Evaluation of Therapeutic Potential of Indolepropionate for the Treatment of Type 2 Diabetes Mellitus in Rats

Abstract

Diabetes mellitus (DM) is a major global public health issue, with current estimates indicating that approximately 463 million adults worldwide are affected by the disease, with around 90% of these cases being type 2 diabetes mellitus (T2DM). This study explores the antidiabetic effects of indolepropionate (IPA) in a rat model of diabetes. Male albino rats were divided into five groups: Control, T2DM, T2DM treated with IPA, only IPA, and T2DM treated with Metformin. T2DM was induced through a combination of a high-fat diet and a streptozotocin (STZ) injection (50 mg/kg). The study assessed parameters including body weight, food and water intake, and blood glucose levels. After that, the histopathological changes in the pancreatic tissues and the oxidative stress such as Enzymes SOD, CAT, and MDA levels were measured. Further, the qRT-PCR analysis of the Akt, pI3K, GLUT-4 and mTOR; the genes that are essential for insulin signaling, was also done. Moreover, the effect of IPA in the treatment of T2DM rats based on untargeted metabolomics was investigated. The results showed that the T2DM group experienced significant weight loss, along with elevated blood glucose and MDA levels, and reduced SOD and CAT activity. Histological analysis revealed significant abnormalities, including damaged pancreatic islet cells and a reduction in islet diameter. Notably, treatment with indolepropionate led to marked improvements in these parameters, demonstrating a reduction in oxidative stress, enhancement in glucose metabolism by increasing insulin sensitivity, and restoration of pancreatic islet physiology. The observed changes in the expression of metabolic regulator gene (PI3K, Akt, GLUT4, mTOR) mRNA levels further confirmed the protective effects of the treatment. This study showed that using metabonomics there are changes in the raised metabolic patterns of T2DM rats. Metabolomics results showed that the endogenous metabolites of T2DM rats were disordered, and IPA can effectively regulate these metabolites in multiple metabolic pathways related to T2DM. Furthermore, in pathway enrichment analysis D-Amino acid metabolism showed the highest enrichment, followed by glyoxylate and dicarboxylate metabolism, sphingolipid metabolism, and glycine, serine, and threonine metabolism.These findings suggest that IPA has significant therapeutic potential against type 2 diabetes, highlighting its promise as a natural therapeutic agent for managing the disease