【作者】 王晓华；

【导师】 成兴波；

【作者基本信息】 苏州大学 ， 内科学（内分泌与代谢病学）（专业学位）， 2021， 博士

【摘要】 目的 2型糖尿病的发病机制在胰岛β细胞方面表现为胰岛素敏感性下降和胰岛β细胞功能受损,在胰岛α细胞方面表现为空腹血清胰高血糖素水平升高、糖负荷后高糖抑制α细胞分泌胰高血糖素的作用减弱。胆汁酸(bileacid,BA)代谢在维持血糖动态平衡的信号通路中起着重要作用,推测胆汁酸可能会影响胰岛素和胰高血糖素在血糖代谢中的作用。因此本研究目的主要是探讨空腹血清总胆汁酸(serum total bile acids,S-TBAs)水平与胰岛素敏感性、胰岛β细胞功能及胰岛α细胞功能的关系:从基线水平和随访改变两方面进行分析。方法1.本研究纳入了 2015年至2018年在我院内分泌代谢科随访的2952名2型糖尿病(T2DM)患者,这些纳入的患者空腹血清总胆汁酸水平在正常范围内。同时对这些糖尿病患者进行随访。2.所有基线入组患者和后期随访患者均进行了 口服葡萄糖耐量试验(OGTT),并同时测定了血糖、C肽和胰高血糖素水平。3.胰岛素敏感性评估:空腹和系统性胰岛素敏感性指标分别使用C肽替代的HOMA稳态模型计算(ISHOMA-cp)和C肽替代的Matsuda指数计算(ISIM-cp)进行评估;胰岛β细胞功能评估:使用C肽替代的胰岛素分泌敏感指数2(ISSI-2)来进行评估(ISSI-2cp)。4.胰岛α细胞功能评估:主要是空腹血清胰高血糖素水平(Fasting glucagon,Fgla)和糖负荷后胰高血糖素水平,糖负荷后胰高血糖素水平使用胰高血糖素曲线下面积(AUCgla)进行评价。5.收集了患者的年龄、性别、体重指数、血压、糖尿病的病程、降糖治疗方案、血脂、肝功能、肾功能和糖化血红蛋白等临床资料。结果1.所有患者T2DM病程为5.27±3.90岁,空腹S-TBAs水平为3.29±1.38μmol/L(正常值参考范围1.3～10.0μmol/L)。2.将S-TBAs进行四分位分组后,随着S-TBAs四分位水平升高,ISHOMA-cp、ISIM-cp和ISSI-2cp均下降(p<0.001),而AUCgla水平显著升高(p<0.001),但Fgla水平没有明显变化(p=0.943)。线性相关分析发现S-TBAs和ISHOMA-cp、ISIM-cp和ISSI-2cp呈负相关(r=-0.212、0.154 和-0.245,p<0.001),与 AUCgla 呈正相关(r=0.323,p<0.001),而与Fgla则无显著相关性(r=0.033,p=0.070)。3.进一步通过多元线性回归分析校正其他临床相关因素后,血清总胆汁酸水平S-TBAs 与 ISHOMA-cp(β=-0.04,t=-2.82,p=0.005)、ISIM-cp(β=-0.11,t=-7.051,p<0.001)、ISSI-2cp(β=-0.15,t=-10.26,p<0.001)和 AUCgla(β=0.29,t=19.08,p<0.001)均存在的独立的相关性。4.对入组患者进行了随访,共有483名T2DM患者完成了平均4年的随访,发现随访4年后S-TBAs水平升高,ISHOMA-cp、ISIM-cp和ISSI2cp水平降低,Fgla和AUCgla水平升高,随访前后变化(Δ)具有统计学意义(p<0.001);相关性分析提示随访变化△S-TBAs 与ΔISHOMA-cp、ΔISIM-cp 和ΔISSI-2cp呈负相关(r=-0.225、-0.170 和-0.269,p<0.001),与△Fgla 和ΔAUCgla呈正相关(r=0.117、0.306,p<0.05);进一步通过多元线性回归分析校正其他临床相关因素后,ΔS-TBAs与ΔISHOMA-cp(β=-0.24,t=-5.836,p<0.001)、ΔISIM-cp(β=-0.13,t=-3.080,p=0.002)、ΔISSI-2cp(β=-0.02,t=-7.255,p<0.001)和ΔAUCgla(β=0.28,t=8.898,p<0.001)独立相关,但不是Fgla的独立影响因素(β=0.02,t=0.522,p=0.602)。结论1.T2DM患者正常范围内空腹S-TBAs水平与空腹胰岛素敏感性指数、系统性胰岛素敏感性指数以及胰岛β细胞功能存在独立负相关性。2.空腹S-TBAs水平与糖负荷后胰高血糖素水平存在独立正相关性,而与空腹胰高血糖素水平无明显相关性。3.随访观察进一步证实了 S-TBAs升高是空腹胰岛素敏感性指数、系统性胰岛素敏感性指数以及胰岛β细胞功能下降改变的独立影响因素,是糖负荷后胰高血糖素升高改变的的独立影响因素。更多还原

