Insulin receptor substrate (IRS) proteins are important intracellular molecules that mediate insulin receptor tyrosine kinase signaling. A decreased content of IRS proteins has been found in insulin-resistant states in animals, humans, and cultured cells under various conditions. However, the molecular mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process.

Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitinproteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.Insulin receptor substrate (IRS) proteins are key molecules in the insulin signaling cascade (79, 80). Upon insulin stimulation, IRS proteins are tyrosyl phosphorylated by insulin receptor tyrosine kinase, forming a signaling complex with many SH2 domain-containing proteins, including phosphatidylinositol (PI) 3-kinase, Grb-2, SHP-2, Fyn, and Nck, and initiating multiple insulin intracellular signals (70,77,79,80). Decreased cellular levels of IRS-1 and IRS-2 have been shown to be associated with insulin resistance in animal and human subjects (1,3,6,26,29,50,53,55,73,84). Furthermore, genetic ablation of either IRS-1 or IRS-2 in mice showed impaired insulin action (3,6,73,83,84), indicating that appropriate levels of IRS proteins are crucial for maintaining normal insulin-regulated metabolism.The cellular levels of IRS-1 are influenced by many factors, including growth factors and cytokines (35,47,49,56,65,85). Studies using cell lines or isolated primary cells chronically exposed to insulin (a condition known to induce impaired insulin signaling) have revealed that the reduced level of IRS-1 protein is due to enhanced degradation (35,49,59,61,62,68). This is consistent with the fact that chronic insulin treatment can induce insulin resistance in healthy human subjects and rats (14,25,32,39), suggesting that one mechanism of insulin resistance is a reduction of the IRS-1 protein level in the major insulin-sensitive tissues.Early studies proposed that the degradation was mediated by calpain, ...

Introduction Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N -acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA. Methods Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. Results A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). Conclusion This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps. Electronic supplementary material The online version of this article (10.1186/s13023-019-1074-9) contains supplementary material, which is available to authorized users.

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Recent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay-at-home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them. Data were from the UCL COVID-19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models. Our analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health. There is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established link between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for people’s physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.