【作者】 卜石；

【导师】 杨文英；

【作者基本信息】 中国协和医科大学 ， 内分泌和代谢病学， 2008， 博士

【摘要】 第一部分吡格列酮和/或生活方式宣教对非糖尿病的高甘油三酯血症人群胰岛素抵抗和胰岛细胞功能的影响——脂毒性2年前瞻性干预研究目的在有高甘油三酯（TG）血症的非糖尿病人群中进行生活方式宣教或生活方式宣教加口服胰岛素增敏剂吡格列酮干预2年,观察游离脂肪酸、胰岛素敏感性、胰岛功能、血糖的改变及相关心、脑血管疾病的危险因子（脂联素、TNF—α,尿微量白蛋白）变化,以探讨生活方式或同时加胰岛素增敏剂干预来预防脂毒性效果和方法。方法采用前瞻性、随机、安慰剂对照的方法,选取无或仅有轻度糖代谢受损的非糖尿病的高TG血症（TG 2.26-4.52mmol/L）者,随机分为安慰剂对照组、生活方式宣教加安慰剂组、生活方式宣教加口服吡格列酮组（15mg/日）,随访干预2年。定期测定体重、腰围、体脂百分含量,血FFA、脂联素、TNF—α、尿微量白蛋白/尿肌酐比值（UACR）,每年进行一次OGTT。结果共有97例入选本研究,66例完成2年随访。2年时吡格列酮干预组FFA低于对照组[0.30mmol/L（0.20-0.45）vs 0.43mmol/L（0.40-0.59）:P＜0.05],内脏脂肪减少（腰围、腰围/臀围下降均大于对照组）,脂联素高于对照组[7216ng/ml（4234-9261）vs 3882ng/ml（2654-5746）:P＜0.05],TNF-α低于对照组[6.38pg/ml（3.32-8.26）vs 12.87pg/ml（9.16-20.31）,P＜0.01],UACR低于对照组[0.31mg/mmol（0.10—0.91）vs 2.28 mg/mmol（1.12—4.01）,P＜0.01],HOMA-IR较基线的增加小于对照组（0.08±0.33 vs 1.20±0.38,P＜0.05）,OGTT早时相胰岛素分泌显著改善（0.5h胰岛素水平高于对照组:102.40±14.49uiu/ml vs 68.13±7.65 uiu/ml,早时相胰岛素分泌指数大于对照组:INS（30-0）min/BG（30-0）min 24.67±3.63 vs 14.16±2.05;P均＜0.05）。单纯生活方式宣教组血脂、腰围、脂联素、UACR等指标有一些有益的改变,但变化较小。多因素分析提示干预后血FFA的变化和是否服用吡格列酮治疗是决定其早时相胰岛素分泌改善的最重要指标。结论在非糖尿病的高TG血症人群应用吡格列酮可能通过改善脂肪组织功能来降低FFA水平,升高脂联素、降低TNF-α等途径改善胰岛素敏感性和β细胞功能,并进一步降低糖尿病和心血管疾病发生风险。单纯生活方式宣教干预力度较弱且难以持久。第二部分基础胰岛素或每日两次预混胰岛素联合口服降糖药治疗的疗效和安全性比较目的比较每日注射两次预混胰岛素血糖控制不理想的2型糖尿病患者转为每日注射一次甘精胰岛素加格列美脲或每日注射两次预混胰岛素加格列美脲的血糖控制和低血糖发生情况。方法为随机、开放、两中心的平行对照研究,治疗期12周,选择每日注射两次预混胰岛素（加或不加口服降糖药治疗）,空腹血糖（FBG）在7.8～16.7mmol/L,HbAlc在7%～10%的2型糖尿病患者80例,随机分至每日注射一次甘精胰岛素加格列美脲3mg或每日注射两次预混诺和灵30R胰岛素加格列美脲3mg治疗组,胰岛素剂量每3天调整一次,至目标FBG≤6.0mmol/L。结果治疗12周后,甘精胰岛素组和预混胰岛素组的HbAlc均较基线水平显著下降,两组HbAlc下降幅度无差异（8.8%→8.0%vs 8.9%→7.8%,P=NS）。治疗期间,预混胰岛素组低血糖发生频率均显著高于甘精胰岛素组(总低血糖事件:123次vs 57次,经证实的低血糖例次（94（76%）vs 21（47%）,x²=23.692 P=0）,其中午餐前低血糖发生尤其显著（64（52%）vs 17（30%）x²=7.762 P=0.005）。甘精胰岛素治疗后HbAlc≤7.5%者达28.2%（11例）,胰岛素剂量为0.58±0.29u.kg^-1.d^-1;HbAlc＞8.5%者占23.1%（9例）,胰岛素剂量为0.66±0.30u.kg^-1.d^-1。甘精胰岛素上述两亚组治疗前HbAlc、糖尿病病程、标准餐后2hC肽水平差异均有显著性[分别为:8.1%±0.8%vs 9.6%±1.2%,10年（6年～14.5年）vs 13年（8年～19.5年）,餐后C肽:2.5nmol/L（1.4 nmol/L～3.3 nmol/L）vs 1.4nmol/L（1.2 nmol/L～2.6 nmol/L）,p值均＜0.05]。结论在本组2型糖尿病患者中,每日注射一次甘精胰岛素联合口服降糖药和每日注射两次预混胰岛素联合口服降糖药相比可以达到同样的血糖控制效果,并且低血糖发生率相对少。治疗前HbAlc水平、糖尿病病程和餐后2h C肽水平是影响一次基础胰岛素联合口服降糖药治疗疗效的主要指标。更多还原

