Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure.

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell-conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography-tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover.

Sustained Improvement in Glycemic Control in Emerging Adults with Type 1 Diabetes 2 Years After the Start of the COVID-19 Pandemic.

INTRODUCTION: Although there were initial concerns that the public health response to the COVID-19 pandemic would adversely affect glycemic control in people with type 1 diabetes, several early continuous glucose monitor (CGM) studies reported an unexpected slight improvement in glucose metrics. Early emerging adulthood (roughly spanning the ages of 18-24 years) is often a vulnerable time in the life of a person with type 1 diabetes. Here, we set out to determine how the care and glucose management of emerging adults with type 1 diabetes changed over a period of approximately 2 years from the start of the COVID-19 pandemic. METHODS: This was a retrospective study of a tertiary referral, multidisciplinary young adult diabetes clinic, spanning before and after the 777-day state of emergency in the City of Toronto. RESULTS: Of 130 emerging adults with type 1 diabetes (80 male, 50 female; mean age 21.0 ± 2.1 years), baseline pre-pandemic HbA1c values were available for 120 individuals. During 24.9 ± 5.4 months of follow-up before and after the start of the COVID-19 pandemic, HbA1c fell from 8.5 ± 1.7% (69.3 ± 18.8 mmol/mol) to 8.1 ± 1.9% (65.2 ± 20.5 mmol/mol) (P < 0.05), with change in HbA1c from pre-lockdown levels being sustained throughout the second year of the pandemic. Over the same period, CGM use rose from 43% to 83%, primarily through increased uptake of intermittently scanned CGM, which is covered through the Ontario Drug Benefit program. Change in HbA1c was most evident in Dexcom G6 real-time CGM users - 0.7 ± 1.2% (- 9.8 ± 17.1 mmol/mol) (P < 0.01 vs. self-monitoring of blood glucose). CONCLUSION: Among emerging adults with type 1 diabetes attending a multidisciplinary clinic in a high-income country, glycated hemoglobin levels are on average 0.4% (4.1 mmol/mol) lower than they were before the pandemic. This reduction in HbA1c is unlikely to be a consequence of early strict lockdowns given the length of time of follow-up. Rather, improved glycemic control coincided with increased utilization of wearable diabetes devices.

Perceptions and Correlates of Distress Due to the COVID-19 Pandemic and Stress Management Strategies Among Adults With Diabetes: A Mixed-Methods Study.

BACKGROUND: Greater risk of adverse health outcomes and public health measures have increased distress among people with diabetes during the coronavirus-2019 (COVID-19) pandemic. The objectives of this study were to explore how the experiences of people with diabetes during the COVID-19 pandemic differ according to sociodemographic characteristics and identify diabetes-related psychosocial correlates of COVID distress. METHODS: Patients with type 1 or 2 diabetes were recruited from clinics and community health centres in Toronto, Ontario, as well as patient networks. Participants were interviewed to explore the experiences of people with diabetes with varied sociodemographic and clinical identities, with respect to wellness (physical, emotional, social, financial, occupational), level of stress and management strategies. Multiple linear regression was used to assess the relationships between diabetes distress, diabetes self-efficacy and resilient coping with COVID distress. RESULTS: Interviews revealed that specific aspects of psychosocial wellness affected by the pandemic, and stress and illness management strategies utilized by people with diabetes differed based on socioeconomic status, gender, type of diabetes and race. Resilient coping (ß=-0.0517; 95% confidence interval [CI], -0.0918 to -0.0116; p=0.012), diabetes distress (ß=0.0260; 95% CI, 0.0149 to 0.0371; p<0.0001) and diabetes self-efficacy (ß=-0.0184; 95% CI, -0.0316 to -0.0052; p=0.007) were significantly associated with COVID distress. CONCLUSIONS: Certain subgroups of people with diabetes have experienced a disproportionate amount of COVID distress. Assessing correlates of COVID distress among people with diabetes will help inform interventions such as diabetes self-management education to address the psychosocial distress caused by the pandemic.

Lung and Kidney ACE2 and TMPRSS2 in Renin-Angiotensin System Blocker-Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19.

The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.