Sepsis induces systemic inflammation and can precipitate multiple organ dysfunctions, including sepsis-associated acute kidney injury (SA-AKI). Diabetes is a known risk factor for SA-AKI and is associated with worse sepsis outcomes. The authors investigated whether pretreatment with imeglimin, a novel oral antihyperglycemic and reported AMP-kinase (AMPK) activator, could mitigate SA-AKI and improve survival in diabetic mice exposed to Escherichia coli. The central hypothesis was that imeglimin preserves mitochondrial function via AMPK enhancement, thereby reducing metabolic deterioration and organ injury during sepsis.
Two diabetic mouse models were used. First, genetically diabetic male C57BLKS/J Iar -+Leprdb/+Leprdb (db/db) mice received either imeglimin-mixed food (Ime) or vehicle food (Veh) for two weeks before challenge. Second, to isolate effects independent of imeglimin’s glucose-lowering action, streptozotocin (STZ)-induced diabetic mice were also studied with the same pretreatment approach. After the two-week feeding period, animals were challenged with an Escherichia coli infection. The source reports that survival and multiple physiologic and biochemical outcomes were subsequently examined.
The study assessed survival after E. coli challenge and indicators of kidney injury. Systemic measures included serum cytokine levels (with specific reporting of IL-6), serum lactate and ketone concentrations, and indices of metabolic state. Renal mitochondrial function was assessed by measuring tubular cell mitochondrial membrane potential and kidney ATP concentration. Protein signaling related to AMPK activity was evaluated using the phosphorylated AMPK to total AMPK (p-AMPK/AMPK) ratio. The authors compared these endpoints between imeglimin-fed and vehicle-fed groups in both diabetic models.
Pretreatment with imeglimin was associated with an improved survival rate after Escherichia coli challenge in both db/db and STZ diabetic mice compared with vehicle controls. Kidney injury following the bacterial challenge was attenuated in the imeglimin groups across both models. Serum IL-6 levels measured after challenge were lower in imeglimin-treated mice than in vehicle-treated mice, suggesting an attenuated systemic inflammatory response. Changes in serum lactate and ketone concentrations were reported, but the patterns differed between the two diabetic models, as described below.
Imeglimin-treated mice showed a higher p-AMPK/AMPK ratio than vehicle-treated mice, consistent with enhanced AMPK signaling. Measures of renal mitochondrial function were better preserved with imeglimin: the mitochondrial membrane potential of tubular cells and kidney ATP content improved in the imeglimin groups for both db/db and STZ mice. The authors infer that imeglimin’s enhancement of AMPK activity contributed to preservation of mitochondrial function and cellular energy stores during the septic challenge.
Although preservation of mitochondrial membrane potential and kidney ATP concentration with imeglimin was consistent across both diabetes models, recovery of fatty acid oxidation and the trajectories of serum lactate and ketone levels differed between db/db and STZ mice. The source indicates these metabolic responses were not identical across models, implying that baseline metabolic state or the diabetes induction method influenced systemic metabolic changes during sepsis and after imeglimin pretreatment.
In these murine models of diabetes, imeglimin pretreatment before Escherichia coli challenge improved survival and attenuated sepsis-associated acute kidney injury. The reported mechanism is preservation of mitochondrial function and ATP content associated with increased AMPK phosphorylation, which likely supported earlier resolution of sepsis-related metabolic deterioration. The authors conclude imeglimin could prevent SA-AKI and increase survival after bacterial challenge via mitochondrial protection mediated by AMPK enhancement. These conclusions are limited to the experimental animal models described.
The investigators declared no conflicts of interest. All animal procedures were performed under institutional ethical standards with IRB approval number 24034-1. Funding included grants from the Japan Society for the Promotion of Science (grant identifiers reported in the source). The article is published under exclusive licence to the Japanese Society of Nephrology.