Pharmacology of Gut Hormone Mimetics for Obesity and Diabetes

The study of gut hormones provides a unique microcosm as to how trends in drug discovery and development have evolved over the last century. With the elucidation of secretin in 1902, discovery of this first gut hormone led to a paradigm shift in how scientists viewed anatomical function. The emphasis was taken away from nerve-based theories and implicated these new chemical messengers in such processes. These chemical messenger proteins were termed “hormones,” and with over a century of hindsight, we now appreciate their huge importance. In the early days of hormone discovery, substances were administered to various animal models and secretions collected and purified to identify potential hormone content. However, nowadays the rapid refinement of scientific techniques, combined with exponential advancements in available technology have led to more elegant research technologies for discovery of other gut hormones. Furthermore, we now understand the full structure of these hormones, their processing from precursors, the enzymes by which they are degraded, their target receptors and the downstream signaling events elicited by receptor activation. Such advancements have been accompanied by synthesis of structurally modified gut hormone mimetics with improved half-life and/or potency over the native hormone, to be used as viable therapeutics for the management of an array of chronic conditions. This review considers many important gut hormones, providing an overview of their function, metabolism, and consideration of how modern peptide chemistry techniques have been employed to modify their structures to provide stable, long-acting and biologically effective peptide mimetics with therapeutic utility especially in diabetes and obesity