Metformin and urination
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Metformin and Urination: A Comprehensive Overview
Metformin's Impact on Proteinuria
Proteinuria Reduction in Hypertensive Rats
Metformin has been shown to reduce proteinuria in spontaneously hypertensive rats (SHR) by activating the HIF-2α-VEGF-A pathway. In a study, SHR treated with metformin exhibited a significant reduction in urinary protein concentration compared to untreated controls. This effect is attributed to the increased production of vascular endothelial growth factor (VEGF)-A in the kidneys, which is mediated by the activation of hypoxia-inducible factor-2α (HIF-2α)1.
Metformin and Urine Concentration
Improvement in Nephrogenic Diabetes Insipidus
Metformin has demonstrated efficacy in improving urine concentration in rodent models of congenital nephrogenic diabetes insipidus (NDI). By stimulating AMP-activated protein kinase (AMPK), metformin increased the abundance of inner medullary urea transporter UT-A1 and aquaporin 2 (AQP2), leading to restored urine osmolality levels. This suggests that metformin could be a promising treatment for conditions characterized by impaired urine concentration2.
Sodium Excretion and Blood Pressure
Increased Urinary Sodium Excretion
Metformin has been found to increase urinary sodium excretion by reducing the phosphorylation of the sodium-chloride cotransporter (NCC). This effect was observed in both acute and chronic administration of metformin in mice, indicating a potential mechanism for its blood pressure-lowering effects. The study confirmed that other renal sodium transporters were not significantly affected by metformin3.
Drug Interactions Affecting Urinary Excretion
Interaction with Atenolol
The co-administration of atenolol, a β1 blocker, with metformin has been shown to significantly decrease the urinary excretion of metformin. This interaction is mediated by the down-regulation of multidrug and toxin extrusion protein 1 (rMate1) in the kidneys. Consequently, this can lead to increased plasma levels of metformin and a higher risk of lactic acidosis, highlighting the importance of monitoring drug interactions in patients receiving metformin4.
Renal Protection and Fibrosis
Amelioration of Renal Fibrosis
Metformin has nephroprotective effects, particularly in reducing renal fibrosis. In a mouse model of unilateral ureteral obstruction (UUO), metformin treatment resulted in decreased expression of fibrosis markers and improved renal function. This protective effect is partly due to the inhibition of TGF-β1-induced epithelial-to-mesenchymal transition (EMT) in renal proximal tubule epithelial cells5.
Pharmacokinetics and Urinary Excretion
Metformin Excretion and Bioavailability
Metformin is primarily excreted unchanged in the urine, with a significant portion of the drug being eliminated through renal pathways. The renal clearance of metformin is closely correlated with creatinine clearance, indicating that renal function significantly influences metformin excretion. This underscores the need for dose adjustments in patients with impaired renal function to prevent drug accumulation and potential adverse effects6 7 8.
Conclusion
Metformin has multifaceted effects on urination, including reducing proteinuria, improving urine concentration in NDI, increasing sodium excretion, and interacting with other drugs to affect urinary excretion. Its nephroprotective properties and influence on renal function make it a valuable drug in managing diabetes and associated renal complications. However, careful consideration of drug interactions and renal function is essential to optimize its therapeutic benefits and minimize risks.
Sources and full results
Most relevant research papers on this topic
Metformin reduces proteinuria in spontaneously hypertensive rats by activating the HIF-2α-VEGF-A pathway.
Metformin reduces proteinuria in long-term high blood pressure rats by activating the HIF-2-VEGF signaling pathway, providing a new mechanism for its renoprotective effects.
Rigorous JournalMetformin improves urine concentration in rodents with nephrogenic diabetes insipidus.
Metformin improves urine concentration in rodent models of congenital nephrogenic diabetes insipidus by stimulating AMPK, suggesting it could be a promising treatment for congenital NDI.
Rigorous JournalMetformin increases urinary sodium excretion by reducing phosphorylation of the sodium-chloride cotransporter.
Metformin reduces blood pressure by increasing urinary sodium excretion by reducing phosphorylation of the sodium-chloride cotransporter, suggesting its role in improving hypertension.
Non-RCT
Animal StudyInhibitory effect of atenolol on urinary excretion of metformin via down-regulating multidrug and toxin extrusion protein 1 (rMate1) expression in the kidney of rats.
Atenolol can inhibit metformin urinary excretion by decreasing renal rMate1 expression, potentially causing potential lactic acidosis when combined with metformin.
Non-RCTAnimal StudyMetformin Ameliorates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits TGF-ß1-Induced Upregulation of Cadherin-6 in Renal Proximal Tubule Epithelial Cells
Metformin prevents renal fibrosis in mice with unilateral ureteral obstruction by inhibiting TGF-1-induced increase of CDH6 expression and EMT in renal proximal tubule epithelial cells.
RCTAnimal StudyRigorous JournalClinical Pharmacokinetics of Metformin
Metformin's pharmacokinetics and clinical response are largely mediated by organic cation transporters, with minimal impact on lactic acidosis risk.
Rigorous Journal
Highly CitedAnalysis of urinary metabolic alteration in type 2 diabetic rats treated with metformin using the metabolomics of quantitative spectral deconvolution 1H NMR spectroscopy
Metformin treatment improves glucose and 1-methylnicotinamide metabolism, increases gut microbiota activity, and suppresses tricarboxylic acid cycle metabolism in type 2 diabetic rats.
Non-RCTAnimal StudyMetformin kinetics in healthy subjects and in patients with diabetes mellitus.
Metformin kinetics in healthy subjects and Type II diabetic patients show a slow elimination phase, potentially causing accumulation in peripheral tissues and potential association with lactic acidosis.
Non-RCTHighly CitedThe Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease
Metformin effectively slows the progression of chronic kidney disease in both diabetic and non-diabetic rats, suggesting its potential use in treating CKD in both diabetic and non-diabetic patients.
RCTAnimal StudyAntihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway
Metformin's anti-hyperglycemic effect is attributed to reduced POMC/ACTH/cortisol levels in the pituitary gland, following AMPK/LXR phosphorylation in the pituitaries.
Non-RCTHighly Cited