The Protective Effects Of GDF11 On Islet ? Cell In Mouse Models Of Type 2 Diabetes And Its Possible Mechanisms

BackgroundType 2 diabetes is an aging-associated disease,characterized by progressive loss of beta cell mass and function over time.Growth differentiation factor 11(GDF11)has been implicated in regulating the development of islets and reversing age-related phenotype in multiple organs.However,information regarding the role of GDF11 in adult pancreatic islets is scarce.AimsThe aim of this study was to investigate the effects of GDF11on ? cell function and mass and its possible mechanisms.MethodsSix-week-old male C57BL/6 mice were rendered diabetic by feeding with high fat diet(HFD)plus daily intraperitoneal injection of 100 mg/kg streptozotocin(STZ).Six-week-old male db/db mice were also used as spontaneous mouse models of type 2 diabetes mellitus.In the study,we investigated the effects of GDF11 on adult islet ? cell using non-genetic and genetic mouse models of type 2 diabetes mellitus.Blood glucose levels,body weights and food intake were monitored weekly.IPGTT and glucose-stimulated insulin secretion(GSIS)were evaluated at the beginning and end of studies.After 6 weeks intervention,serum HbAlc,TG,TC,FFA,insulin,glucagon were measured respectively.The mRNA expression of PDX-1,MafA,NKX6.1,and Insulin2 were assessed by RT-PCR.At the end of the study,the pancreatic tissue were weighed,divided longitudinally and taken for histological examination or measurement of hormone content.For histological examination,the ? cell mass,? cell size,a cell mass and the frequency of ? cell proliferation and apoptosis were calculated.The expression of Smad2,P-Smad2,Smad3,P-Smad3,AKT,P-AKT,FoxO1,P-FoxO1,S6K1 and P-S6K1 in islet were examined by western blot.ResultsThese results suggested that injection of rGDFl 1 in a group of normal control mice did not affect any of the parameters examined in the study and these animals were indistinguishable from vehicle-treated control mice.However,both rGDF11 and AAV-GDF11 intervention significantly decreased fasting blood glucose,HbAlc and lipid profile,reduced glucagon levels,improved glucose tolerance,increased fasting and glucose-stimulated insulin secretion and upregulated the expression of PDX-1,MafA,NKX6.1 and Insulin2 in two different mouse models of type 2 diabetes.In addition,both rGDF1 1 and AAV-GDF11 intervention could maintain(3 cell mass and mitigate ? cell apoptosis.In contrast,GDF11 repletion has no effect on a cell mass,? cell size and ? cell proliferation.Moreover,GDF11 replenishment increased pancreatic insulin content,but did not affect pancreatic glucagon content.In addition,neutralization of GDF11 in the circulation did not affect any parameters in the normal control mice,whereas elevated 6-h fasting blood glucose and HbAlc levels and reduced serum insulin levels in diabetic mice.Furthermore,GDF11 antibody worsened glucose tolerance,perturbed acute insulin response to glucose and promoted ? cell apoptosis.Mechanistically,both rGDF11 and AAV-GDF11 treatment restored Smad2 phosphorylation,but has no apparent effect on Smad3 phosphorylation.Also,GDF11 replenishment elevated AKT phosphorylation and FoxO1 phosphorylation.Meanwhile,S6K1 phosphorylation was unchanged by GDF11 restoration.ConclusionsTaken together,our data show for the first time that GDF11 could improve the metabolic abnormalities,suppress inappropriate glucagon secretion,preserve ? cell function and mitigate P cell apoptosis through the activation of Smad2 and PI3K-AKT-FoxO1 pathways.On the contrary,neutralization of GDF11 induced opposite effects.These results clearly suggest a critical role of GDF11 in the regulation of ?cell function and mass.Thus,the identification of GDF 11 opening up a new avenue for the treatment of type 2 diabetes.