脐带间充质干细胞输注对2型糖尿病合并非酒精性脂肪性肝病患者的疗效评估:一项前瞻性临床试验的事后分析

Efficacy of UC-MSC infusion in patients with coexisting type 2 diabetes mellitus and nonalcoholic fatty liver disease:A post hoc analysis of a prospective clinical trial

背景2型糖尿病(type 2 diabetes mellitus,T2DM)和非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)常并发,二者共患可加剧并发症及靶器官的损害。近年来国内外间充质干细胞治疗代谢病正在兴起,但其临床研究比较缺乏。目的分析脐带来源的间充质干细胞(umbilical cord-derived mesenchymal stem cell,UC-MSC)对T2DM和NAFLD共病患者的治疗效果。方法本研究是一项前瞻性、单中心、随机、双盲试验的事后分析,选取2015年10月—2018年12月就诊于解放军总医院第一医学中心内分泌科的T2DM合并NAFLD患者,按照随机化原则1∶1分配至UC-MSC组和安慰剂组。对治疗前后患者的血糖控制水平、胰岛素抵抗水平、肝超声结果、肝纤维化程度、部分脂质代谢和肝功能指标进行比较。结果UC-MSC组男22例,女11例,平均年龄(51.36±8.85)岁;安慰剂组男性22例,女性10例,平均年龄(50.47±8.42)岁;两组性别、年龄及基线信息差异无统计学意义(P>0.05)。在治疗9周后,UC-MSC空腹血糖水平显著低于治疗前[(7.46±1.79)mmol/L vs(8.33±1.80)mmol/L,P=0.001],并在治疗9周[(7.46±1.79)mmol/L vs(8.19±1.95)mmol/L,P=0.007]和20周[(7.51±1.77)mmol/L vs(9.10±2.78)mmol/L,P=0.002]时显著低于安慰剂组。同时,糖化血红蛋白达标(<7.0%)比例在治疗的第9周(60.60%vs 28.10%,P=0.008)、第20周(51.50%vs 25.00%,P=0.028)和第48周(48.50%vs 12.50%,P=0.002),UC-MSC组患者显著高于安慰剂组。在第20周,UC-MSC组在肝超声检查结果上呈现出改善的患者比例高于安慰剂组(45.45%vs 18.75%,P=0.021)。高胰岛素正葡萄糖钳夹实验结果显示,UC-MSC组在第9周和第48周的葡萄糖输注率较基线有所提高,并在第48周显著高于安慰剂组[(4.77±1.70)mg/(min·kg)vs(3.57±1.76)mg/(min·kg),P=0.007]。UC-MSC组在治疗过程中三酰甘油和γ-谷氨酰转移酶水平持续优于基线水平,总胆固醇在第9周和第48周均显著低于基线,丙氨酸转移酶在第20周显著降低,而天冬氨酸转移酶水平在各时间点均无显著变化。结论UC-MSC治疗可在一定程度上改善T2DM合并NAFLD患者的血糖控制、胰岛素敏感性、脂肪肝表现及脂质代谢状况。

Background Type 2 diabetes mellitus(T2DM)and nonalcoholic fatty liver disease(NAFLD)are often comorbid conditions,and their coexistence can exacerbate complications and damage target organs.In recent years,stem cell therapy for metabolic diseases using mesenchymal stem cell(MSC)has been emerging both domestically and internationally.However,clinical studies on their therapeutic effects are still sparse.Objective To investigate the therapeutic potential of umbilical cord-derived mesenchymal stem cell(UC-MSC)in the amelioration of T2DM and NAFLD comorbidity.Methods A prospective,single-center,randomized,double-blind trial was conducted in the Endocrinology Department of the First Medical Center of Chinese PLA General Hospital from October 2015 to December 2018.A total of 65 patients with T2DM and NAFLD were enrolled and assigned on a 1:1 basis to either the UC-MSC group(33 patients)or the placebo group(32 patients).Comparisons were made between pre-and post-treatment levels of blood glucose control,insulin resistance,liver ultrasound findings,degree of liver fibrosis,and selected lipid metabolism and liver function indicators.Results In the UC-MSC group,there were 22 males and 11 females,with an average age of 51.36±8.85 years;in the placebo group,there were 22 males and 10 females,with an average age of 50.47±8.42 years.There were no statistically significant differences in gender,age,and baseline data between the two groups(P>0.05).After 9 weeks of treatment,fasting blood glucose levels in the UC-MSC group were significantly lower than baseline([7.46±1.79]vs[8.33±1.80],P=0.001),and they were also significantly lower than the placebo group at 9 and 20 weeks([7.46±1.79]vs[8.19±1.95],P=0.007;[7.51±1.77]vs[9.10±2.78],P=0.008).Additionally,at weeks 9,20,and 48 of treatment,a significantly higher proportion of patients in the UC-MSC group achieved the HbA1c target(<7.0%)compared to the placebo group(60.60%vs 28.10%,P=0.008;51.50%vs 25.00%,P=0.028;48.50%vs 12.50%,P=0.002).At week 20,a higher proportion of patients in the UC-MSC group showed improvement in liver ultrasound examinations compared to the placebo group(45.45%vs 18.75%,P=0.021).Hyperinsulinemic-euglycemic clamp test results indicated an increase in glucose infusion rates in the UC-MSC group at weeks 9 and 48 compared to baseline,with a significant difference from the placebo group at week 48([4.77±1.70]vs[3.57±1.76],P=0.007).The UC-MSC group also showed sustained improvements over baseline levels for triglycerides(TG)and gamma-glutamyl transferase(GGT),a significant reduction in total cholesterol(TC)at weeks 9 and 48,and a significant decrease in alanine transaminase(ALT)at week 20,while aspartate transaminase(AST)levels showed no significant change at any time points.Conclusion UC-MSC therapy can improve glycemic control to some extent,enhance hepatic structure and function,boost insulin sensitivity,and modulate lipid metabolism in patients with concurrent T2DM and NAFLD.