Strowski Mathias Z, Cashen Doreen E, Birzin Elizabeth T, Yang Lihu, Singh Vandana, Jacks Thomas M, Nowak Krzysztof W, Rohrer Susan P, Patchett Arthur A, Smith Roy G, Schaeffer James M
Medizinische Klinik m. S. Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
Endocrinology. 2006 Oct;147(10):4664-73. doi: 10.1210/en.2006-0274. Epub 2006 Jul 20.
Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.
生长抑素可抑制胰高血糖素和胰岛素的分泌。胰高血糖素在2型糖尿病的高血糖症中起显著作用。尽管生长抑素具有抑制胰高血糖素分泌的功能，但由于其同时抑制胰岛素分泌，故无法降低2型糖尿病患者的血糖水平。生长抑素通过五种药理学特性不同的受体亚型（sst(1)-sst(5)）在细胞水平介导其作用。胰腺A细胞表达sst(2)，而B细胞表达sst(5)。在本研究中，我们描述了一种使用高度选择性的sst(2)非肽激动剂（化合物1）治疗2型糖尿病的新方法。化合物1可有效抑制从野生型小鼠分离的胰岛分泌胰高血糖素，而sst(2)缺陷型胰岛的胰高血糖素分泌则未受抑制。化合物1不影响非空腹胰岛素浓度。在sst(2)缺陷型小鼠中，化合物1对胰高血糖素或血糖水平无任何影响，证实了其对sst(2)的选择性。在非空腹状态的2型糖尿病动物模型中，用化合物1治疗后，循环中的胰高血糖素和血糖水平降低。在空腹状态下，化合物1可使血糖降低约25%。总之，抑制胰高血糖素分泌的小分子sst(2)选择性激动剂为开发口服生物利用度高的2型糖尿病治疗药物提供了一种新方法。
