Eli Lilly and Company, Indianapolis, IN, USA.
Adv Exp Med Biol. 2012;728:214-28. doi: 10.1007/978-1-4614-0887-1_14.
The prevalence of obesity and diabetes has been dramatically increasing during the last decade suggesting a greater patient need for more efficacious and safer drugs. Large molecule therapy has played an important role in diabetes since the discovery of insulin. This legacy was continued upon the introduction of Humulin (first recombinant insulin), Humalog (first engineered insulin) and Byetta (first incretin mimetic). Several other protein therapeutics, such as leptin, adiponectin, bone morphogenic protein-9 and others, are currently in or considered for therapeutic development. Among them, FGF21 is one of the most promising candidates given its outstanding pharmacologic benefits for nearly each and every abnormality of a metabolic disease and lack of apparent side effects in a variety of animal models. Thus, FGF21 represents a novel and appealing therapeutic reagent for Type 2 diabetes mellitus, obesity, dyslipidemia, cardiovascular and fatty liver diseases. The in vitro biology, genetic animal models and in vivo pharmacology of FGF21 will be discussed in this chapter.
在过去的十年中，肥胖症和糖尿病的患病率显著增加，这表明患者对更有效和更安全的药物的需求更大。自胰岛素发现以来，大分子治疗在糖尿病中发挥了重要作用。Humulin（第一代重组胰岛素）、Humalog（第一代工程胰岛素）和 Byetta（第一代肠促胰岛素类似物）的问世延续了这一传统。目前还有其他几种蛋白质治疗药物，如瘦素、脂联素、骨形态发生蛋白-9 等，正在或考虑用于治疗开发。其中，FGF21 是最有前途的候选药物之一，因为它对代谢疾病的几乎每种异常都具有出色的药理益处，并且在各种动物模型中没有明显的副作用。因此，FGF21 是 2 型糖尿病、肥胖症、血脂异常、心血管疾病和脂肪肝的一种新型有吸引力的治疗试剂。本章将讨论 FGF21 的体外生物学、遗传动物模型和体内药理学。
