Laboratory of Molecular and Cellular Medicine, Departments of Cellular and Physiological Sciences and Surgery, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
Vitam Horm. 2010;84:111-50. doi: 10.1016/B978-0-12-381517-0.00004-7.
In the 1970s, glucose-dependent insulinotropic polypeptide (GIP, formerly gastric inhibitory polypeptide), a 42-amino acid peptide hormone, was discovered through a search for enterogastrones and subsequently identified as an incretin, or an insulinotropic hormone secreted in response to intraluminal nutrients. Independent of the discovery of GIP, the K-cell was identified in small intestine by characteristic ultrastructural features. Subsequently, it was realized that K-cells are the predominant source of circulating GIP. The density of K-cells may increase under conditions including high-fat diet and obesity, and generally correlates with plasma GIP levels. In addition to GIP, K-cells secrete xenin, a peptide with as of yet poorly understood physiological functions, and GIP is often colocalized with the other incretin hormone glucagon-like peptide-1 (GLP-1). Differential posttranslational processing of proGIP produces 30 and 42 amino acid versions of GIP. Its secretion is elicited by intraluminal nutrients, especially carbohydrate and fat, through the action of SGLT1, GPR40, GPR120, and GPR119. There is also evidence of regulation of GIP secretion via neural pathways and somatostatin. Intracellular signaling mechanisms of GIP secretion are still elusive but include activation of adenylyl cyclase, protein kinase A (PKA), and protein kinase C (PKC). GIP has extrapancreatic actions on adipogenesis, neural progenitor cell proliferation, and bone metabolism. However, the clinical or physiological relevance of these extrapancreatic actions remain to be defined in humans. The application of GIP as a glucose-lowering drug is limited due to reduced efficacy in humans with type 2 diabetes and its potential obesogenic effects demonstrated by rodent studies. There is some evidence to suggest that a reduction in GIP production or action may be a strategy to reduce obesity. The meal-dependent nature of GIP release makes K-cells a potential target for genetically engineered production of satiety factors or glucose-lowering agents, for example, insulin. Transgenic mice engineered to produce insulin from intestinal K-cells are resistant to diabetes induced by a beta-cell toxin. Collectively, K-cells and GIP play important roles in health and disease, and both may be targets for novel therapies.
在 20 世纪 70 年代，葡萄糖依赖性胰岛素促分泌多肽（GIP，前身为胃抑制多肽）是一种 42 个氨基酸的肽类激素，通过对肠抑胃肽的研究发现，并随后被鉴定为肠促胰岛素，即一种响应肠腔内营养物质分泌的胰岛素促分泌激素。在发现 GIP 的同时，通过特征性的超微结构特征，在小肠中发现了 K 细胞。随后，人们意识到 K 细胞是循环 GIP 的主要来源。在高脂肪饮食和肥胖等情况下，K 细胞的密度可能会增加，并且通常与血浆 GIP 水平相关。除了 GIP，K 细胞还分泌 xenin，这是一种生理功能尚不清楚的肽，GIP 通常与另一种肠促胰岛素激素胰高血糖素样肽-1（GLP-1）共定位。前 GIP 的差异翻译后加工产生 30 个和 42 个氨基酸的 GIP 版本。其分泌是由肠腔内营养物质（特别是碳水化合物和脂肪）通过 SGLT1、GPR40、GPR120 和 GPR119 的作用引起的。也有证据表明，GIP 的分泌可以通过神经途径和生长抑素进行调节。GIP 分泌的细胞内信号机制仍然难以捉摸，但包括激活腺苷酸环化酶、蛋白激酶 A（PKA）和蛋白激酶 C（PKC）。GIP 对脂肪生成、神经祖细胞增殖和骨代谢具有胰腺外作用。然而，这些胰腺外作用在人类中的临床或生理相关性仍有待确定。由于在 2 型糖尿病患者中的疗效降低以及啮齿动物研究表明其潜在的肥胖作用，将 GIP 作为降糖药物的应用受到限制。有一些证据表明，减少 GIP 的产生或作用可能是减少肥胖的一种策略。GIP 的释放依赖于进餐，这使得 K 细胞成为通过基因工程产生饱腹感因子或降糖剂（例如胰岛素）的潜在靶点。通过工程改造从肠 K 细胞产生胰岛素的转基因小鼠对胰岛细胞毒素诱导的糖尿病具有抗性。总之，K 细胞和 GIP 在健康和疾病中发挥着重要作用，两者都可能成为新型治疗方法的靶点。
