二甲双胍治疗初发2型糖尿病酮症合并非酒精性脂肪性肝病的随机对照研究

目的观察二甲双胍对于初发2型糖尿病酮症合并非酒精性脂肪性肝病（NAFLD）患者的效果并探讨其机制。方法采用前瞻性病例对照研究，选取2010年1月至2011年12月我院内分泌科住院的初发2型糖尿病酮症合并NAFLD患者60例，据随机数字表法分为2组：胰岛素组（INS组）30例和胰岛素＋二甲双胍组（INS＋MET组）30例，INS组男性24例，女性6例，平均年龄为（37±9）岁，INS＋MET组男性22例，女性8例，平均年龄为（39±10）岁。两组患者在人组时年龄、糖尿病病程、体质指数、腰臀比、血压、糖化血红蛋白（HbA1C）、血脂各指标及肝脏酶谱、初始胰岛素剂量之间具有可比性。2组均予静脉纠酮补液治疗及胰岛素强化治疗酮体转阴后，INS组继续单纯胰岛素控制血糖，INS＋MET组在使用胰岛素基础上联合二甲双胍（0．5g，每日3次）治疗，观察治疗12、24周后2组体质指数、血糖、HbA1c及肝酶指标、血脂及肝脏超声学积分变化；比较2组胰岛素日剂量、稳态模型胰岛素抵抗指数（HOMA—IR）和血浆脂联素和肿瘤坏死因子-α的变化。计量资料间比较采用t检验，等级资料以率的比较采用X^2检验。结果2组治疗后空腹血糖、餐后血糖及HbA1c均显著下降，2组HbA1c达标率无明显差异（INS组和INS＋MET组分别为86．7％比82．8％，X^2=0．174，P〉0．05）；INS＋MET组治疗后体质指数、甘油三酯、低密度脂蛋白胆固醇水平均明显低于INS组（t=3．648、2．883、2．699，均P〈0．05）；INS＋MET组治疗12和24周ALT分别较治疗前下降13．2％和32．2％（t=4．264、4．976，均P〈0．05），γ-谷氨酰转肽酶（γGGT）则分别下降23．1％和37．5％（t=6．364、6．315，均P〈0．05）。治疗后INS＋MET组肝脏B超积分明显低于INS组（2．8±1．3比3．7±1．4，t=2．311，P〈0．05）；治疗后INS＋MET组HOMA-IR较INS组明显改善（2．7±0．8比3．8±1．0，t=0．219，P〈0．05），胰岛素日剂量是INS组的41．8％，肿瘤坏死因子-α明显低于INS组[（28±9）比（36±9）ng／L，t=3．110，P〈0．05]，而脂联素水平高于INS组[（7．2±1．2）比（5．5±1．4）μg/L，t=5．023，P〈0．05]。结论二甲双胍可改善初发2型糖尿病酮症合并NAFLD患者胰岛素抵抗、降低患者肝酶指标、改善肝脏影像学转归，其机制可能涉及对脂肪细胞因子脂联素、肿瘤坏死因子-α水平的影响。

Effect of metformin on newly diagnosed type 2 diabetes with diabetic ketoacidosis and nonalcoholic fatty liver disease

Objective To study the effects of metformin on newly diagnosed type 2 diabetes with diabetic ketoacidosis （DK） and nonalcoholic fatty liver disease （NAFLD）. Methods Sixty newly diagnosed type 2 diabetes patients with DK and NAFLD admitted in our hospital from 2010 January to 2011 December were enrolled in this study. The subjects were randomly divided into 2 groups according to randomized number table： insulin group （INS） and insulin plus metformin group （INS ＋ MET）. The INS group included 24 males and 6 females, with an average age of （37 ± 9） years. The INS ＋ MET group included 22 males and 8 females, with an average age of （39 ± 10） years. The age, diabetic duration, body mass index （BMI）, waist-hip ratio （WHR）, blood pressure, glycated hemoglobin Alc （HbAlc）, plasma lipid concentration, liver enzyme and insulin dosage at baseline between the two groups were matched. After ketoacidosis was cured and blood glucose was controlled with intensive insulin therapy, the patients in INS group were treated with insulin alone, and the INS ＋ MET group were treated with metformin 1.5 g/d and insulin. BMI, blood glucose, HbAlc, liver enzyme, plasma lipid concentration, liver sonographic parameters, homeostasis model assessment-insulin resistance （ HOMA-IR ） , the levels of adiponectin and tumor necrosis factor-α （TNF-α） were measured at the beginning and 12, 24 weeks after the therapy. Difference of measurement data was compared with t test and X^2 test was used for ranked data analysis.Results After 24-week of therapy, fasting blood glucose, 2 h postprandial blood glucose and HbAlc were decreased in the same extent in both groups. There was no difference in HbAlc compliance rate between the two groups （86. 7% vs 82.8% in INS and INS ＋ MET group, X^2 = 0. 174, P 〉 0. 05）. BMI, triglyceride and low density lipoprotein-cholesterol were significantly improved in INS ＋ MET group compared to those in INS group（t = 3. 648, 2. 883, 2. 699, all P 〈 0. 05 ）. The level of alanine transaminase （ALT） in INS ＋ MET group dropped by 13.2% and 32. 2% （t = 4. 264, 4. 976, both P 〈 0. 05 ）and γ-glutamyl transferase （γGGT） dropped by 23. 1% and 37.5% （t =6.364, 6.315, both P 〈0.05） after 12- and 24-week of therapy. Ultrasonic scores （2. 8 ± 1.3 vs 3.7 ± 1.4, t = 2. 311, P 〈 0. 05 ） and insulin resistance （ HOMAIR：2. 7±0. 8 vs 3.8 ± 1.0, t =0. 219, P 〈0. 05） were significantly improved in INS ＋ MET group than those in INS group. The level of adiponectin （ （7.2 ± 1.2） vs （5.5 ± 1.4） μg/L, t = - 5. 023, P 〈 0. 05 ） was significantly higher and TNF-α（（28 ±9） vs （36 ±9） ng/L, t =3. 110, P 〈0.05） was significantly lower in INS ＋ MET than those in INS group. Conclusions Metformin could improve insulin resistance, liver enzyme and liver uhrasonic scores when used in newly diagnosed type 2 diabetes with DK and NAFLD. Increased levels of adiponectin as well as decreased plasma TNF-α may involved in the therapeutic effects.