Genipin And Insulin Combined Treatment Improves Implant Osseointegration In Type 2 Diabetic Rats

Background:With the rapid development of dental implant technology,the implant denture restoration has become the best way to repair the dentition defect.Implant dentures not only have good retention and stability,but also have aesthetics and functions,which greatly improve the life quality of patients.But type 2 diabetes is an unfavorable factor for bone metabolism around implants.Current studies have shown that type 2 diabetes is related to secondary osteoporosis,and type 2 diabetes with osteoporosis and other comprehensive factors can lead to a decrease in the osseointegration capacity of implants.Type 2 diabetes mellitus(T2DM)has a harmful effect on the stability and osseointegration of dental implants.T2DM induces mitochondrial damage by inhibiting AMPK signaling,resulting in oxidative stress and poor osteogenesis in the peri-implant bone area.Genipin is a major component of gardenia fruits with strong antioxidant,anti-inflammation,and anti-diabetic actions,and it also can activate mitochondrial quality control via the AMPK pathway.Objectives:The purpose of this study was to investigate the effects of genipin and insulin treatment on implant osseointegration in T2DM rats and explore the underlying mechanisms.So as to find the ways to improve the implants osseointegration of T2DM rats,with a final target being to conquer limitation of implantation in T2DM patients.Methods:Streptozotocin-induced diabetic rats received implant surgery in their femurs,and were then assigned to five groups that were subjected to different treatments for three months:control group,T2DM group,insulin-treated T2DM group(10 IU/kg),genipin-treated T2DM group(50mg/kg),and the genipin and insulin combination-treated T2DM group.Then,we regularly assessed the weight and glucose levels of the animals.Rats were euthanized at three months after the implantation procedure,and the femora were harvested for microscopic computerized tomography analysis,biomechanical tests,and different histomorphometric assessment(including hard tissue slicing,HE staining,Masson staining and immunohistochemical staining),and to explore the potential mechanism of genipin on improving the osseointegration of implants.Results:The results indicated that the highest blood glucose and oxidative stress levels were measured and lower pAMPK expression levels were observed for the T2DM group,resulting in the poorest osseointegration.The combination-treated T2DM group mitigated hyperglycemia and normalized,reactivated AMPK signaling,and alleviated oxidative stress as well as reversed the negative effect of osseointegration.There were beneficial changes observed in the T2DM-genipin and T2DM-insulin groups,but these were less in comparison to the combination treatment group.However,the osteogenesis effect of the genipin alone treatment group was better than that of the T2DM group,and the genipin alone treatment group had a higher expression level of pAMPK and a lower level of oxidative stress.Conclusion:This study proposes the pharmacological effects of genipin on improving bone regeneration in T2DM rats.Our study suggests that treatment with genipin in combination with insulin could be an effective method for promoting implant osseointegration in T2DM rats,which may be related to the activation of AMPK signaling and antioxidant capacity by genipin.However,whether the results of this study can be directly applied to humans requires a lot of experiments and exploration.