【Abstract】 Objective Type 2 diabetes is characterized by declined insulin ensitivity,impaired islet β-cell function,elevated fasting plasma glucagon levels and impaired suppression of glucagon secretion in α-cells following oral source of hyperglycaemia.Bile acids metabolism plays a dominant role in the signaling pathways maintaining glycemic homeostasis,so we hypothesized that bile acids may have impact on action of insulin and glucagon.Therefore,the aims of this study is to explore the the association of fasting serum total bile acids(S-TBAs)with insulin sensitivity,islet β-cell function and α-cell function in patients with type 2 diabetes(T2DM):analysis from both baseline and follow-up.Methods1.Total 2952 patients with T2DM and with fasting S-TBAs in normal range were recruited for this study from 2015 to 2018.At the same time,these patients were further received a follow-up.2.All patients enrolled at baseline and patients at follow-up were received an oral glucose tolerance test for the synchronous measurement of fasting and postchallenge glucose,C-peptide and glucagon.3.Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment(HOMA)and Matsuda index using C-peptide,ISHOMA-cp and ISIM-cp,respectively.Islet β-cell function was assessed by Insulin Secretion-Sensitivity Index-2 using C-peptide(ISSI-2cp).4.Fasting glucagon levels(Fgla)were determined,and postchallenge glucagon levels were assessed by the area unde the glucagon curve(AUCgla)during oral glucose tolerance tests.5.Other clinical data such as age,gender,body mass index,blood press,diabetic duration,diabetic treatments,lipid profiles,liver function,kidney function and HbAlc were aslo collected.Results1.The recruited patients had diabetic duration for 5.2713.90 years and normal fasting S-TBAs for 3.29±1.38μmol/L(range 1.3-10.0μmol/L).2.Metabolic parameters,ISHOMA-cp,ISIM-cp and ISSI-2cp decreased,while AUCgla notably increased across ascending quartiles of S-TBAs(all p for trend<0.001),but not fasting glucagon.Moreover,S-TBAs were inversely correlated with ISHOMA-cp,ISIM-cp and ISSI-2cp(r=-0.21,-0.15 and-0.25,respectively,p<0.001),and positively correlated with AUCgla(r=0.32,p<0.001),but not with fasting glucagon(r=0.033,p=0.07).3.Furthermore,after adjusting for other clinical covariates by multiple liner regression analyses,the S-TBAs were independently associated with SHOMA-cp(β=-0.04,t=-2.82,p=0.005),ISIM-cp(β=-0.11,t=-7.05,p<0.001),ISSI-2cp(β=-0.15,t=-10.26,p<0.001)and AUCgla(β=0.29,t=19.08,p<0.001).4.Finally,total 483 patients with T2DM were completed a follow-up for an average of 4 years.After 4 years of follow-up,the levels of S-TBAs were increased,the levels of ISHOMA-cp,ISIM-cp and ISSI-2cp were decreased,and the levels of Fgla and AUCgla were increased.The changes(Δ)before and after follow-up were statistically significant(p<0.001).Linear correlation analysis showed that the ΔS-TBAs were negatively correlated with ΔISHOMA-cp,ΔISIM-cp and ΔISSI-2cp(r=0.225,-0.170 and-0.269,p<0.001),and positively correlated with ΔFgia and ΔAUCgla(r=0.117 and 0.306,p<0.05).Moreover,after adjusting for other clinical covariates by multiple linear regression analysis,ΔS-TBAs was independently associated with ΔISHOMA-cp(β=-0.24,t=-5.836,p<0.001),ΔISIM-cp(β=-0.13,t=-3.080,p<0.002),ΔISSI-2cp(β=-0.02,t=-7.255,p<0.001)and ΔAUCgla(β=0.28,t=8.898,p<0.001),but not with Fgla(β=0.02,t=0.522,p=0.602).Conclusions1.Fasting S-TBAs within the normal reference range were inversely associated with fasting and systemic insulin sensitivity indices,and integrated islet β-cell function in patients with T2DM.2.Fasting S-TBA levels were postively associated with glucagon levels in response to glucose challenge in patients with T2DM,but not with fasting glucagon levels.3.Follow-up analysis further confirmed that the an increase of fasting S-TBAs contributed to a decrease of fasting insulin sensitivity index,systemic insulin sensitivity index and islet β-cell function,and to an increase of glucagon levels in response to glucose challenge in patients with T2DM.更多还原