Hormones that are involved in metabolic homeostasis: Overview of the past century and future perspectives

Abstract

The year 2021 marks the 100th anniversary of the discovery of insulin. Although insulin industry has reached ∼30 billion US dollars per year, it is not an ultimate cure for diabetes. This is mainly due to the development and progression of insulin resistance in patients with Type 2 diabetes (T2D). Dozens of other hormones have been discovered that are directly or indirectly involved in metabolic homeostasis. Those discoveries have added to our knowledge on the complexity of energy or metabolic homeostasis and advanced our view that hormones may not necessarily be produced in classical endocrine organs. In addition to insulin, important metabolic hormones include incretins (GLP-1 and GIP) produced in the gut, leptin in adipose tissues, and FGF21 in the liver. Among them, FGF21 has been recognized as a target for dietary polyphenol interventions. Here we have summarized the development of GLP-1 receptor agonists as therapeutic agents for T2D and recent clinical trials with engineered FGF21 analogous. We have also presented our view on the existence of GLP-1-FGF21 axis in improving insulin tolerance and discussed recent literature on the development of dual agonists as future therapeutic agents for T2D and other metabolic disorders. • Insulin resistance is the major obstacle in treating diabetes. • In addition to insulin, GLP-1, Leptin, and FGF21 are also key metabolic hormones. • GLP-1 and FGF21 analogues can attenuate insulin resistance. • FGF21 is among the key mediators of dietary polyphenol intervention. • Dual agonists and multiple agonists are potential future therapeutics.