Pancreaticβ-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes(T2D).Reserving insulin-producingβ-cells and hence restoring insulin pr...Pancreaticβ-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes(T2D).Reserving insulin-producingβ-cells and hence restoring insulin production are gaining attention in translational diabetes research,andβ-cell replenishment has been the main focus for diabetes treatment.Significant findings inβ-cell proliferation,transdifferentiation,pluripotent stem cell differentiation,and associated small molecules have served as promising strategies to regenerateβ-cells.In this review,we summarize current knowledge on the mechanisms implicated inβ-cell dynamic processes under physiological and diabetic conditions,in which genetic factors,age-related alterations,metabolic stresses,and compromised identity are critical factors contributing toβ-cell failure in T2D.The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promotingβ-cell proliferation,inducing non-β-cell transdifferentiation,and reprograming stem cell differentiation.Although a significant challenge remains for each of these strategies,the recognition of the mechanisms responsible forβ-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenousβ-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.展开更多
Background:Pancreaticβ-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions.Deficits inβ-cell compensatory capacity result ...Background:Pancreaticβ-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions.Deficits inβ-cell compensatory capacity result in hyperglycemia and type 2 diabetes(T2D).However,the mechanism in the regulation ofβ-cell compensative capacity remains elusive.Nuclear factor-Y(NF-Y)is critical for pancreatic islets’homeostasis under physiological conditions,but its role inβ-cell compensatory response to insulin resistance in obesity is unclear.Methods:In this study,using obese(ob/ob)mice with an absence of NF-Y subunit A(NF-YA)inβ-cells(ob,Nf-yaβKO)as well as rat insulinoma cell line(INS1)-based models,we determined whether NF-Y-mediated apoptosis makes an essential contribution toβ-cell compensation upon metabolic stress.Results:Obese animals had markedly augmented NF-Y expression in pancreatic islets.Deletion ofβ-cell Nf-ya in obese mice worsened glucose intolerance and resulted inβ-cell dysfunction,which was attributable to augmentedβ-cell apoptosis and reactive oxygen species(ROS).Furthermore,primary pancreatic islets from Nf-yaβKO mice were sensitive to palmitate-inducedβ-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response,which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase(JNK)and cleaved caspase-3.These detrimental effects were completely relieved by ROS scavenger.Ultimately,forced overexpression of NF-Y in INS1β-cell line could rescue palmitate-inducedβ-cell apoptosis,dysfunction,and mitochondrial impairment.Conclusion:Pancreatic NF-Y might be an essential regulator ofβ-cell compensation under metabolic stress.展开更多
基金National Natural Science Foundation of China(Nos.82270846 and 81770814)Sichuan Science and Technology Program(No.2023JDRC0095)National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(No.Z20201010)
文摘Pancreaticβ-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes(T2D).Reserving insulin-producingβ-cells and hence restoring insulin production are gaining attention in translational diabetes research,andβ-cell replenishment has been the main focus for diabetes treatment.Significant findings inβ-cell proliferation,transdifferentiation,pluripotent stem cell differentiation,and associated small molecules have served as promising strategies to regenerateβ-cells.In this review,we summarize current knowledge on the mechanisms implicated inβ-cell dynamic processes under physiological and diabetic conditions,in which genetic factors,age-related alterations,metabolic stresses,and compromised identity are critical factors contributing toβ-cell failure in T2D.The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promotingβ-cell proliferation,inducing non-β-cell transdifferentiation,and reprograming stem cell differentiation.Although a significant challenge remains for each of these strategies,the recognition of the mechanisms responsible forβ-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenousβ-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.
基金National Natural Science Foundation of China(Nos.82270846,32200933 and 81770814)National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(No.Z20201010)Sichuan Natural Science Foundation(No.23NSFSC4132)
文摘Background:Pancreaticβ-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions.Deficits inβ-cell compensatory capacity result in hyperglycemia and type 2 diabetes(T2D).However,the mechanism in the regulation ofβ-cell compensative capacity remains elusive.Nuclear factor-Y(NF-Y)is critical for pancreatic islets’homeostasis under physiological conditions,but its role inβ-cell compensatory response to insulin resistance in obesity is unclear.Methods:In this study,using obese(ob/ob)mice with an absence of NF-Y subunit A(NF-YA)inβ-cells(ob,Nf-yaβKO)as well as rat insulinoma cell line(INS1)-based models,we determined whether NF-Y-mediated apoptosis makes an essential contribution toβ-cell compensation upon metabolic stress.Results:Obese animals had markedly augmented NF-Y expression in pancreatic islets.Deletion ofβ-cell Nf-ya in obese mice worsened glucose intolerance and resulted inβ-cell dysfunction,which was attributable to augmentedβ-cell apoptosis and reactive oxygen species(ROS).Furthermore,primary pancreatic islets from Nf-yaβKO mice were sensitive to palmitate-inducedβ-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response,which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase(JNK)and cleaved caspase-3.These detrimental effects were completely relieved by ROS scavenger.Ultimately,forced overexpression of NF-Y in INS1β-cell line could rescue palmitate-inducedβ-cell apoptosis,dysfunction,and mitochondrial impairment.Conclusion:Pancreatic NF-Y might be an essential regulator ofβ-cell compensation under metabolic stress.