| Aims:Glucagon-like peptide-1(GLP-1)production in a cells is stimulated in Type 2 Diabetes Mellitus(T2DM),and forms paracrine/autocrine pathways in? and ? cells through GLP-1 receptor(GLP-1R).But the effects of local GLP-1/GLP-1R axis on ? cell mass remain unclear.We investigated the possible role of local GLP-1/GLP1R axis in promoting ? cell redifferentiation and ? to ? cell transdifferentiation.Methods:Ins2eGFP mice were generated for ? cell lineage tracing.Firstly,6-week-old male Ins2eGFP mice were randomly divided into SD and T2DM groups(n=24 per group).SD group was used as control.T2DM was induced using high-fat diet(HFD)and intramural injection of streptozotocin(40 mg/kg/d for 3 days).Phenotypic changes in ? cells and intra-islet GLP-1/GLP-1R/Dipeptidyl peptidase-4(DPP4)axis were investigated by immunofluorescence,electron microscope,RT-PCR,Elisa and WB analysis Secondly,6-week-old male mice were randomly divided into SD,T2DM,T2DM+Lira and T2DM+Ex9-39 groups(n=24 per group).Mice of T2DM+Lira and T2DM+Ex9-39 groups were injected intraperitoneally with liraglutide(0.8mg/kg/d)and Exendin-3(9-39)(0.1mg/kg/d)daily for 4 weeks respectively.Phenotypic changes in ? and ? cells were investigated by immunofluorescence staining,electron microscope,RT-PCR,Elisa and WB analysis.Thereafter,isolated mice islets and Min6 ? cell line were incubated in vitro with 0.5mmol/L PA.Effects of liraglutide on insulin,FoxO1,PDX1,NKX6.1 expression and PI3K/AKT/FoxO1 signalling were investigatedResults:? cells dedifferentiation occurred in T2DM mice,a subset of which transdifferentiated into ? cells.Meanwhile,GLP-1R signalling in ? and ? cells were activated by endogenous GLP-1 as a result of stimulated production of GLP-1 in ? cells and reduced degradation of GLP-1 by ? cell expressed DPP4 Activation of GLP-1R signalling restored ? cell function by promoting ? cell redifferentiation and possible ? to ? cell transdifferentiation,which might be partially mediated by PI3K/AKT/FoxO1 pathwayConclusions:We demonstrate that ? cell dedifferentiation is one of the mechanisms underlying ? cell failure in HFD+STZ induced T2DM mice model.Islet local GLP-1/GLP-1R/DPP4 axis is novel paracrine/autocrine pathways regulating ? and ? cells fate,which plays an important role in preserving functional ? cell mass under metabolic stress by promoting ? cell redifferentiation and possible ? to ? cell transdifferentiation.Thus,intra-islet GLP-1/GLP-1R/DPP4 axis provides new therapeutic target and research avenue for in vivo restoration of functional ? cell mass in diabetes treatmentAims:In vivo ? cells neogenesis may be one way to treat diabetes.In this article,we aimed to investigate the effect of glucagon-like peptide-1(GLP-1)on ? cells neogenesis in Type 2 Diabetes Mellitus(T2DM).Mehods:Six-week-old male C57BL/6J mice were randomly divided into three groups:Control,T2DM and T2DM+Lira.T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin(40 mg/kg/d for 3 days).At 8 weeks after streptozotocin injection,T2DM+Lira group was injected intraperitoneally with GLP-1 analogue liraglutide(0.8 mg/kg/d)for 4 weeks.Results:Apparently for the first time,we report the appearance of a tubuli-vesicular structure connected to pancreas in all adult mice from each group.The tubuli-vesicular structure was characterized by scattered single mono-hormonal cells expressing insulin,GLP-1,somatostatin,or pancreatic polypeptide,and four-hormonal cells.Mono-hormonal cells in it were small,newborn,immature cells that rapidly proliferated and expressed cell markers indicative of immaturity.Liraglutide facilitated neogenesis and rapid growth of acinar cells,pancreatic ducts and blood vessels in tubuli-vesicular structure Meanwhile,scattered hormonal-cells aggregated into cell clusters and grew into larger islets;four-hormonal cells differentiated into mono-hormonal cells Extensive growth of exocrine and endocrine glands resulted in the generation of neogenetic pancreas following liraglutide treatmentConclusions:Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud,which liraglutide facilitates in adult T2DM mice. |
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