Stevenson R W, Hutson N J, Krupp M N, Volkmann R A, Holland G F, Eggler J F, Clark D A, McPherson R K, Hall K L, Danbury B H
Department of Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340.
Diabetes. 1990 Oct;39(10):1218-27. doi: 10.2337/diab.39.10.1218.
The effects of CP 68722 (racemic englitazone) were examined in ob/ob mice, in adipocytes and soleus muscles from ob/ob mice, and in 3T3-L1 adipocytes. Administration of englitazone at 5-50 mg.kg-1.day-1 lowered plasma glucose and insulin dose dependently without producing frank hypoglycemia in either the diabetic or nondiabetic lean animals. The glucose-lowering effect in ob/ob mice preceded the reduction in hyperinsulinemia. On cessation of drug, plasma insulin returned to untreated levels within 48 h, whereas plasma glucose rose slowly over 5 days. Englitazone (50 mg/kg) for 11 days lowered plasma glucose (22.2 +/- 1.4 to 14.0 +/- 1.9 mM), insulin (7.57 +/- 0.67 to 1.64 +/- 0.60 nM), nonesterified fatty acids (1813 +/- 86 to 914 +/- 88 microM), glycerol (9.20 +/- 0.98 to 4.94 +/- 0.03 mM), triglycerides (1.99 +/- 0.25 to 1.03 +/- 0.11 g/L), and cholesterol (6.27 +/- 0.96 to 3.87 +/- 0.57 mM), but no effects were observed 3 h after a single dose. Basal and insulin-stimulated lipogenesis were enhanced in adipocytes from ob/ob mice treated with 50 mg/kg englitazone for 11 days compared with lipogenesis in cells from vehicle-treated controls. Treatment of ob/ob mice with 50 mg/kg englitazone reversed the defects in insulin-stimulated glycolysis (from [3-3H]glucose) and glycogenesis and basal glucose oxidation (from [1-14C]glucose) in isolated soleus muscles. Englitazone (30 microM) stimulated 2-deoxy-D-glucose transport in 3T3-L1 adipocytes from 0.37 +/- 0.03 to 0.65 +/- 0.06 and 1.53 nmol.min-1.mg-1 protein at 24 and 48 h, respectively. Thus, englitazone has 1) insulinomimetic and insulin-enhancing actions in vitro and 2) glucose-, insulin-, triglyceride-, and cholesterol-lowering properties in an animal model of non-insulin-dependent diabetes mellitus (NIDDM) in which sulfonylureas have little or no effect. Thus, this new agent may have beneficial effects including a reduced risk of hypoglycemia in patients with NIDDM.
研究了CP 68722（消旋恩格列净）对ob/ob小鼠、ob/ob小鼠的脂肪细胞和比目鱼肌以及3T3-L1脂肪细胞的影响。以5-50mg·kg-1·天-1的剂量给予恩格列净可使糖尿病或非糖尿病瘦动物的血糖和胰岛素剂量依赖性降低，且不会导致明显低血糖。ob/ob小鼠的降糖作用先于高胰岛素血症的减轻。停药后，血浆胰岛素在48小时内恢复到未治疗水平，而血浆葡萄糖在5天内缓慢上升。给予50mg/kg恩格列净11天可使血浆葡萄糖（从22.2±1.4降至14.0±1.9mM）、胰岛素（从7.57±0.67降至1.64±0.60nM）、非酯化脂肪酸（从1813±86降至914±88μM）、甘油（从9.20±0.98降至4.94±0.03mM）、甘油三酯（从1.99±0.25降至1.03±0.11g/L）和胆固醇（从6.27±0.96降至3.87±0.57mM）降低，但单次给药3小时后未观察到效果。与用载体处理的对照细胞中的脂肪生成相比，用50mg/kg恩格列净处理11天的ob/ob小鼠脂肪细胞中的基础和胰岛素刺激的脂肪生成增强。用50mg/kg恩格列净处理ob/ob小鼠可逆转分离的比目鱼肌中胰岛素刺激的糖酵解（来自[3-3H]葡萄糖）、糖原生成和基础葡萄糖氧化（来自[1-14C]葡萄糖）的缺陷。恩格列净（30μM）分别在24小时和48小时时将3T3-L1脂肪细胞中的2-脱氧-D-葡萄糖转运从0.37±0.03刺激至0.65±0.06和1.53nmol·min-1·mg-1蛋白。因此，恩格列净具有1）体外拟胰岛素和增强胰岛素的作用，以及2）在非胰岛素依赖型糖尿病（NIDDM）动物模型中具有降低血糖、胰岛素、甘油三酯和胆固醇的特性，而磺脲类药物对此几乎没有或没有作用。因此，这种新药可能具有有益作用，包括降低NIDDM患者低血糖的风险。
