Therapeutic role of gut microbial metabolite indole propionic acid in a rat model of high-fat diet/Streptozotocin-Induced diabetes: enhancing glucose metabolism, antioxidant defense and PI3K/Akt/GLUT4 signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by insulin resistance, chronic hyperglycemia, and oxidative stress. Recent research has highlighted the therapeutic potential of gut microbiota-derived metabolites in regulating glucose homeostasis.

AIM: This study evaluated the antidiabetic effects of indole propionic acid (IPA) in a streptozotocin-induced diabetic rat model.

METHOD: Male Wistar rats (n = 30) were divided into Control, T2DM, T2DM + IPA, T2DM+metformin, and IPA-only groups. Following four weeks of oral IPA administration, biochemical, histological, molecular, and metabolomic assessments were performed.

RESULTS: IPA treatment significantly reduced fasting blood glucose levels, improved body weight, and normalized food intake in diabetic rats. Histopathological analysis revealed that IPA preserved pancreatic islet architecture and increased both islet cell counts and diameter. Furthermore, IPA markedly enhanced antioxidant defenses by elevating superoxide dismutase (SOD) and catalase (CAT) activities while reducing malondialdehyde (MDA) content in pancreatic tissue. Molecular analysis showed that IPA upregulated the expression of key insulin signaling genes-PI3K, Akt, and GLUT4-in skeletal muscle and downregulated mTOR expression in pancreatic tissue, indicating improved insulin sensitivity. Molecular docking suggested a potential direct interaction between IPA and GLUT4/PI3K, supporting the gene expression data.

CONCLUSION: These findings highlight the multifaceted antidiabetic potential of IPA, supporting its use as a promising therapeutic agent for managing T2DM and its associated metabolic dysfunctions.