The National Center for Drug Screening, Shanghai, China.
PLoS One. 2010 Dec 3;5(12):e14205. doi: 10.1371/journal.pone.0014205.
Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance.
METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment.
CONCLUSIONS/SIGNIFICANCE: Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism.
胰高血糖素样肽-1（GLP-1）被认为是葡萄糖稳态的重要调节剂。利用 GLP-1 类似物治疗糖尿病已经产生了临床益处。有效的口服治疗的主要障碍是难以找到非肽类 GLP-1 受体（GLP-1R）激动剂。虽然其口服生物利用度仍然存在重大挑战，但 Boc5 是此类化合物中的第一种，已证明在糖尿病小鼠中具有 GLP-1R 激动作用。本研究旨在探讨亚慢性 Boc5 治疗是否可以恢复血糖控制并诱导饮食诱导肥胖（DIO）小鼠的可持续体重减轻，DIO 小鼠是人类肥胖和胰岛素抵抗的动物模型。
方法/主要发现：DIO 小鼠每周接受 Boc5（0.3、1 和 3 mg）治疗 3 次，共 12 周。定期监测体重、体重指数（BMI）、食物摄入量、空腹血糖、腹腔内葡萄糖耐量和胰岛素诱导的葡萄糖清除率。葡萄糖刺激胰岛素分泌、β细胞质量、胰岛大小、身体成分、血清代谢谱、脂肪生成、脂肪分解、脂肪肥大以及肝脏和肌肉中的脂质沉积也在 12 周给药后进行了测量。Boc5 剂量依赖性地降低了 DIO 小鼠的体重、BMI 和食物摄入量。这些变化与脂肪质量、脂肪细胞肥大和外周组织脂质积累的显著减少有关。Boc5 治疗还通过显著改善胰岛素敏感性和正常化β细胞质量来恢复血糖控制。Boc5（3 mg）处理可降低肥胖小鼠分离的脂肪细胞中基础但增强胰岛素介导的葡萄糖摄取和去甲肾上腺素刺激的脂肪分解。此外，Boc5 处理可在不同程度上使循环瘦素、脂联素、甘油三酯、总胆固醇、非酯化脂肪酸和高密度脂蛋白/低密度脂蛋白比值正常化。
结论/意义：Boc5 可能通过多种协同机制产生代谢益处，并通过非肽类 GLP-1R 激动作用成为肥胖和糖尿病治疗的有吸引力的工具。
