Ahrén Bo, Taborsky Gerald J, Havel Peter J
Department of Medicine, Lund University, Lund, Sweden.
Metabolism. 2002 Jan;51(1):12-9. doi: 10.1053/meta.2002.29007.
To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.
为深入了解1型糖尿病患者胰高血糖素对胰岛素诱导的低血糖反应丧失的机制，在四氧嘧啶处理的小鼠中，对糖尿病3个月期间胰高血糖素对4种不同刺激的反应进行了检测。在注射四氧嘧啶（60mg/kg）后1、6和12周，给过夜禁食的糖尿病小鼠注射根皮苷（0.1g/kg），以使急性刺激给药前糖尿病小鼠的血糖水平与非糖尿病对照小鼠的血糖水平相匹配。尽管根皮苷治疗使基线胰高血糖素水平升高，但在1周时，胰高血糖素对胰岛素（2U/kg腹腔注射[IP]）诱导的低血糖反应并未受损。然而，糖尿病6周和12周后，该反应降低了60%以上（P<.05）。相比之下，糖尿病1、6或12周后，胰高血糖素对精氨酸（0.25g/kg静脉注射[IV]）的反应并未降低，排除了A细胞反应普遍受损的可能性。糖尿病6周和12周后，胰高血糖素对神经低血糖剂2-脱氧葡萄糖（2-DG；500mg/kg静脉注射）的反应受损，与对胰岛素诱导的低血糖反应一样（P<.05），这表明对外源胰岛素潜在抑制作用的超敏反应不是导致这种损害的机制。最后，糖尿病动物中胰高血糖素对胆碱能激动剂卡巴胆碱（0.53μmol/kg静脉注射）的反应未受损，这排除了A细胞对自主神经刺激反应性存在缺陷的可能性。数据表明，四氧嘧啶糖尿病小鼠中胰高血糖素对胰岛素诱导的低血糖反应受损并非由于A细胞反应性普遍受损、胰岛素抑制作用导致的脱敏或A细胞对自主神经刺激的反应受损。可能解释胰高血糖素对胰岛素诱导的低血糖反应后期丧失的其余机制包括：（1）A细胞对低血糖刺激的识别缺陷，或（2）已知由低血糖刺激激活的A细胞自主神经输入缺陷。
