Correlation Of SGLT2 Inhibitors With Sympathetic Nerve Activity In Diabetic Patients

Objective:Sodium-glucose cotransporter2(SGLT2)inhibitors are a novel hypoglycemic agent for the treatment of type 2 diabetes mellitus(T2DM)with clear protective effects in the heart and kidneys,but the mechanism is not yet clear.Sympathetic nerves are closely related to the heart and kidney,but the effect of SGLT2 inhibitors on them is controversial.In this paper,we propose to investigate the effect of SGLT2 inhibitors on sympathetic nerve activity through animal experimental meta-analysis and clinical trials.The effects of dapagliflozin on body weight,body mass index(BMI),fasting blood glucose(FBG),glycated hemoglobin A1c(Hb A1c),islet function,urine micro-albumin(m ALB)and urine creatinine were investigated.m ALB),urine creatinine(UCr),urine microalbumin/UCr(ACR),left ventricle ejection fraction(LVEF),and its association with the serum sympathetically active substance norepinephrine(NE).Norepinephrine(NE)and Tyrosine hydroxylase(TH).Method:1.Part I meta-analysis section: The literature related to SGLT2 inhibitors and sympathetic nerves was searched from China Knowledge Network,Wanfang database,Vipshop journal resource database,Pub Med,Cochrane Library,Embase and other databases,and literature screening was performed to obtain data from randomized controlled animal experiments,and Meta-analysis was performed using Rev Man 5.3software to evaluate the effects of SGLT2 inhibition on sympathetic nerves.The search language was restricted to Chinese and English,and the search timeframe was built up to January 28,2023.For the included literature valid outcome indicators included one of them: myocardial NE level,myocardial TH level,plasma NE level,plasma TH level,renal NE level,renal TH level,adipose NE level,adipose TH level.2.Part II clinical trial section: One hundred patients with T2 DM admitted to Mudan People’s Hospital in Heze City from June 2021 to July 2022 were studied.Those who received conventional hypoglycemic drugs(metformin or acarbose)were the diabetic group(50 cases),and those who added dapagliflozin 10 mg once/d to conventional treatment were the dapagliflozin group(50 cases),and were treated for 3 months,and the Clinical data and serum were collected before and after treatment.Body weight,BMI,FBG,Hb A1 c,fasting C peptide,fasting insulin,1h postprandial C peptide,1h postprandial insulin,2h postprandial C peptide,2h postprandial insulin,m ALB,UCr,ACR,LVEF and serum were collected from patients in both groups before and after treatment.Elisa method was used to detect NE and TH levels in patients’ serum and analyze the relationship between sympathetic activity after dapagliflozin treatment and The correlation between sympathetic activity and cardioprotective effect of cardiac,renal and pancreatic islets after dapagliflozin treatment.Results:1.Part I meta-analysis: 659 publications were obtained by database search,and 8 animal experiments(371 animals in total)met the inclusion criteria,and the quality of the entered literature was high.Sensitivity analysis after excluding the study of Xuping Yang et al.showed that SGLT2 inhibitors significantly reduced NE and TH levels relative to the control group.Subgroup analysis suggested that SGLT2 inhibitors significantly increased NE and TH levels in adipose tissue;SGLT2 inhibitors significantly decreased myocardial,renal,and serum TH levels;and dapagliflozin and enagliflozin significantly decreased NE and TH levels.2.Part II clinical trials:(1)After 3 months of treatment,the differences in weight,FBG,Hb A1 c,1h postprandial insulin,2h postprandial C-peptide,2h postprandial insulin,m ALB,UCr,ACR,and cardiac function index LVEF before and after treatment were significant in both groups.(2)Sympathetic nerve activity index test showed that the difference between the pre-and post-treatment difference of serum NE and TH levels in both groups was significant.(3)Correlation analysis showed that after 3 months of treatment,serum NE was negatively correlated with 2h postprandial C peptide in the dapagliflozin group;serum TH was positively correlated with m ALB,UCr,fasting C peptide,1h postprandial insulin,2h postprandial C peptide,2h postprandial insulin and LVEF in the dapagliflozin group.(4)Multiple linear regression results suggested that after 3 months of treatment,2h postprandial insulin was negatively correlated with Hb A1 c in the diabetic group,2h postprandial insulin was negatively correlated with FBG and positively correlated with TH in the dapagliflozin group;UCr was positively correlated with Hb A1 c in the diabetic group,and UCr was negatively correlated with NE in the dapagliflozin group;LVEF was positively correlated with Hb A1 c in the diabetic group,and LVEF was positively correlated with Hb A1 c in the dapagliflozin group LVEF was positively correlated with Hb A1 c and negatively correlated with NE in the dapagliflozin group.(5)There was a significant difference in serum TH levels at different ages in the dapagliflozin group.Conclusions:1.Part I meta-analysis:SGLT2 inhibitors can inhibit myocardial,renal,and serum sympathetic activity,and can increase sympathetic activity in adipose tissue,and the effect of SGLT2 inhibitors,dapagliflozin and enagliflozin,on sympathetic activity is more significant,and the effect may be related to the distribution site of sympathetic nerves.2.Part II clinical trials:(1)After 3 months of treatment,cardiac and renal functions of patients in the dapagliflozin group were improved,and the levels of sympathetic activity indicators NE and TH were suppressed to some extent.(2)The levels of sympathetic activity indexes NE and TH in the dapagliflozin group were correlated with the cardiorenal protective effect,and there were significant differences in the levels of sympathetic activity indexes TH in the dapagliflozin group at different ages.(3)Inhibition of sympathetic activity by dapagliflozin may be a potential mechanism for its cardiorenal protective effect,and the benefit may be more significant in the elderly.