Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.

糖尿病的特征是高血糖、功能性胰岛β细胞团的丧失、降糖胰岛素的缺乏和糖异生胰高血糖素的持续α细胞分泌。尽管如此，还没有针对这些潜在过程的疗法可用。因此，我们对 300,000 种化合物进行了高通量筛选和广泛的药物化学优化，并在此报告了 SRI-37330 的发现，这是一种口服生物可利用的无毒小分子，可有效地将小鼠从链脲佐菌素和肥胖诱导 ( db / db） 糖尿病。有趣的是，在大鼠细胞以及小鼠和人类胰岛中，SRI-37330 抑制了硫氧还蛋白相互作用蛋白的表达和信号传导，我们之前发现该蛋白在糖尿病中升高并对胰岛功能产生不利影响。此外，SRI-37330 治疗抑制了胰高血糖素的分泌和功能，减少了肝葡萄糖的产生，并逆转了肝脂肪变性。因此，这些研究描述了一种新设计的化合物，与目前可用的疗法相比，它可以提供一种独特而有效的治疗糖尿病的方法。