Protective role of harmol against β-cell toxicity and glucose dysregulation in type 2 diabetes mellitus.

Hypogonadism in males has been identified as one of the risk factors for type 2 diabetes mellitus (T2DM). Testosterone treatment is beneficial for T2DM in both preclinical and clinical studies. Testosterone enhances insulin secretion and maintains β-cell health by activating androgen receptors (AR). However, testosterone therapy is associated with several side effects. Therefore, we aim to test novel selective androgen receptor modulators (SARMs) in T2DM, as they are demonstrated to produce fewer side effects than testosterone. We utilized structure-based drug design methods to identify promising molecules. The mouse insulinoma (MIN6) cell line was used to evaluate the test compounds' cytoprotective effects and insulin secretion capabilities. Gene expression of neurogenin-3 (NGN3) and gene network analysis were conducted to confirm the AR-mediated activity of the test compounds. Harmol was identified as a novel SARM through in-silico and in-vitro studies, which was also validated by the Hershberger assay. Ligandrol, a known SARM, served as a standard molecule. Harmol and ligandrol protected pancreatic β-cells from toxicity induced by streptozotocin and high glucose levels. They also elevated insulin secretion in MIN6 cells. Harmol and ligandrol enhanced the gene expression of the AR-dependent neurogenin-3 gene, which is crucial for pancreatic β-cell regeneration. Gene network analysis also confirmed the AR-mediated activity of harmol. Harmol and ligandrol improved glucose tolerance in diabetic male rats induced by a high-fat diet and streptozotocin. Our results suggest that harmol could serve as a novel anti-diabetic agent for T2DM with a unique mechanism that targets AR for β-cell revival and enhances glucose tolerance.