【Abstract】 OBJECTIVE—To explore the effects and strategies of lifestyle or/and pioglitazone intervention on lipotoxicity.RESEARCH DESIGN and METHODS—Nondiabetic subjects with hypertriglyceridaemia（TG 2.26-4.52mmol/L） were randomly assigned to receive one tablet of placebo（CON） or diet and exercise education plus one tablet of placebo（LIF）,or diet and exercise education plus 15 mg/day pioglitazone（PIO） for 24months.Before and during the intervention,body composition,body fat distribution[waist circumference（WR）,waist-to-hip ratio（WHR）],plasma adiponectin,plasma TNF-α,urine albumin/creatine ratio（UACR）,insulin sensitivity andβcell function were assessed.RESULTS—We enrolled 97subjects in this study[baseline data:BMI 26.8±3.1 kg/m²,WHR 0.97±0.04,FFA 0.5mmol/L（0.4—0.7）,TG 2.93mmol/L（2.51—3.49）], 66subjects completed this 2-year study.At the end of the second year,compared with CON group,FFA in PIOgroup were significantly lower[0.30mmol/L（0.20-0.45） vs 0.43mmol/L（0.40-0.59）;P＜0.05];WR and WHR decreased larger;plasma adiponectin were higher[7216ng/ml（4234～9261） vs 3882ng/ml（2654～5746）;P＜0.05];plasma TNF—αwere lower（6.38pg/ml（3.32～8.26） vs 12.87pg/ml（9.16～20.31）,P＜0.01）, UACR were lower（0.31mg/mmol（0.10～0.91） vs 2.28 mg/mmol（1.12～4.01）, P＜0.01）、HOMA—IR increment from baseline were smaller（0.08±0.33 vs 1.20±0.38,P＜0.05）,early insulin secretion response increased larger（0.5h—insulin in OGTT:102.40±14.49uiu/ml vs 68.13±7.65 uiu/ml, iNS（30-0）min/BG（30-0）min（IGR）:24.67±3.63 vs 14.16±2.05;all P＜0.05）。The decrease in plasma FFA was strongly and independently associated with IGR2y.Some of the above parameters ameliorated in LIF group,but the degree was limited and couldn’t last very long. CONCLUSIONS—We show for the first time that pioglitazone used in nondiabetic subjects with hypertriglyceridaemia can decrease FFA by improving adipose tissue function,induce increase in serum adiponectin,decrease in TNF-αand UACR.All these factors contribute to amelioration of insulin resistance andβcell function.And may predict the reduction in incidence of diabetes and risk of future cardiovascular disease. OBJECTIVE- To compare the efficacy and safety of glargine or premixed insulin twice daily in combination with glimepiride in Type 2 Diabetes.RESEARCH DESIGN AND METHODS-In a 12-week,two-center,open,parallel group clinical trial,80 type 2 diabetic patients treated with twice-daily premixed 30R insulin with or without OAD（s）（fasting blood glucose[FBG]7.8 mmol/L～16.7mmol/L,HbA1c7%～10%） were randomized to once-daily morning insulin glargine plus glimepiride 3mg or premixed 30R insulin（70/30） twice-daily plus glimepiride 3mg.Insulin dosage was titrated to target FBG≤6.0mmol/L using a three-day forced-titration algorithm.RESULTS-Mean HbA1c reduction from baseline were similar in glargine group and premixed insulin group（8.8%→8.0%vs 8.9%→7.8%,P=NS）.However, hypoglycemic episodes were significantly higher in premixed-insulin-treated subjects than in glargine-treated subjects,(total:123 vs 57;proved hypoglycemic episodes （94（76%） vs 21（47%）,χ²=23.692 P＜0.001）,The frequency of hypoglycemia before lunch was especially greater in premixed-insulin-treated subjects（64（52%） vs 17（30%）χ²=7.762 P=0.005）.Several subjects from the premixed arm experienced too frequent hypoglycemic episodes to be recorded during 10AM～11AM almost every day.Subgroup analysis for patients treated with glargine:28.2%（11 cases） of the patients in this subgroup attained HbA1c≤7.5%.Mean daily dosage for glargine at 12w were 0.58±0.29 u.kg^-1.d^-1 in this subgroup.23.1%（9 cases） patients with HbA1c＞8.5%,mean daily dosage for glargine were 0.66±0.30 u.kg^-1.d^-1 at 12w. There were significant differences of baseline HbA1c,diabetes duration and baseline postprandial C-peptide between the two subgroups in glargine arm（HbA1c:8.1%±0.8%vs 9.6%±1.2%;duration:10years（6～14.5） vs 13years（8～19.5）;postprandial c peptide:2.5nmol/L（1.4～3.3） vs 1.4nmol/L（1.2～2.6）,all P＜0.05）.CONCLUSIONS-Some type 2 diabetic patients treated with twice-daily injection of 70/30 with or without OAD（s） can be effectively and safely switched to basal insulin plus OAD.Pretreatment HbA1c,diabetes duration and postprandial C peptide are the key factors that closely related to efficacy of this new regimen.更多还原