胰島素強(qiáng)化治療β細(xì)胞功能的作用

1、超越超越細(xì)胞功能衰竭細(xì)胞功能衰竭-短程胰島素強(qiáng)化治療的作用PP-HI-CN-04262022-6-29N Engl J Med 2013;368:572-3. 輕度高血糖即引起輕度高血糖即引起細(xì)胞功能細(xì)胞功能明顯障礙明顯障礙急性胰島素反應(yīng)FPG水平與急性胰島素應(yīng)答Weir GC, et al. Ann N Y Acad Sci. 2013 Apr;1281:92-105. 時(shí)間時(shí)間(分鐘分鐘)血糖79-8990-99100-114115-149150-349N24207312高糖毒性使細(xì)胞功能得不到正常發(fā)揮當(dāng)FPG在正常水平4.5-5.6mM(80-109mg/dL)時(shí)，胰島素分泌在數(shù)分鐘后出

2、現(xiàn)明顯峰值當(dāng)FPG在6.4mM(115mg/dL)時(shí)，急性GSIS(葡萄糖刺激的胰島素分泌)幾乎完全消失長期血糖控制有利于長期血糖控制有利于細(xì)胞功能的長期保護(hù)細(xì)胞功能的長期保護(hù)6年隨訪結(jié)果：年隨訪結(jié)果：2組血糖控制情況、胰島功能無明顯差異組血糖控制情況、胰島功能無明顯差異Harrison LB, et al. J Investig Med. 2014 Apr;62(4):676-86諾和銳諾和銳 30 + 3M二甲雙胍二甲雙胍1.0 bid 諾和銳諾和銳30 + 二甲雙胍二甲雙胍1.0 bid （INS）二甲雙胍二甲雙胍1.0bid + 格列本脲格列本脲1.25mg bid + 吡格列酮吡格列

3、酮 45mg qd （TOT）新診斷新診斷T2DM胰島素治療后序貫口服藥物或維持胰島素治療胰島素治療后序貫口服藥物或維持胰島素治療新診斷新診斷T2DM短期胰島素強(qiáng)化治療存在挑戰(zhàn)短期胰島素強(qiáng)化治療存在挑戰(zhàn)僅有一半的患者達(dá)到臨床緩解隨著時(shí)間延長緩解率不斷下降Lancet Diabetes Endocrinol 2013; 1:2834Li YB et al. Diabetes Care, 2004, 27:2597-602Weng JP, Li YB, et al. Lancet, 2008,371:1357-60Liu LHLi YB. Diabetes Technol Ther.2012;14

4、:756-61Chen ALLi YB. Diabetes Care, 2012,35:474-81早期胰島素聯(lián)合強(qiáng)化治療的探索早期胰島素聯(lián)合強(qiáng)化治療的探索-1新診斷T2DM 160例單純CSIICSII+羅格列酮CSII+硫辛酸CSII+二甲雙胍血糖正?；?w血糖正?；?w血糖正?；?w血糖正?；?w基線評(píng)估停用胰島素泵，隨訪3個(gè)月羅格列酮及二甲雙胍使用3個(gè)月Huang Zhimin. Diabetes Technol Ther. 2013,15: 859-869.聯(lián)用二甲雙胍：減少胰島素用量，改善無藥聯(lián)用二甲雙胍：減少胰島素用量，改善無藥血糖控制率血糖控制率3月時(shí)血糖正常率CSIICSII

5、+ROSCSII+METCSII+ALA胰島素劑量CSIICSII+ROSCSII+METCSII+ALAHuang 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.聯(lián)用二甲雙胍，進(jìn)一步改善聯(lián)用二甲雙胍，進(jìn)一步改善AIR、H

6、OMA B 聯(lián)用聯(lián)用TZD，降低肌細(xì)胞內(nèi)脂肪含量，降低肌細(xì)胞內(nèi)脂肪含量(IMCL)更顯著更顯著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 base

7、line after CSII suspension in homeostasis model assessment of insulin resistance (HomaIR) and intramyocellular lipid (IMCL) and malondialdehyde (MDA)levels基礎(chǔ)研究提示：基礎(chǔ)研究提示：GLP-1 Analog通過通過Akt/FoxO1/p27通路影響通路影響INS-1細(xì)胞的增殖細(xì)胞的增殖Fang Donghong. Molecular Medicine Reports 2012, 5: 233-238Liraglutide down-regu

