Shi Z Q, Rastogi K S, Lekas M, Efendic S, Drucker D J, Vranic M
Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Endocrinology. 1996 Aug;137(8):3193-9. doi: 10.1210/endo.137.8.8754739.
The aim of this study was to determine whether the impaired glucagon response to insulin-induced hypoglycemia in the diabetic rat can be improved by correction of hyperglycemia independent of insulin. Four groups of age-matched male Sprague-Dawley rats (246 +/- 13 g BW) were studied: 1) normal controls (NC; n = 7); 2) diabetic, untreated (DU; n = 6); 3) diabetic, treated for 5-7 days using sustained release (2-3 U/day) insulin implants (DI; n = 6); and 4) diabetic, treated for 3-4 days with phlorizin (0.4 g/kg), given sc twice daily (DP; n = 7). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). Basal plasma glucose was 7.4 +/- 0.3 mM in NC, but rose to 14.5 +/- 2.2 mM in DU. Basal hyperglycemia was corrected with phlorizin and insulin treatments (5.5 +/- 0.5 and 6.7 +/- 0.8 mM, respectively). NC rats responded to insulin-induced hypoglycemia with a rapid and marked increase in glucagon (peak, 2059 +/- 311 pg/ml). The glucagon response was blunted in DU (635 +/- 180 pg/ml) and was partially improved by prolonged normalization of glycemia in DP (1335 +/- 295 pg/ml; P < 0.05). Plasma somatostatin levels in all diabetic groups were 2- to 3-fold higher in the basal state, but were not different during hypoglycemia, than those in NC rats. Compared to levels in NC rats, diabetes resulted in decreased insulin, but elevated glucagon and somatostatin concentrations in the pancreatic tissue. Treatment with both insulin and phlorizin reversed the changes in the pancreatic content of both glucagon and somatostatin. Pancreatic proglucagon messenger RNA did not show significant differences among the four groups in either state. Insulin treatment in the DI group resulted in a delayed and much smaller increase in the glucagon response (740 +/- 138 pg/ml) to hypoglycemia despite normalization of glycemia. We, therefore, conclude that in streptozotocin-diabetic rats, the impaired glucagon responsiveness to hypoglycemia is significantly improved by insulin-independent correction of hyperglycemia, suggesting the importance of normoglycemia per se in maintaining, at least in part, the glucose sensitivity of pancreatic alpha-cells.
本研究的目的是确定糖尿病大鼠中胰高血糖素对胰岛素诱导的低血糖反应受损是否能通过独立于胰岛素的高血糖纠正得到改善。研究了四组年龄匹配的雄性斯普拉格 - 道利大鼠（体重246±13克）：1）正常对照组（NC；n = 7）；2）未治疗的糖尿病组（DU；n = 6）；3）使用缓释胰岛素植入物（2 - 3单位/天）治疗5 - 7天的糖尿病组（DI；n = 6）；4）用根皮苷（0.4克/千克）皮下注射每日两次治疗3 - 4天的糖尿病组（DP；n = 7）。通过单次注射链脲佐菌素（65毫克/千克）诱导糖尿病。NC组的基础血浆葡萄糖为7.4±0.3毫摩尔/升，但DU组升至14.5±2.2毫摩尔/升。根皮苷和胰岛素治疗纠正了基础高血糖（分别为5.5±0.5和6.7±0.8毫摩尔/升）。NC组大鼠对胰岛素诱导的低血糖反应是胰高血糖素迅速且显著增加（峰值为2059±311皮克/毫升）。DU组的胰高血糖素反应减弱（635±180皮克/毫升），而DP组通过长期血糖正常化部分改善了该反应（1335±295皮克/毫升；P < 0.05）。所有糖尿病组的基础状态下血浆生长抑素水平比NC组大鼠高2至3倍，但在低血糖期间无差异。与NC组大鼠相比，糖尿病导致胰腺组织中胰岛素水平降低，但胰高血糖素和生长抑素浓度升高。胰岛素和根皮苷治疗均逆转了胰高血糖素和生长抑素胰腺含量的变化。在两种状态下，四组之间胰腺胰高血糖素原信使核糖核酸均未显示出显著差异。尽管血糖正常化，但DI组的胰岛素治疗导致对低血糖的胰高血糖素反应延迟且幅度小得多（740±138皮克/毫升）。因此，我们得出结论，在链脲佐菌素诱导的糖尿病大鼠中，通过独立于胰岛素的高血糖纠正可显著改善胰高血糖素对低血糖的反应受损，这表明血糖正常本身至少在一定程度上对维持胰腺α细胞的葡萄糖敏感性很重要。
