Koopmans S J, Maassen J A, Radder J K, Frölich M, Krans H M
Department of Endocrinology and Metabolic Diseases University Hospital, Leiden, The Netherlands.
Biochim Biophys Acta. 1992 Jan 23;1115(3):230-8. doi: 10.1016/0304-4165(92)90059-4.
Whole body glucose uptake (BGU) and hepatic glucose production (HGP) at maximal plasma insulin concentrations (+/- 5000 microU/ml) were determined by eu- (EC) (6 mM) and hyperglycemic (HC) (20 mM) clamps (120 min), combined with [3-3H]glucose infusion, in normal and streptozotocin-treated (65 mg/kg) 3-day diabetic, conscious rats. In normal rats, during EC, BGU was 12.4 +/- 0.4 mg/min and during HC, when urinary glucose loss was 0.54 +/- 0.09 mg/min, BGU was 25.5 +/- 1.6 mg/min. However, throughout the final 60 min of HC, glucose infusion rate (GIR) was not constant but a linear decline in time (r = -0.99) of 17%, P less than 0.0001, was observed indicating a hyperglycemia-induced desensitization process. In diabetic rats, during EC, BGU was 7.7 +/- 0.3 mg/min and during HC, BGU was 15.5 +/- 1.4 mg/min. Throughout the final 60 min of HC, GIR was constant, suggesting that the hyperglycemia-induced desensitization process was already completed. In normal and diabetic rats, HGP was similar: during EC 0.2 +/- 0.5 mg/min and 0.1 +/- 0.5 mg/min, and during HC 0.4 +/- 0.4 mg/min and 0.5 +/- 0.6 mg/min, respectively. In vitro adipocyte and muscle insulin receptor studies showed normal to increased receptor number and increased receptor autophosphorylation in diabetic compared to normal rats.
(i) 3-day diabetic rats show, at maximal plasma insulin concentrations, insulin resistance to BGU, but not to HGP. The resistance to BGU is equally present (reduction of 38%) at eu- and hyperglycemic levels as compared to normal rats. (ii) 3-day diabetic rats reveal no defect in adipocyte and muscle insulin receptor function. These data indicate that the diabetes induced insulin resistance for BGU is at the post-receptor level and due to a decreased maximal capacity (Vmax) for glucose uptake, with no change in affinity, or Km.
通过正常血糖（EC）（6 mM）和高血糖（HC）（20 mM）钳夹（120分钟），结合[3-3H]葡萄糖输注，在正常和经链脲佐菌素治疗（65 mg/kg）3天的糖尿病清醒大鼠中，测定最大血浆胰岛素浓度（±5000微单位/毫升）时的全身葡萄糖摄取（BGU）和肝脏葡萄糖生成（HGP）。在正常大鼠中，在正常血糖钳夹期间，BGU为12.4±0.4毫克/分钟，在高血糖钳夹期间，当尿糖丢失为0.54±0.09毫克/分钟时，BGU为25.5±1.6毫克/分钟。然而，在高血糖钳夹的最后60分钟内，葡萄糖输注速率（GIR）并非恒定不变，而是随时间呈线性下降（r = -0.99），下降了17%，P<0.0001，表明存在高血糖诱导的脱敏过程。在糖尿病大鼠中，正常血糖钳夹期间，BGU为7.7±0.3毫克/分钟，高血糖钳夹期间，BGU为15.5±1.4毫克/分钟。在高血糖钳夹的最后60分钟内，GIR保持恒定，表明高血糖诱导的脱敏过程已经完成。在正常和糖尿病大鼠中，HGP相似：正常血糖钳夹期间分别为0.2±0.5毫克/分钟和0.1±0.5毫克/分钟，高血糖钳夹期间分别为0.4±0.4毫克/分钟和0.5±0.6毫克/分钟。体外脂肪细胞和肌肉胰岛素受体研究显示，与正常大鼠相比，糖尿病大鼠的受体数量正常或增加，受体自身磷酸化增加。
（i）3天糖尿病大鼠在最大血浆胰岛素浓度下，对BGU表现出胰岛素抵抗，但对HGP无抵抗。与正常大鼠相比，在正常血糖和高血糖水平下，对BGU的抵抗均同样存在（降低38%）。（ii）3天糖尿病大鼠在脂肪细胞和肌肉胰岛素受体功能方面无缺陷。这些数据表明，糖尿病诱导的对BGU的胰岛素抵抗发生在受体后水平，是由于葡萄糖摄取的最大能力（Vmax）降低，而亲和力或Km无变化。
