Ader M, Richey J M, Bergman R N
University of Southern California School of Medicine, Department of Physiology and Biophysics, Los Angeles 90033, USA.
Diabetologia. 1998 Nov;41(11):1327-36. doi: 10.1007/s001250051073.
To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (KG) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic (16.7 mmol/l) hyperinsulinaemic (60 pmol x min(-1) x kg(-1)) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simultaneous sampling of arterial blood and hindlimb lymph. Alloxan induced fasting hyperglycaemia (12.9 +/- 2.3 vs 5.7 +/- 0.2 mmol/l; p = 0.018 vs pre-treatment) and variable insulinopenia (62 +/- 14 vs 107 +/- 19 pmol/l; p = 0.079). The acute insulin response, however, was suppressed by alloxan (integrated insulin from 0-10 min: 155 +/- 113 vs 2745 +/- 541 pmol x l(-1) x 10 min(-1); p = 0.0027), resulting in pronounced glucose intolerance (KG: 0.99 +/- 0.19 vs 3.14 +/- 0.38 min(-1); p = 0.0002 vs dogs treated with saline). During clamps, steady state arterial insulin was higher in dogs treated with alloxan (688 +/- 60 vs 502 +/- 38 pmol/l; p = 0.023) due to a 25% reduction in insulin clearance (p = 0.045). Lymph insulin concentrations were also raised (361 +/- 15 vs 266 +/- 27 pmol/l; p = 0.023), such that the lymph to arterial ratio was unchanged by alloxan (0.539 +/- 0.022 vs 0.533 +/- 0.033; p = 0.87). Despite higher lymph insulin, glucose uptake (Rd) was significantly diminished after injection of alloxan (45.4 +/- 2.5 vs 64.3 +/- 6.5 micromol x min(-1) x kg(-1); p = 0.042). This was reflected in resistance of target tissues to the lymph insulin signal (deltaRd/ delta lymph insulin: 3.389 +/- 1.093 vs 11.635 +/- 2.057 x 10(-6) x l x min(-1) x kg(-1) x pmol(-1) x l(-1); p = 0.012) which correlated strongly with the KG (r = 0.86; p = 0.0001). In conclusion, alloxan induces insulinopenic diabetes, with glucose intolerance and insulin resistance at the target tissue level. Alloxan treatment, however, does not alter lymph insulin kinetics, indicating that insulin resistance of Type 1 (insulin-dependent) diabetes mellitus reflects direct impairment at the cellular level.
为了确定长期胰岛素缺乏是否会改变胰岛素跨内皮的转运，我们对用四氧嘧啶（50mg/kg；n = 8）或生理盐水注射（n = 6）后的犬类进行了血浆和淋巴动力学评估。在治疗前及治疗后18天，通过注射葡萄糖评估葡萄糖耐量（KG）和急性胰岛素反应。两天后，对部分犬类（每组n = 5）进行高血糖（16.7mmol/l）高胰岛素血症（60pmol·min⁻¹·kg⁻¹）葡萄糖钳夹试验，并同时采集动脉血和后肢淋巴样本。四氧嘧啶诱导了空腹高血糖（12.9±2.3 vs 5.7±0.2mmol/l；与治疗前相比，p = 0.018）和不同程度的胰岛素缺乏（62±14 vs 107±19pmol/l；p = 0.079）。然而，四氧嘧啶抑制了急性胰岛素反应（0 - 10分钟的整合胰岛素：155±113 vs 2745±541pmol·l⁻¹·10min⁻¹；p = 0.0027），导致明显的葡萄糖不耐受（KG：0.99±0.19 vs 3.14±0.38min⁻¹；与生理盐水治疗的犬相比，p = 0.0002）。在钳夹试验期间，四氧嘧啶治疗的犬类稳态动脉胰岛素水平较高（688±60 vs 502±38pmol/l；p = 0.023），原因是胰岛素清除率降低了25%（p = 0.045）。淋巴胰岛素浓度也升高了（361±15 vs 266±27pmol/l；p = 0.023），因此四氧嘧啶并未改变淋巴与动脉胰岛素浓度的比值（0.539±0.022 vs 0.533±0.033；p = 0.87）。尽管淋巴胰岛素水平较高，但注射四氧嘧啶后葡萄糖摄取（Rd）显著降低（45.4±2.5 vs 64.3±6.5μmol·min⁻¹·kg⁻¹；p = 0.042）。这反映在靶组织对淋巴胰岛素信号的抵抗上（ΔRd/Δ淋巴胰岛素：3.389±1.093 vs 11.635±2.057×10⁻⁶·l·min⁻¹·kg⁻¹·pmol⁻¹·l⁻¹；p = 0.012），且与KG密切相关（r = 0.86；p = 0.0001）。总之，四氧嘧啶诱导胰岛素缺乏性糖尿病，伴有葡萄糖不耐受和靶组织水平的胰岛素抵抗。然而，四氧嘧啶治疗并未改变淋巴胰岛素动力学，表明1型（胰岛素依赖型）糖尿病的胰岛素抵抗反映了细胞水平的直接损伤。
