Metformin is a widely used first-line therapy for type 2 diabetes, and studies increasingly point to its protective effects on the kidney. However, the mechanisms underlying metformin’s renal benefits, especially how it acts in different anatomical regions of the kidney, have remained unclear.
A recent study, published in Life Metabolism, employed cutting-edge spatial multi-omics to produce the first detailed map of how metformin modulates metabolism and protein expression across different zones of the diabetic kidney. Their findings offer key insight into how metformin works at the molecular level and provide a new framework for region-targeted therapy in diabetic nephropathy (DN).
Using MALDI mass spectrometry imaging (MALDI-MSI), the team profiled metabolic changes in diabetic mouse kidneys and found eight spatially distinct metabolites linked to DN severity (Figure 1). These include NADH, p-cresol sulfate, and inosinic acid, which were enriched in pathways such as purine metabolism, steroid hormone synthesis, and CoA biosynthesis. The changes were region-specific, appearing differently in the cortex, outer medulla, and inner medulla of the kidney. Strikingly, metformin treatment shifted these spatial metabolic signatures toward normal in a zone-specific fashion. It boosted levels of protective metabolites, like inosinic acid and NADH, in certain regions, while suppressing harmful ones like p-cresol sulfate elsewhere. This suggests that metformin does not act uniformly throughout the kidney but rather fine-tunes function precisely by zone.
Proteomic analysis further revealed that Nphs2, a key protein involved in kidney filtration, was a top metformin-responsive target. Through network modeling and co-expression analysis, the researchers found that distinct kidney regions were associated with unique protein modules and pathways ranging from insulin signaling to purine and CoA metabolism. The study also demonstrated that metformin significantly improved blood glucose, insulin resistance, and kidney pathology in diabetic mice. At the cellular level, it inhibited IL-17 expression and upregulated Nphs2, supporting its anti-inflammatory and nephroprotective roles.
This study for the first time to integrate spatial metabolomics and proteomics to decode metformin’s effects in diabetic kidney disease. By mapping how metformin works region by region, the study has laid a foundation for future interventions that could target metabolic dysfunctions in specific kidney compartments.
DOI：https://doi.org/10.1093/lifemeta/loaf019