Pancreatic β-cell failure,clinical implications,and therapeutic strategies in type 2 diabetes

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.

Nuclear factor-Y mediates pancreatic β-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress

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.