Yang Gangyi, Li Ling
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PRC.
J Chin Med Assoc. 2003 Apr;66(4):210-6.
Milrinone is a widely-used phosphodiesterase III (PDE3)-selective inhibitor. Recently, it was shown that milrinone increased hepatocyte glucose production, glycerol release, insulin secretion and fatty acid oxidation in vitro. Considering these results, it is important to know whether milrinone can induce insulin resistance in vivo.
In order to investigate the effects of a selective PDE3 inhibitor on insulin secretion, glucose and lipolysis levels and dose-response relationship, varying doses of milrinone were injected into the right internal jugular vein in conscious rats, and blood glucose, plasma free fatty acid (FFA) and insulin levels were observed. The effects of milrinone on glucose metabolism and insulin sensitivity were assessed by using a hyperinsulinaemic-euglycemic clamping.
Chronically catheterized nonstressed rats were administered varying doses of milrinone (1, 5, 25 micromol/kg) and were compared with controls not treated with milrinone. After dosing, plasma FFA levels in the 3 milrinone groups significantly increased compared with before dosing and the controls. The percentages of elevation of FFA by the different milrinone doses were very similar, 50%, 52%, 55% for 1, 5 and 25 micromol/kg, respectively, at 2 min after dosing, suggesting that lipolysis is very sensitive to the effect of milrinone. However, the effect of milrinone on glucose concentration was detectable only in 25 micromol/kg group, and the plasma insulin levels were significantly elevated in the 5 and 25 micromol/kg milrinone groups, indicating that there was a dose-response relationship between milrinone and insulin and glucose levels. During hyperinsulinemic clamping, there were a significant increase in plasma FFA (173.1 +/- 15.2 to 633.8 +/- 87.3 microEq/L, p < 0.01) and a significant decrease in glucose infusion rates (GIR) to about 21%, and a slight increase in plasma insulin after milrinone treatment.
These data suggest that milrinone impaired the abilities of insulin to suppress lipolysis and insulin-mediated glucose utilization in peripheral tissue, despite having a slight increase in insulin secretion. Therefore, we conclude that milrinone administration induces an acute insulin resistance in vivo, and that may limit the therapeutic value of milrinone for human diabetic subjects.
米力农是一种广泛应用的磷酸二酯酶III（PDE3）选择性抑制剂。最近的研究表明，米力农在体外可增加肝细胞葡萄糖生成、甘油释放、胰岛素分泌及脂肪酸氧化。鉴于这些结果，了解米力农在体内是否会诱导胰岛素抵抗具有重要意义。
为研究选择性PDE3抑制剂对胰岛素分泌、血糖和脂解水平的影响以及剂量反应关系，将不同剂量的米力农注入清醒大鼠的右颈内静脉，观察血糖、血浆游离脂肪酸（FFA）和胰岛素水平。采用高胰岛素-正常血糖钳夹技术评估米力农对葡萄糖代谢和胰岛素敏感性的影响。
对长期插管且未受应激的大鼠给予不同剂量的米力农（1、5、25微摩尔/千克），并与未用米力农治疗的对照组进行比较。给药后，3个米力农组的血浆FFA水平与给药前及对照组相比显著升高。不同剂量米力农引起的FFA升高百分比非常相似，给药后2分钟时，1、5和25微摩尔/千克剂量组分别为50%、52%、55%，表明脂解对米力农的作用非常敏感。然而，仅在25微摩尔/千克剂量组可检测到米力农对葡萄糖浓度的影响，且5和25微摩尔/千克米力农组的血浆胰岛素水平显著升高，表明米力农与胰岛素及葡萄糖水平之间存在剂量反应关系。在高胰岛素钳夹期间，米力农治疗后血浆FFA显著升高（从173.1±15.2升至633.8±87.3微当量/升，p<0.01），葡萄糖输注率（GIR）显著降低至约21%，血浆胰岛素略有升高。
这些数据表明，尽管米力农使胰岛素分泌略有增加，但它损害了胰岛素抑制脂解和外周组织中胰岛素介导的葡萄糖利用的能力。因此，我们得出结论，给予米力农会在体内诱导急性胰岛素抵抗，这可能会限制米力农对人类糖尿病患者的治疗价值。
