胰岛素强化治疗β细胞功能的作用.pptx

胰岛素强化治疗细胞功能的作用,*,N Engl J Med 2013;368:572-3.,轻度高血糖即引起细胞功能明显障碍,急性胰岛素反应,FPG水平与急性胰岛素应答,Weir GC,et al.Ann N Y Acad Sci.2013Apr;1281:92-105.,时间(分钟),血糖,79-89,90-99,100-114,115-149,150-349,N,24,20,7,3,12,高糖毒性使细胞功能得不到正常发挥,当FPG在正常水平4.5-5.6mM(80-109mg/dL)时，胰岛素分泌在数分钟后出现明显峰值,当FPG在6.4mM(115mg/dL)时，急性GSIS(葡萄糖刺激的胰岛素分泌)几乎完全消失,长期血糖控制有利于细胞功能的长期保护,6年随访结果：2组血糖控制情况、胰岛功能无明显差异,Harrison LB,et al.J Investig Med.2014 Apr;62(4):676-86,诺和锐 30+3M,二甲双胍1.0 bid,诺和锐30+二甲双胍1.0 bid（INS）,二甲双胍1.0bid+格列本脲1.25mg bid,+吡格列酮 45mg qd（TOT）,新诊断T2DM胰岛素治疗后序贯口服药物或维持胰岛素治疗,新诊断T2DM短期胰岛素强化治疗存在挑战,仅有一半的患者达到临床缓解随着,时间延长缓解率不断下降,Lancet Diabetes Endocrinol 2013;1:2834,Li YB et al.Diabetes Care,2004,27:2597-602,Weng JP,Li YB,et al.Lancet,2008,371:1357-60,Liu LHLi YB.Diabetes Technol Ther,.,2012;14:756-61,Chen ALLi YB.Diabetes Care,2012,35:474-81,早期胰岛素联合强化治疗的探索-1,新诊断T2DM 160例,单纯CSII,CSII+罗格列酮,CSII+硫辛酸,CSII+二甲双胍,血糖正常化2w,血糖正常化2w,血糖正常化2w,血糖正常化2w,基线评估,停用胰岛素泵，随访3个月,罗格列酮及二甲双胍使用3个月,Huang Zhimin.,Diabetes Technol Ther.,2013,15:859-869.,联用二甲双胍：减少胰岛素用量，改善无药血糖控制率,3月时血糖正常率,CSII,CSII+ROS,CSII+MET,CSII+ALA,胰岛素剂量,CSII,CSII+ROS,CSII+MET,CSII+ALA,Huang Zhimin.,Diabetes Technol Ther.,2013,15:859-869.,Insulin dosages and days to target during continuous subcutaneous insulin infusion.,Proportions of patients achieving HbA1c 7%,6.5%,and 6%in each treatment group.,点击添加文本,点击添加文本,点击添加文本,点击添加文本,联用二甲双胍，进一步改善AIR、HOMA B,联用TZD，降低肌细胞内脂肪含量(IMCL)更显著,Huang Zhimin.,Diabetes Technol Ther.,2013,15:859-869.,Changes from baseline after CSII suspension and at month 3 in homeostasis model assessment of b-cell function(HomaB),acute insulin response(AIR),and proinsulin to insulin ratio.,Changes from baseline after CSII suspension in homeostasis model assessment of insulin resistance(HomaIR)and intramyocellular lipid(IMCL)and malondialdehyde(MDA)levels,基础研究提示：,GLP-1 Analog,通过Akt/FoxO1/p27通路影响INS-1细胞的增殖,Fang Donghong.,Molecular Medicine Reports,2012,5:233-238,Liraglutide down-regulates the expression of p27 mRNA.Following stimulation with 10 and 100 nM liraglutide for 24 h,the mRNA levels of p27 in INS-1 cells were significantly decreased when compared with