Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.Peer reviewe

Hyperbaric oxygen therapy activates hypoxia‐inducible factor 1 (HIF‐1), which contributes to improved wound healing in diabetic mice

Hyperbaric oxygen (HBO) therapy has been used as an adjunctive therapy for diabetic foot ulcers, although its mechanism of action is not completely understood. Recently, it has been shown that HBO mobilizes the endothelial progenitor cells (EPCs) from bone marrow that eventually will aggregate in the wound. However, the gathering of the EPCs in diabetic wounds is impaired because of the decreased levels of local stromal‐derived factor‐1α (SDF‐1α). Therefore, we investigated the influence of HBO on hypoxia‐inducible factor 1 (HIF‐1), which is a central regulator of SDF‐1α and is down‐regulated in diabetic wounds. The effects of HBO on HIF‐1α function were studied in human dermal fibroblasts, SKRC7 cells, and HIF‐1α knock‐out and wild‐type mouse embryonic fibroblasts using appropriate techniques (Western blot, quantitative polymerase chain reaction, and luciferase hypoxia‐responsive element reporter assay). Cellular proliferation was assessed using H3‐thymidine incorporation assay. The effect of HIF in combination with HBOT was tested by inoculating stable HIF‐1α‐expressing adenovirus (Adv‐HIF) into experimental wounds in db/db mice exposed to HBO. HBO activates HIF‐1α at several levels by increasing both HIF‐1α stability (by a non‐canonical mechanism) and activity (as shown both by induction of relevant target genes and by a specific reporter assay). HIF‐1α induction has important biological relevance because the induction of fibroblast proliferation in HBO disappears when HIF‐1α is knocked down. Moreover, the local transfer of stable HIF‐1α‐expressing adenovirus (Adv‐HIF) into experimental wounds in diabetic (db/db mice) animals has an additive effect on HBO‐mediated improvements in wound healing. In conclusion, HBO stabilizes and activates HIF‐1, which contributes to increased cellular proliferation. In diabetic animals, the local transfer of active HIF further improves the effects of HBO on wound healing

Self-management and hospitalization in 615 Swedish patients with Addison's disease during the coronavirus disease 2019 pandemic : a retrospective study

Objective: Autoimmune Addison's disease (AAD) entails a chronic adrenal insufficiency and is associated with an increased risk of severe infections. It is, however, unknown how patients with AAD were affected by the coronavirus disease 2019 (COVID-19) pandemic of 2020- 2021. This study was aimed at investigating the incidence of COVID-19 in patients with AAD in Sweden, the self-adjustment of medications during the disease, impact on social aspects, and treatment during hospitalization. Additionally, we investigated if there were any possible risk factors for infection and hospitalization. Design and methods: Questionnaires were sent out from April to October 2021 to 813 adult patients with AAD in the Swedish Addison Registry. The questionnaires included 55 questions inquiring about COVID-19 sickness, hospital care, medications, and comorbidities, focusing on the pre-vaccine phase. Results: Among the 615 included patients with AAD, COVID-19 was reported in 17% of which 8.5% required hospital care. Glucocorticoid treatment in hospitalized patients varied. For outpatients, 85% increased their glucocorticoid dosage during sickness. Older age (P= .002) and hypertension (P=.014) were associated with an increased risk of hospital care, while younger age (P<.001) and less worry about infection (P= .030) were correlated with a higher risk of COVID-19. Conclusions: In the largest study to date examining AAD during the COVID-19 pandemic, we observed that although one-fifth of the cohort contracted COVID-19, few patients required hospital care. A majority of the patients applied general recommended sick rules despite reporting limited communication with healthcare during the pandemic

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1-4) and ligands (Jagged 1-2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)-Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs

Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension.

Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity

The mRNA expression of IGF-I, IGF-II and IGF-IR in the skin of liver-specific IGF-I deficient mice versus WT control animals with or without diabetes.

<p>The mRNA expression of IGF-I, IGF-II and IGF-IR in the skin of liver-specific IGF-I deficient mice versus WT control animals with or without diabetes.</p