Koopmans S J, Sips H C, Krans H M, Radder J K
Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden. The Netherlands.
Diabetologia. 1996 Apr;39(4):391-400. doi: 10.1007/BF00400670.
Short-term exposure of tissues to pulses of insulin generally leads to an enhancement of insulin action. We have investigated the possible beneficial effects of long-term near-physiological continuous vs pulsatile intravenous insulin treatment of insulin-deficient streptozotocin (70 mg/kg) diabetic rats on blood glucose control, in vivo insulin action and in vitro insulin action in isolated adipocytes. First, we determined the 24-h peripheral plasma insulin profiles in normal rats under precisely controlled mealfeeding conditions. Basal plasma insulin levels (40 +/- 9 microU/ml) oscillate with a periodicity of 11.9 +/- 0.9 min (p < 0.05), and an amplitude of 60 +/- 10%. Subsequently, the 24-h insulin profile was mimicked in diabetic (D) rats by a continuous (c) or pulsatile (p) (6-min double, 6-min off) insulin infusion rate for 2 weeks, using a programmable pumpswivel unit. Control (C) rats received vehicle treatment. In Cc, Dc, Cp and Dp daily urinary glucose loss and average plasma glucose levels were 0 +/- 0, 7.5 +/- 4.4, 0 +/- 0, 0.8 +/- 0.4 mmol and 6.7 +/- 0.2, 11.5 +/- 2.7, 6.6 +/- 0.1, 5.9 +/- 1.4 mmol/l, respectively. Hypoglycaemia (< 3 mmol/l) was observed in 10 and 20% of the blood samples collected from Dc and Dp rats, respectively. After 2 weeks of treatment, in vivo peripheral and hepatic insulin action was measured by the hyperinsulinaemic euglycaemic (6 mmol/l) clamp with [3-3H]-glucose infusion. Pre-clamp counter-regulatory hormone levels were similar among rats. Compared to Cc and Cp, Dc showed a reduction in insulin sensitivity and responsiveness for peripheral glucose uptake whereas Dp only showed a reduction in insulin sensitivity. Suppression of hepatic glucose production by insulin was similar among rats. After 2.5 weeks of treatment, epididymal adipocytes were isolated. Specific [125I]-insulin binding, basal and insulin-stimulated [U-14C]-glucose uptake and isoproterenol-stimulated glycerol output were comparable among rat adipocytes. The inhibition of glycerol output by insulin was identical in Cp and Dp (V(max) = 48.6 +/- 6.1 and 42.3 +/- 4.6%) but blunted in Dc vs Cc (V(max) = 8.2 +/- 4.6 vs 44.0 +/- 7.2%, p < 0.01) adipocytes, suggesting a post-binding defect in the antilipolytic action of insulin in Dc rats. In conclusion, long-term near-physiological pulsatile intravenous insulin replacement in insulin-deficient diabetic rats is more efficient than continuous delivery in reducing blood glucose, lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.
组织短期暴露于胰岛素脉冲通常会导致胰岛素作用增强。我们研究了长期近生理水平的持续静脉输注胰岛素与脉冲式静脉输注胰岛素对链脲佐菌素（70mg/kg）诱导的胰岛素缺乏型糖尿病大鼠血糖控制、体内胰岛素作用及分离脂肪细胞的体外胰岛素作用的可能有益影响。首先，我们在精确控制的进食条件下测定了正常大鼠24小时外周血浆胰岛素谱。基础血浆胰岛素水平（40±9微单位/毫升）以11.9±0.9分钟的周期振荡（p<0.05），振幅为60±10%。随后，使用可编程泵旋转装置，通过连续（c）或脉冲式（p）（6分钟输注、6分钟停输）胰岛素输注速率，对糖尿病（D）大鼠模拟24小时胰岛素谱，持续2周。对照（C）大鼠接受赋形剂处理。在Cc、Dc、Cp和Dp组中，每日尿糖丢失量和平均血浆葡萄糖水平分别为0±0、7.5±4.4、0±0、0.8±0.4毫摩尔和6.7±0.2、11.5±2.7、6.6±0.1、5.9±1.4毫摩尔/升。分别从Dc和Dp大鼠采集的血液样本中，10%和20%出现低血糖（<3毫摩尔/升）。治疗2周后，通过高胰岛素正常血糖（6毫摩尔/升）钳夹并输注[3-3H] -葡萄糖来测量体内外周和肝脏胰岛素作用。钳夹前的反调节激素水平在大鼠之间相似。与Cc和Cp相比，Dc在外周葡萄糖摄取方面的胰岛素敏感性和反应性降低，而Dp仅表现出胰岛素敏感性降低。胰岛素对肝脏葡萄糖生成的抑制在大鼠之间相似。治疗2.5周后，分离附睾脂肪细胞。大鼠脂肪细胞中特异性[125I] -胰岛素结合、基础和胰岛素刺激的[U-14C] -葡萄糖摄取以及异丙肾上腺素刺激的甘油输出相当。胰岛素对甘油输出的抑制在Cp和Dp组中相同（Vmax = 48.6±6.1%和42.3±4.6%），但在Dc组与Cc组脂肪细胞中减弱（Vmax = 8.2±4.6%对44.0±7.2%，p<0.01），这表明Dc大鼠胰岛素抗脂解作用存在结合后缺陷。总之，在胰岛素缺乏型糖尿病大鼠中，长期近生理水平的脉冲式静脉胰岛素替代在降低血糖、减少糖尿、增加胰岛素敏感性和抑制脂解方面比持续输注更有效。
