Miyazaki Yoshinori, Matsuda Masafumi, DeFronzo Ralph A
University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas 78229-3900, USA.
Diabetes Care. 2002 Mar;25(3):517-23. doi: 10.2337/diacare.25.3.517.
To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes.
A total of 58 diet-treated patients with type 2 diabetes (aged 54 +/- 1 years; 34 men and 24 women; BMI 31.5 +/- 0.6 kg/m(2)) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT).
Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c (delta=-2.0 and -2.9%), FPG (delta=-66 and -97 mg/dl), and mean PG during OGTT (delta=-84 and -107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index (delta area under the curve [AUC] insulin/deltaAUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13 +/- 0.03 to 0.27 +/- 0.05, P < 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000/(square-root (FPG x FPI) x (PG x PI)) where PG and PI equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8 +/- 0.3 to 2.5 +/- 0.3, P < 0.05) or 45 mg (1.6 +/- 0.2 to 2.7 +/- 0.6, P < 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG x FPI)[k/(FPG x FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13 +/- 0.02 to 0.21 +/- 0.03, P < 0.05) and 45 mg (0.11 +/- 0.02 to 0.24 +/- 0.06, P < 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=-0.58), FPG (r=-0.47), mean PG during the OGTT (r=-0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed.
Pioglitazone improves glycemic control through the dose-dependent enhancement of beta-cell function and improved whole-body and hepatic insulin sensitivity.
研究吡格列酮对2型糖尿病患者血糖控制、胰岛素敏感性及胰岛素分泌的剂量反应效应。
共58例接受饮食治疗的2型糖尿病患者（年龄54±1岁；男性34例，女性24例；体重指数31.5±0.6kg/m²）被随机分配接受安慰剂（n = 11）或每日7.5mg（n = 13）、15mg（n = 12）、30mg（n = 11）或45mg（n = 11）的吡格列酮治疗，为期26周。在26周前后，受试者接受75g口服葡萄糖耐量试验（OGTT）。
接受每日7.5mg或15mg吡格列酮治疗的患者，空腹血糖（FPG）、空腹血浆胰岛素（FPI）浓度以及OGTT期间的血浆葡萄糖（PG）和胰岛素浓度均无变化。接受每日30mg和45mg吡格列酮治疗的患者，HbA1c（变化值=-2.0%和-2.9%）、FPG（变化值=-66和-97mg/dl）以及OGTT期间的平均PG（变化值=-84和-107mg/dl）与安慰剂组相比均显著降低。每日45mg吡格列酮组的空腹血浆胰岛素显著降低，但OGTT期间的平均血浆胰岛素未发生变化。OGTT期间的胰岛素生成指数（曲线下面积变化值[AUC]胰岛素/曲线下面积变化值[AUC]葡萄糖）在每日30mg和45mg吡格列酮组中显著升高（从0.13±0.03至0.27±0.05，P<0.05）。从OGTT中，我们先前推导了一个综合的全身胰岛素敏感性指数（ISI），其与通过胰岛素钳夹技术直接测量的结果具有良好的相关性。接受每日30mg（从1.8±0.3至2.5±0.3，P<0.05）或45mg（从1.6±0.2至2.7±0.6）吡格列酮治疗的患者，全身ISI[ISI = 10,000 /（FPG×FPI的平方根）×（PG×PI），其中PG和PI等于OGTT期间的平均血浆葡萄糖和胰岛素浓度]显著升高。在基础状态下，肝脏ISI[k/（FPG×FPI），与用氚标记葡萄糖直接测量的结果密切相关]在接受每日30mg（从0.13±0.02至0.21±0.03，P<0.05）和45mg（从0.11±0.02至0.24±0.06，P<0.05）吡格列酮治疗的患者中升高。观察到吡格列酮剂量与HbA1c变化（r = -0.58）、FPG变化（r = -0.47）、OGTT期间平均PG变化（r = -0.46）、胰岛素生成指数变化（r = 0.34）、肝脏ISI变化（r = 0.44）以及全身ISI变化（r = 0.36）之间存在显著相关性。
吡格列酮通过剂量依赖性增强β细胞功能以及改善全身和肝脏胰岛素敏感性来改善血糖控制。