8、lates 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 a

9、nd 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.AIR 能預(yù)測(cè)緩解不明確能預(yù)測(cè)緩解不明確Li Yanbing et al. Diabetes Care , 2004,27:2597-602The comparison of -c

10、ell function before and after CSII between the remission (n32) and nonremission (n 36) groups. *P 0.05.空腹血糖可預(yù)測(cè)治療后的長期緩解空腹血糖可預(yù)測(cè)治療后的長期緩解Liu Jianbin. Endocrine Journal 2013, 60 (6), 725-7326.1 治療后的FPG可預(yù)測(cè)患者的長期緩解 調(diào)整BMI、性別、年齡后，停泵后FPG7.0患者高血糖復(fù)發(fā)風(fēng)險(xiǎn)升高2.76倍， 而AIR及HOMA-B未能進(jìn)入最終的模型 6.1-7.07.0N=188治療后治療后1月的月的1,5脫水葡

11、萄糖醇水平可預(yù)測(cè)緩解脫水葡萄糖醇水平可預(yù)測(cè)緩解切點(diǎn)為8.9 mg/L 特異性, 83.3%;敏感性,78.6%; 陽性預(yù)測(cè)值, 94.3%;陰性預(yù)測(cè)值, 52.6%在停用CSII治療后1月隨訪時(shí)的1，5AG可預(yù)測(cè)1年緩解的可能研究提示年輕、治療后HOMA-IR較低的患者長期緩解可能也較高N=64Liu Liehua. Diabetes Technol Ther. 2012 Sep;14(9):756-61care abilitynegative attitude(belief in) importance of careself-care adherenceChen Ailing. Diabe

12、tes Care, 2012,35:474-81治療后患者的態(tài)度及依從性影響緩解治療后患者的態(tài)度及依從性影響緩解獲得緩解的患者對(duì)疾病具有更正面的態(tài)度緩解組非緩解組緩解組非緩解組依從性高、治療后PPG較低，以及基線HOMA-IR可預(yù)測(cè)長期緩解HOMA B和AIR未能進(jìn)入最終的模型治療后患者的態(tài)度及依從性影響緩解治療后患者的態(tài)度及依從性影響緩解Chen Ailing. Diabetes Care, 2012,35:474-81達(dá)標(biāo)所需時(shí)間逐年縮短達(dá)標(biāo)所需時(shí)間逐年縮短Huang Zhimin,Li Yanbing. Diabetes Technol. Ther. 15 (2013) 859-869.

13、Jianping Weng & Yanbing Li, et al. Lancet 2008, 371: 1753-1760Ke weijian, Liu liehua,Li Yanbing. Jouranal of diabetes research. 2015. Ahead of print.Li Yanbing et al. DiabetesCare , 2004,27:2597-602胰島素清除糖毒性對(duì)胰島素清除糖毒性對(duì)細(xì)胞去分化的影響細(xì)胞去分化的影響2022-6-29 胰島素治療組胰島去分化的比例顯著下降 表達(dá)前體細(xì)胞標(biāo)志的細(xì)胞顯著下降 提示胰島素治療可逆轉(zhuǎn)細(xì)胞的逆分化 Ce

14、ll Metabolism 19, 872882, May 6, 2014 對(duì)攜帶Kir6.2 ATP不敏感突變小鼠進(jìn)行胰島素治療評(píng)估去分化的變化2022-6-29細(xì)胞休整與功能的恢復(fù)細(xì)胞休整與功能的恢復(fù) N=36，病程(6.85.6)年，A1C (10.82.4)% 在強(qiáng)化治療過程中，精氨酸刺激后的C肽受到抑制 抑制的幅度可能與細(xì)胞功能恢復(fù)的程度有關(guān)。劉娟.中華糖尿病雜志，2014，6（30）：1029-35.Figure : CP levels, fasting and after AST.*差異具有統(tǒng)計(jì)學(xué)意義（P0.05） 棕櫚酸增加棕櫚酸增加miR 34a的表達(dá)，從而增加的表達(dá)，從而增加caspase-3的活化片段蛋白的的活化片段蛋白的 表達(dá)表達(dá)棕櫚通過上調(diào)棕櫚通過上調(diào)MiR-34a促進(jìn)促進(jìn)細(xì)胞凋亡細(xì)胞凋亡Lin Xiaojie. J Diabetes Res 2014;2014:258695.miR