the control group.,(A)In comparison to the control group,the phosphorylation of FoxO1 markedly increased in the 10 and 100 nM liraglutide treatment groups.By contrast,the levels did not ignificantly differ between the two treatment groups.,(B)The activation of Akt was markedly enhanced in response to liraglutide treatment.,点击添加文本,点击添加文本,点击添加文本,点击添加文本,AIR 能预测缓解不明确,Li Yanbing et al.,Diabetes Care,2004,27:2597-602,The comparison of-cell function before and after CSII between the remission(n32)and nonremission(n 36)groups.*P 0.05.,点击添加文本,点击添加文本,点击添加文本,点击添加文本,空腹血糖可预测治疗后的长期缓解,Liu Jianbin.,Endocrine Journa,l 2013,60(6),725-732,6.1,治疗后的FPG可预测患者的长期缓解,调整BMI、性别、年龄后，停泵后FPG7.0患者高血糖复发风险升高2.76倍，而AIR及HOMA-B未能进入最终的模型,6.1-7.0,7.0,N=188,治疗后1月的1,5脱水葡萄糖醇水平可预测缓解,切点为8.9 mg/L,特异性,83.3%;,敏感性,78.6%;,阳性预测值,94.3%;,阴性预测值,52.6%,在停用CSII治疗后1月随访时的1，5AG可预测1年缓解的可能,研究提示年轻、治疗后HOMA-IR较低的患者长期缓解可能也较高,N=64,Liu Liehua.,Diabetes Technol Ther,.,2012 Sep;14(9):756-61,care ability,negative attitude,(belief in)importance of care,self-care adherence,Chen Ailing,.Diabetes Care,2012,35:474-81,治疗后患者的态度及依从性影响缓解,获得缓解的患者,对疾病具有更正面的态度,缓解组,非缓解组,缓解组,非缓解组,点击添加文本,点击添加文本,点击添加文本,点击添加文本,依从性高、治疗后PPG较低，以及基线HOMA-IR可预测长期缓解,HOMA B和AIR未能进入最终的模型,治疗后患者的态度及依从性影响缓解,Chen Ailing.Diabetes Care,2012,35:474-81,点击添加文本,点击添加文本,点击添加文本,点击添加文本,达标所需时间逐年缩短,Huang Zhimin,Li Yanbing.Diabetes Technol.Ther.15(2013)859-869.,Jianping Weng&Yanbing Li,et al.Lancet 2008,371:1753-1760,Ke weijian,Liu liehua,Li Yanbing.Jouranal of diabetes research.2015.Ahead of print.,Li Yanbing et al.DiabetesCare,2004,27:2597-602,胰岛素清除糖毒性对细胞去分化的影响,*,胰岛素治疗组胰岛去分化的比例显著下降,表达前体细胞标志的细胞显著下降,提示胰岛素治疗可逆转细胞的逆分化,Cell Metabolism 19,872882,May 6,2014,对携带Kir6.2 ATP不敏感突变小鼠,进行胰岛素治疗评估去分化的变化,*,细胞休整与功能的恢复,N=36，病程(6.85.6)年，A1C(10.82.4)%,在强化治疗过程中，精氨酸刺激后的C肽受到抑制,抑制的幅度可能与细胞功能恢复的程度有关。,刘娟.中华糖尿病杂志，2014，6（30）：1029-35.,Figure:CP levels,fasting and after AST.,*差异具有统计学意义（P0.05）,棕榈酸增加miR 34a的表达，从而增加caspase-3的活化片段蛋白的 表达,棕榈通过上调MiR-34a促进细胞凋亡,Lin Xiaojie.,J Diabetes Res,2014;2014:258695.,miR-34a和Bcl-2 mRNA 3-UTR之间的关系*P0.05,Bcl-2是miR-34a的直接靶点,miR-34a、棕榈酸通过降低Bcl-2 mRNA 3UTR发挥其对凋亡的作用,Lin Xiaojie,.J Diabetes Res,2014;2014:258695.,