| Objective: Type 2 diabetes has become a global disease with an increasing incidence.Long-term hyperglycemia involving macro-and micro vessels causes multiple organ systems dysfunction,plays an important risk factor of high mortality.Vasodilation dysfunction,affects the regulation of vascular tension and structure.Hemodynamics,determined by vascular load,vasoconstriction and relaxation,excitability,plays an important role in the diabetic angiopathy.Therefore,improving hemodynamics and vascular endothelial dysfunction is the focus of the prevention of diabetic angiopathy.Sodium-glucose cotransporter(SGLT)-2 inhibitor is a new type of hypoglycemic drugs which can reduce blood glucose by increasing urinary glucose excretion.In this study,through research of arterial blood flow velocity and other indexes in patients,as well as diabetic model mice and in vitro arterial ring tissue culture,the effects on hemodynamics and vascular endothelial function in type 2 diabetes were observed.Methods: 1.Clinical study: 59 patients were randomly divided into experimental group(n=33)and control group(n=26).The experimental group was given dapagliflozin 10 mg Qd.and the control group was given acarbose 50 mg Tid.for 12 weeks.The clinical hematuria test,blood flow velocity and resistance index of heart,cerebrovascular and lower limb arteries were observed.2.Intervention experiment in vitro: Vascular ring tissue culture was used to explore the effect of SGLT-2i pretreatment on vascular activity under high glucose.The changes of contractile and diastolic function of vascular rings were detected by myograph technique.Vasoconstriction was induced by high potassium(KCL)and phenylephrine(PHE),and vasodilation induced by acetylcholine(ACh)and nitroprusside(SNP)(endothelium-dependent and independent).3.Model intervention experiment: Established the type 2 diabetes mice model,the effect of vasodilation function was studied on basis of diabetic vascular injury in vivo.Results: 1.Clinical study results: In the course of the study,a total of 5 cases dropped out(3 in the experimental group and 2 in the control group),and finally 54 cases were included.Both groups have hypoglycemic effect,and acarbose has more significant effect.Dapagliflozin could reduce body mass index and waist-hip ratio(P<0.05),reduce plasma triglyceride,liver transaminase,creatinine and uric acid levels(P<0.05),and increase glomerular filtration rate by 12.2%(P<0.05).The levels of urinary β2-microglobulin,ACR,24-hour urinary protein and microalbumin decreased,indicating the significant improvement of renal function in the experimental group.For hemodynamic indexes,LVEF in cardiac ultrasound increased by 5.5%,blood flow velocity of femoral artery,anterior tibial artery and dorsalis pedis artery decreased after treatment,and there was no significant difference in resistance index.Dapagliflozin improved the degree of arterial stenosis and hemodynamics of lower extremities,but had no significant effect on cerebral artery.In the subgroup analysis,for the patients with severe obesity,the improvement of LVEF and femoral artery hemodynamics were more significant in the severe obesity group.In the higher Hb A1 c group and overweight group,the improvement of dorsalis pedis artery blood flow was more significant,and it was positively correlated with the change of plasma triglyceride level,and the effect was the highest,while the change of hemoglobin had the least effect on the change of blood flow velocity of dorsalis pedis artery.2.Vitro experiment: Cultured aortic rings under high glucose(25mmol/L)selectively inhibited the endothelium-dependent vasodilation induced by ACh in thoracic aortic rings,but had no significant effect on vasoconstriction.Pretreatment with dapagliflozin(0.5-1-5μM),canagliflozin(1-5-10μM)and empagliflozin(0.5-1-5μM)could protect endothelium-dependent vasodilation,there was no difference among them and had no effect on smooth muscle relaxation induced by SNP.3.Model experiment: In the model,8 weeks treatment of three SGLT-2 inhibitors could attenuate the injury of endothelium-dependent vasodilation,and had the effects of weight protection and hypoglycemia.Conclusion: SGLT-2 inhibitors may improve the hemodynamics of heart and lower extremity in type 2 diabetes by reducing blood lipids and improving endotheliumdependent vasodilation dysfunction,delaying the occurrence and development of diabetic vascular complications. |
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