The β2-Adrenoceptor Agonist Formoterol Reverses Metabolic Dysfunction in the Diabetic Proximal Tubule

Diabetic kidney disease (DKD) is characterized by metabolic dysregulation and mitochondrial dysfunction that are in part driven by elevated glucose. This study assessed the metabolic changes in the renal proximal tubule in the early onset of DKD. Furthermore, we evaluated the effect of the β2-adrenoceptor agonist formoterol in reversing metabolic disruptions in diabetic mouse kidneys. Metabolomic analysis using liquid chromatography-mass spectrometry detected 270 biochemicals in each sample. Thirteen-week-old diabetic db/db mice treated with vehicle were characterized by increased aromatic and branched-chain amino acids in renal cortex compared to vehicle-treated db/+ mice. In contrast, glycine, sarcosine, and alanine were decreased. Conversely, 8 out of 11 biochemicals associated with the glycolysis pathway, including glucose, glucose-6-phosphate, and glucose-1-phosphate, were reduced in the renal cortex of vehicle-treated db/db mice compared to db/+ mice. Furthermore, carnitines, lysolipids, cholesterol, and the steroid hormone corticosterone were increased in vehicle-treated db/db mice compared to db/+ control mice. Treatment with formoterol restored amino acid profiles and corrected glycolytic and glycogen pathways, indicating an improved metabolic balance. Formoterol treatment normalized lipid and steroid levels and mitigated markers of lipid dysregulation. These data provide insights into the early metabolic alterations in hyperglycemia and mitochondrial dysfunction in the renal cortex. Importantly, this work demonstrates that formoterol treatment reverses many of these early metabolic signatures, further supporting its use as a therapeutic for DKD. SIGNIFICANCE STATEMENT: This study identifies metabolic alterations in the kidneys of diabetic mice and is the first to evaluate the effect of the β2-adrenoceptor agonist formoterol on metabolism in the kidney. The study results showed that formoterol restores amino acid, carbohydrate, and nucleotide metabolism in a mouse model of diabetic kidney disease.