Metformin Applications in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and end-stage renal failure worldwide. Sustained hyperglycaemia in type 2 diabetes induces glomerular hyperfiltration, oxidative stress and low-grade inflammation, leading to structural changes such as mesangial expansion, glomerulosclerosis and tubulointerstitial fibrosis. Metformin, the first-line glucose-lowering agent, exerts renoprotective effects beyond glycaemic control. At a molecular level, metformin activates AMP-activated protein kinase (AMPK), thereby inhibiting pro-fibrotic pathways including TGF-β1-driven extracellular matrix deposition and suppressing NF-κB-mediated inflammation. It also reduces oxidative injury by attenuating mitochondrial reactive oxygen species and delaying renal cellular senescence. Preclinical models consistently demonstrate that metformin ameliorates tubular damage, podocyte injury and fibrotic remodelling, while observational clinical studies associate its use with slower progression to end-stage renal disease and reduced cardiovascular mortality in patients with moderate renal impairment. Dosing adjustments and monitoring of renal function are essential to minimise the risk of lactic acidosis in advanced stages of DKD. Integration of metformin therapy with newer agents such as SGLT2 inhibitors and GLP-1 receptor agonists may offer complementary benefits, highlighting its central role in a multifaceted approach to preserving kidney function in diabetes.

Research from Nature Portfolio

A study using a short-term model of ureteral obstruction in mice has demonstrated that metformin’s renoprotective effects occur independently of organic cation transporters OCT1/2 and the AMPK-β1 subunit. Despite reduced intrarenal drug uptake and diminished AMPK activation in knockout strains, metformin treatment still attenuated tubular damage and inflammatory responses. These findings challenge the notion that metformin’s renal actions require traditional hepatic transport or canonical AMPK pathways, suggesting alternative intracellular targets that may be exploited in early stages of kidney injury.

Metformin Applications in Diabetic Kidney Disease publication trend

The graph below shows the total number of articles in metformin applications in diabetic kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Diabetic kidney disease (DKD): progressive renal impairment resulting from long-standing diabetes.

AMP-activated protein kinase (AMPK): an intracellular enzyme regulating energy balance and stress responses.

Organic cation transporters (OCTs): membrane proteins that facilitate cellular uptake of metformin and other organic cations.

Tubulointerstitial fibrosis: accumulation of extracellular matrix in renal tubules and interstitium leading to scarring.

Transforming growth factor-β1 (TGF-β1): a cytokine that drives fibrotic processes and extracellular matrix deposition.

NF-κB pathway: a transcription factor network central to the regulation of inflammation.

References

1. Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment. Aging and Disease (2024).
2. Metformin and Canagliflozin Are Equally Renoprotective in Diabetic Kidney Disease but Have No Synergistic Effect. International Journal of Molecular Sciences (2023).
3. Metformin Attenuates Renal Fibrosis in a Mouse Model of Adenine-Induced Renal Injury Through Inhibiting TGF-β1 Signaling Pathways. Frontiers in Cell and Developmental Biology (2021).
4. Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney. Scientific Reports (2016).
5. Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin. Journal of Diabetes Research (2012).
6. Metformin Reduces the Senescence of Renal Tubular Epithelial Cells in Diabetic Nephropathy via the MBNL1/miR‐130a‐3p/STAT3 Pathway. Oxidative Medicine and Cellular Longevity (2020).
7. Significance of Metformin Use in Diabetic Kidney Disease. International Journal of Molecular Sciences (2020).
8. Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists. International Journal of Molecular Sciences (2021).