Rheb1 as a novel β-cell regulator connecting mTORC1, AMPK, and NOTCH1 pathways for efficient diabetes therapy
Abstract
This editorial comments on the study by Yang et al, emphasizing the Ras homolog enriched in brain 1 (Rheb1) core function in restoring functional β-cell mass in diabetes, as crucial for β-cell proliferation and survival. It has been revealed that Rheb1 promotes β-cell regeneration through a dual pathway, activating mammalian target of rapamycin complex 1 and simultaneously inhibiting AMP-activated protein kinase (AMPK). Blocking mammalian target of rapamycin complex 1 while stimulating AMPK was necessary to halt β-cell expansion, challenging traditional single-target approaches. Rheb1 also supported β-cell identity by triggering neurogenic locus notch homolog protein 1 signaling and interacting with hepatocyte nuclear factor 4 alpha, linked to maturity-onset diabetes of the young 1. An age-related decline of Rheb1 in human islets suggests its role in diminished regenerative capacity in adulthood. These findings make Rheb1 a promising therapeutic target for rejuvenating β-cells by linking nutrient sensing and energy regulation. Focusing on Rheb1 could alter diabetes treatment, merging proliferation with identity preservation for next-generation therapies. The gaps and translational opportunities, from Rheb1 modulators to biomarkers, were emphasized, advocating for interdisciplinary collaboration to maximize this pathway for positive clinical outcomes. Additional studies are needed to thoroughly investigate AMPK's involvement in the Rheb1 metabolic biomarker associated with…
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