Anle138b improves insulin resistance in mice and its possible signal pathways

• Anle138b significantly improves insulin resistance by reducing hyperglycemia, hyperinsulinemia, and dyslipidemia in high-fat diet-induced mice, with enhanced glucose tolerance and lowered HOMA-IR. • Restores organ structure and function, alleviating hepatic steatosis, pancreatic acinar damage, and ectopic fat deposition while reducing liver and epididymal fat indices. • Mechanistically targets SREBP-1c and ADRA2A pathways, downregulating their expression in metabolic tissues (liver, pancreas, muscle), offering a novel dual-target strategy for metabolic disorders. Insulin resistance (IR), a hallmark of metabolic syndrome, is characterized by diminished tissue sensitivity to insulin, leading to hyperglycemia, hyperinsulinemia, and strong associations with metabolic disorders, such as hypertension, obesity, and type 2 diabetes mellitus (T2DM). In this study, we investigated the therapeutic potential of anle138b, a highly active small-molecule compound derived from 3,5-diphenylpyridine (DPP), in treating IR. Using a C57BL/6J mouse model with stable metabolic dysfunction, induced by a high-fat diet, we demonstrate that anle138b treatment improved key metabolic parameters compared to controls. Specifically, anle138b reduced fasting blood glucose, serum triglycerides, total cholesterol, and fasting insulin levels, and improved HOMA-IR (homeostasis model assessment of IR) scores. Additionally, anle138b enhanced glucose tolerance and lowered elevated organ indices, including liver index and epididymal fat index. Histopathological analysis revealed morphological recovery of pancreatic acinar cells and hepatic cord architecture, along with reduced ectopic fat deposition. Mechanistically, qPCR and western blot analyses showed that anle138b downregulated the mRNA and protein expression of both SREBP-1c and ADRA2A in the pancreas, liver, and skeletal muscle. These findings suggest that anle138b ameliorates IR by modulating SREBP-1c- and ADRA2A-mediated signaling pathways. Given the growing need for novel hypoglycemic and lipid-lowering agents, anle138b represents a promising therapeutic candidate for metabolic disorders, offering a potential strategy to combat diabetes and IR.