ArticleDiabetologia2012
The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice.
Article in Diabetologia, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 63 citations in OpenAlex.
- Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK-648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction.Clinical and translational science · 2017Trial
- Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.Journal of ovarian research · 2015Trial
- The cAMP-phosphodiesterase PDE4B2 controls peroxisome proliferator-activated receptor γ expression and the initiation of adipogenesis in 3T3-L1 cells.American journal of physiology. Endocrinology and metabolism · 2025Article
- Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics.Biomedicines · 2025Review
- A real-world disproportionality analysis of roflumilast using the US food and drug administration adverse event reporting system data.Frontiers in drug safety and regulation · 2025Article
- Exploring the Antidiabetic Potential ofPlants (Basel, Switzerland) · 2024Article
- Effects on Lipid Profile after One Year of Apremilast Therapy in Patients with Psoriasis: A Monocentric Experience.Life (Basel, Switzerland) · 2024Article
- Roflumilast ameliorates diabetic nephropathy in rats through down-regulation of JAK/STAT signaling pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice.International journal of molecular sciences · 2023Article
- Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Effect of the phosphodiesterase 4 inhibitor apremilast on cardiometabolic outcomes in psoriatic disease-results of the Immune Metabolic Associations in Psoriatic Arthritis study.Rheumatology (Oxford, England) · 2022Article
- FGF1 and insulin control lipolysis by convergent pathways.Cell metabolism · 2022Article
- BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation.Autophagy · 2021Article
- Review
- Article
- New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19.European journal of pharmacology · 2020Review
- Role of Phosphodiesterase in the Biology and Pathology of Diabetes.International journal of molecular sciences · 2020Review
- Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.ACR open rheumatology · 2020Article
- Epigenetic Alterations Are Associated With Gastric Emptying Disturbances in Diabetes Mellitus.Clinical and translational gastroenterology · 2020Observational
- Phosphodiesterase 4 inhibitor plus metformin is superior to metformin alone for the treatment of polycystic ovary syndrome: A rat model study.Experimental and therapeutic medicine · 2019Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisThe cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects.
methodsPlasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA(1c), blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.
resultsSingle treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5- and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA(1c) by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolin-induced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. CONCLUSIONS/
interpretationOur results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.
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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 Socratic graph.