Liang Y, Lubkin M, Sheng H, Scislowski P W, Cincotta A H
Ergoscience, Pre-clinical Research laboratory, 100 First Ave., 4th Floor, Charlestown, MA 02129, USA.
Biochim Biophys Acta. 1998 Oct 21;1405(1-3):1-13. doi: 10.1016/s0167-4889(98)00092-5.
One of the characteristics of obesity-associated diabetes is an elevated fasting plasma insulin concentration with a weak insulin secretory response to subsequent glucose stimulation. Evidence suggests that hyperglycemia and hyperlipidemia may contribute to the initiation and progression of this disordered islet glucose sensing. It has been proposed that reducing hyperglycemia and hyperlipidemia per se may improve islet glucose sensing. Here we studied glucose-dependent insulin release in islets isolated from ob/ob mice treated with dopamine agonists (bromocriptine and SKF38393, BC/SKF) which significantly reduced circulating glucose and lipid levels of ob/ob mice. Islets from BC/SKF-treated mice showed a marked decrease of the elevated basal insulin release to levels similar to lean mice. Such treatment also induced a higher secretory response to glucose stimulation compared with that in ob/ob mice with sustained hyperglycemia and hyperlipidemia. Similarly, when islets from untreated ob/ob mice were cultured for 7 days in 11 mM glucose in the absence of free fatty acid, the basal insulin release was significantly decreased and high glucose stimulated insulin release increased compared with that from islets cultured in medium containing 30 mM glucose and 2 mM oleate. The BC/SKF-induced reduction of elevated basal insulin release was associated with decreased hexokinase activity and basal cyclic AMP content in islet tissue. Our results demonstrate that dopamine agonist treatment improves basal insulin release in ob/ob mice and this effect may be mediated, in part, by a reduction of hyperglycemia and hyperlipidemia.
肥胖相关性糖尿病的特征之一是空腹血浆胰岛素浓度升高，且对随后的葡萄糖刺激胰岛素分泌反应较弱。有证据表明，高血糖和高血脂可能促成这种胰岛葡萄糖感知紊乱的起始和进展。有人提出，降低高血糖和高血脂本身可能改善胰岛葡萄糖感知。在此，我们研究了从用多巴胺激动剂（溴隐亭和SKF38393，BC/SKF）治疗的ob/ob小鼠分离的胰岛中的葡萄糖依赖性胰岛素释放，多巴胺激动剂显著降低了ob/ob小鼠的循环葡萄糖和脂质水平。BC/SKF治疗小鼠的胰岛显示，升高的基础胰岛素释放显著降低至与瘦小鼠相似的水平。与持续高血糖和高血脂的ob/ob小鼠相比，这种治疗还诱导了对葡萄糖刺激更高的分泌反应。同样，当未处理的ob/ob小鼠的胰岛在无游离脂肪酸的11 mM葡萄糖中培养7天时，基础胰岛素释放显著降低，与在含30 mM葡萄糖和2 mM油酸的培养基中培养的胰岛相比，高糖刺激的胰岛素释放增加。BC/SKF诱导的基础胰岛素释放升高的降低与胰岛组织中己糖激酶活性和基础环磷酸腺苷含量的降低有关。我们的结果表明，多巴胺激动剂治疗可改善ob/ob小鼠的基础胰岛素释放，且这种作用可能部分由高血糖和高血脂的降低介导。
