The effects of linoleate on insulin action in skeletal muscle cells

Emerging evidence suggests that an important mechanism for the negative feedback control of insulin signalling involves the inhibition of tyrosine phosphorylation of IRS-1 by its prior serine/threonine (ser/thr) phosphorylation. IRS-1 ser/thr phosphorylation has been linked to the dissociation of IRS-1 from the insulin receptor and PI3K, and its degradation via a proteasome-dependent pathway. Studies in animal models have shown that increases in plasma free fatty acids (FFAs) are associated with reduced IRS-1-signalling, and so it has been postulated that elevated FFA cause insulin resistance by activating pathways that negatively regulate insulin action, including hyper-phosphorylation of ser/thr residues in IRS-1. We have shown that in the case of linoleate-induced insulin resistance in L6 rat skeletal muscle cells, the inhibition of IRS-1-dependent signalling arises via effects on both the phosphorylation status and degradation of IRS-1, which are mediated, in part, by IKKb. In addition, the reduction of IRS-1 mRNA levels allude to transcriptional effects of linoleate treatment that also contribute to the observed reduction in the total levels of this protein. PtdOH, particularly dilinoleoyl PtdOH, was found to be significantly increased in linoleate treated L6 cells, and sufficient to induce at least some of the effects on insulin-signalling that are observed upon linoleate treatment. It is unlikely, however, that IKKb and PtdOH are components of the same inhibitory pathway, since inhibiting IKKb activity did not alleviate the effects of PtdOH on IRS-1 tyrosine (tyr) phosphorylation. Moreover, although an integral component of the mechanism by which linoleate induces insulin-resistance in L6 cells, it appears that restoring IRS-1 function in linoleate treated cells is not sufficient to reverse insulin resistance. Hence, we hypothesise that linoleate induces multiple inhibitory pathways in L6 cells, with at last two of these involving IKKb- and PtdOH-dependent inhibition of IRS-1 signalling, which act in parallel to reduce glucose disposal and cause insulin resistance in this model

The Impact of the COVID-19 Pandemic on Patients With CKD: Systematic Review of Qualitative Studies

Rationale & Objective: COVID-19 disproportionately affects people with co-morbidities, including chronic kidney disease (CKD). The aim of this study was to describe the impact of COVID-19 on people with CKD and their caregivers. Study Design: A systematic review of qualitative studies. Setting & Study Populations: Primary studies that reported the experiences and perspectives of adults with CKD and/or caregivers were eligible. Search Strategy & Sources: MEDLINE, Embase, PsycINFO, CINAHL were searched from database inception to October 2022. Data Extraction: Two authors independently screened the search results. Full texts of potentially relevant studies were assessed for eligibility. Any discrepancies were resolved by discussion with another author. Analytical Approach: A thematic synthesis was used to analyze the data. Results: Thirty-four studies involving 1962 participants were included. Four themes were identified: exacerbating vulnerability and distress (looming threat of COVID-19 infection, intensifying isolation, aggravating pressure on families); uncertainty in accessing health care (overwhelmed by disruption of care, confused by lack of reliable information, challenged by adapting to telehealth, skeptical about vaccine efficacy and safety); coping with self-management (waning fitness due to decreasing physical activity, diminishing ability to manage diet, difficulty managing fluid restrictions, minimized burden with telehealth, motivating confidence and autonomy); and strengthening sense of safety and support (protection from lockdown restrictions, increasing trust in care, strengthened family connection). Limitations: Non-English studies were excluded and the inability to delineate themes based on stage of kidney and treatment modality. Conclusions: Uncertainty in accessing health care during the COVID-19 pandemic exacerbated vulnerability, emotional distress, and burden, and led to reduced capacity to self-manage among patients with CKD and their caregivers. Optimizing telehealth and access to educational and psychosocial support may improve self-management, and the quality and effectiveness of care during a pandemic, mitigating potentially catastrophic consequences in people with CKD. Registration: Study not registered

Establishing a Core Outcome Measure for Peritoneal Dialysis-related Peritonitis: A Standardized Outcomes in Nephrology—Peritoneal Dialysis Consensus Workshop Report

IntroductionPeritoneal dialysis (PD)-related peritonitis is one of the leading causes of discontinuation of PD and is considered a critically important outcome for patients on PD. However, there is no universally accepted method of measuring this outcome in clinical trials.MethodsWe convened an online consensus workshop to establish a core outcome measure for PD-related peritonitis in clinical trials.ResultsA total of 53 participants, including 18 patients and caregivers, from 12 countries engaged in breakout discussions in this workshop. Transcripts were analyzed thematically. We identified the following 3 themes: (i) feasibility and applicability across diverse settings, which reflected the difficulty with implementing laboratory-based measures in resource-limited environments; (ii) ensuring validity, which included minimizing false positives and considering the specificity of symptoms; and (iii) being meaningful and tangible to patients, which meant that the measure should be easy to interpret, reflect the impact that symptoms have on patients, and promote transparency by standardizing the reporting of peritonitis among dialysis units.ConclusionA core outcome measure for PD-related peritonitis should include both symptom-based and laboratory-based criteria. Thus, the International Society for Peritoneal Dialysis (ISPD) definition of peritonitis is acceptable. However, there should be consideration of reporting suspected peritonitis in cases where laboratory confirmation is not possible. The measure should include all infections from the time of catheter insertion and capture both the rate of infection and the number of patients who remain peritonitis free. A core outcome measure with these features would increase the impact of clinical trials on the care and decision-making of patients receiving PD