Gut peptide agonism in the treatment of obesity and diabetes

Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism.