A recent study in the World Journal of Diabetes by Yang et al explored how Rheb1 signaling influenced pancreaticβcell fate and its potential as a therapeutic target.This invited commentary by a senior diabetes resear...A recent study in the World Journal of Diabetes by Yang et al explored how Rheb1 signaling influenced pancreaticβcell fate and its potential as a therapeutic target.This invited commentary by a senior diabetes researcher discussed the findings of Yang et al in the context of current knowledge onβcell biology,providing critical insight into the role of Rheb1 inβcell survival and function and the prospects for diabetes treatment.Key outcomes of the study were interpreted alongside established literature on Rheb1-mechanistic target of rapamycin signaling in islet cells.Rheb1 emerges as a pivotal regulator ofβcell growth and insulin secretory function,aligning with evidence thatβcell-specific Rheb1 deletion impairsβcell mass and glucose-stimulated insulin secretion.The commentary highlighted how modulating this pathway could preserve or restore theβcell population in diabetes while cautioning about potential off-target effects(e.g.inαcells).Targeting Rheb1 signaling represents a promising new frontier in diabetes therapy to enhanceβcell resilience;however,a balanced approach addressing both its benefits and risks is essential.This letter discussed the scientific implications and future research directions needed to translate Rheb1 modulation into clinical application for diabetes.展开更多
BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein o...BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein of mTOR,is a potential thera-peutic target forβcell in diabetes,while the underlying mechanisms remains un-known.METHODS Islets samples were collected from mouse and human donors.Min6 transformed cell line and mouse models including pancreatic orβ-cell specific knockout of Rheb1mice were established.Rapamycin(an mTORC1 inhibitor)and AICAR(an AMPK activator)was used to investigate mTORC1 or AMPK signaling inβcells.The effect of Rheb1 onβcell function via mTORC1,AMPK or other pathways were assessed using western blotting and immunofluorescence,etc.RESULTS In this study,we demonstrate that Rheb1 is highly expressed in islets from young human donors(below the age of 18)compared to adults.Furthermore,our findings reveal that Rheb1 facilitatesβ-cell proliferation through both mTORC1 and AMPK signaling pathways,rather than solely relying on mTORC1.Specifically,we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-inducedβcell proliferation,while the combination of AICAR and rapamycin fully inhibits Rheb1-inducedβcell proliferation in Min6 transformed cell line and mouse islets.In addition,our study highlights the role of Rheb1 in maintainingβcell identity through activation of mTORC1 and Notch1 signaling pathways.Moreover,we also found that Rheb1 could positively regulate HNF4αinβcells,which is a significant transcription factor forβ-cell development and differentiation.CONCLUSION Overall,our findings reveal that Rheb1 regulatesβcell proliferation and identity andβ-cell development related significant marker,providing a promising novel therapeutic target for diabetes.展开更多
文摘A recent study in the World Journal of Diabetes by Yang et al explored how Rheb1 signaling influenced pancreaticβcell fate and its potential as a therapeutic target.This invited commentary by a senior diabetes researcher discussed the findings of Yang et al in the context of current knowledge onβcell biology,providing critical insight into the role of Rheb1 inβcell survival and function and the prospects for diabetes treatment.Key outcomes of the study were interpreted alongside established literature on Rheb1-mechanistic target of rapamycin signaling in islet cells.Rheb1 emerges as a pivotal regulator ofβcell growth and insulin secretory function,aligning with evidence thatβcell-specific Rheb1 deletion impairsβcell mass and glucose-stimulated insulin secretion.The commentary highlighted how modulating this pathway could preserve or restore theβcell population in diabetes while cautioning about potential off-target effects(e.g.inαcells).Targeting Rheb1 signaling represents a promising new frontier in diabetes therapy to enhanceβcell resilience;however,a balanced approach addressing both its benefits and risks is essential.This letter discussed the scientific implications and future research directions needed to translate Rheb1 modulation into clinical application for diabetes.
基金Supported by National Natural Science Foundation of China,No.82430029,No.82330025,No.82370807,and No.82070807Leading Talents Program of Hunan Province,No.2022RC3078Natural Science Foundation of Hunan Province,China,No.2021JJ30976.
文摘BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein of mTOR,is a potential thera-peutic target forβcell in diabetes,while the underlying mechanisms remains un-known.METHODS Islets samples were collected from mouse and human donors.Min6 transformed cell line and mouse models including pancreatic orβ-cell specific knockout of Rheb1mice were established.Rapamycin(an mTORC1 inhibitor)and AICAR(an AMPK activator)was used to investigate mTORC1 or AMPK signaling inβcells.The effect of Rheb1 onβcell function via mTORC1,AMPK or other pathways were assessed using western blotting and immunofluorescence,etc.RESULTS In this study,we demonstrate that Rheb1 is highly expressed in islets from young human donors(below the age of 18)compared to adults.Furthermore,our findings reveal that Rheb1 facilitatesβ-cell proliferation through both mTORC1 and AMPK signaling pathways,rather than solely relying on mTORC1.Specifically,we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-inducedβcell proliferation,while the combination of AICAR and rapamycin fully inhibits Rheb1-inducedβcell proliferation in Min6 transformed cell line and mouse islets.In addition,our study highlights the role of Rheb1 in maintainingβcell identity through activation of mTORC1 and Notch1 signaling pathways.Moreover,we also found that Rheb1 could positively regulate HNF4αinβcells,which is a significant transcription factor forβ-cell development and differentiation.CONCLUSION Overall,our findings reveal that Rheb1 regulatesβcell proliferation and identity andβ-cell development related significant marker,providing a promising novel therapeutic target for diabetes.
