ArticleDiabetes2011
APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice.
Article in Diabetes, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 63 citations in OpenAlex.
- Improvement of Vascular Insulin Sensitivity by Ranolazine.International journal of molecular sciences · 2023Article
- Glucagon-Like Peptide 1 Receptor Agonists Versus Sodium-Glucose Cotransporter 2 Inhibitors for Atherosclerotic Cardiovascular Disease in Patients With Type 2 Diabetes.Cardiology research · 2023Review
- Flavanol Consumption in Healthy Men Preserves Integrity of Immunological-Endothelial Barrier Cell Functions: Nutri(epi)genomic Analysis.Molecular nutrition & food research · 2022Article
- RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism.Cell death discovery · 2022Review
- The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.Nature communications · 2021Article
- Extracellular Vesicles Derived from Intermittent Hypoxia-Treated Red Blood Cells Impair Endothelial Function Through Regulating eNOS Phosphorylation and ET-1 Expression.Cardiovascular drugs and therapy · 2021Article
- Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.American journal of physiology. Endocrinology and metabolism · 2020 · on this mapArticle
- Tribbles Homolog 3-Mediated Vascular Insulin Resistance Contributes to Hypoxic Pulmonary Hypertension in Intermittent Hypoxia Rat Model.Frontiers in physiology · 2020Article
- Adiponectin for the treatment of diabetic nephropathy.The Korean journal of internal medicine · 2019Review
- Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium.Microcirculation (New York, N.Y. : 1994) · 2018Article
- Endothelial overexpression of endothelin-1 modulates aortic, carotid, iliac and renal arterial responses in obese mice.Acta pharmacologica Sinica · 2017Article
- APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes.Diabetologia · 2017Article
- The impact of insulin resistance on the kidney and vasculature.Nature reviews. Nephrology · 2016Review
- The effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment.Saudi journal of biological sciences · 2016Article
- APPL1 acts as a protective factor against podocytes injury in high glucose environment.International journal of clinical and experimental pathology · 2015Article
- Adiponectin and insulin cross talk: the microvascular connection.Trends in cardiovascular medicine · 2014Review
- The role of adiponectin signaling in metabolic syndrome and cancer.Reviews in endocrine & metabolic disorders · 2014Review
- Adiponectin signaling in the liver.Reviews in endocrine & metabolic disorders · 2014Review
- APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor.Cell reports · 2014Article
- Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function.Diabetologia · 2013Article
Corrections and comments
- Correction · 2016-09-26Duplication of/in Image · Error in Image · Investigation by Journal/Publisher ·
- Erratum issued
Authors and funding
10 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveInsulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells. RESEARCH DESIGN AND
methodsBoth APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.
resultsInsulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.
conclusionsAPPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.