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Abstract：
The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.
摘要：
肠道来源的肠促胰岛素激素胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）在进餐后分泌，并协同作用以促进餐后胰岛素分泌。此外，当血浆葡萄糖浓度高于正常的空腹浓度时,GLP-1抑制胰高血糖素分泌,而GIP在低葡萄糖水平时促胰高血糖素作用。最近显示，设计用于共激活GLP-1和GIP受体的双重肠促胰岛素受体激动剂可引起血糖控制的显着改善（平均血红蛋白A1c降低1.94％）和体重大幅下降（平均体重减轻11.3kg）在一项包括超重/肥胖2型糖尿病患者在内的临床试验中使用最高剂量（每周15mg）治疗26周后。这里,我们描述了两种肠促胰岛素调节胰高血糖素α细胞分泌的机制，综述GLP-1和GIP联合给药对胰高血糖素分泌的影响，并讨论胰高血糖素在使用新型单分子双重GLP-1/GIP受体激动剂观察到的治疗效果中的潜在作用。对于临床医生和研究人员来说，这份手稿提供了对肠促胰岛素生理学和药理学的理解，并提供对未来抗糖尿病和肥胖治疗的机械见解。
