid Substitution , Insulin Receptor Substrate Proteins/metabolism , Insulin Resistance , Muscle, Skeletal/metabolism , Alanine/genetics , Alanine/metabolism , Animals , Blotting, Western , Dietary Fats/administration & dosage , Dietary Fats/pharmacology , Female , Glucose Clamp Technique , Glucose Tolerance Test , Immunoprecipitation , Insulin/metabolism , Insulin Receptor Substrate Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Muscle, Skeletal/drug effects , Phosphorylation/drug effects , Serine/genetics , Serine/metabolism , Triglycerides/metabolism
19.
J Clin Invest ; 117(7): 1995-2003, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17571165

ABSTRACT

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKCtheta in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. Wild-type mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin-stimulated glucose uptake in skeletal muscle and hepatic insulin resistance. Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1- (IRS-1-) and IRS-2-associated PI3K activity in muscle and liver, respectively. In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. Furthermore, these changes were associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKCtheta activity in whole-body fat-matched UCP3 transgenic mice. These results suggest that increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus.


Subject(s)
Gene Expression Regulation , Insulin Resistance , Ion Channels/metabolism , Lipid Metabolism , Mitochondrial Proteins/metabolism , Muscle, Skeletal/metabolism , AMP-Activated Protein Kinases , Aging/physiology , Animals , Enzyme Activation , Hormones/blood , Humans , Insulin/blood , Ion Channels/genetics , Isoenzymes/metabolism , Male , Mice , Mice, Transgenic , Mitochondrial Proteins/genetics , Multienzyme Complexes/metabolism , Protein Kinase C/metabolism , Protein Kinase C-theta , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Uncoupling Protein 3 , Weight Gain
20.
Cell Metab ; 5(2): 151-6, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17276357

ABSTRACT

Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha(2) activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with beta-guanidinopropionic acid (beta-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.


Subject(s)
Aging , Mitochondria/enzymology , Multienzyme Complexes/metabolism , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Guanidines/administration & dosage , Guanidines/pharmacology , Male , Mitochondria/drug effects , Physical Conditioning, Animal , Propionates/administration & dosage , Propionates/pharmacology , Rats , Rats, Inbred F344 , Ribonucleotides/pharmacology
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