Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity

Abstract

Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients’ convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone. Graphical abstract available for this article. Diabetes is a chronic disease with many faces, and persons affected by diabetes are continuously confronted with challenges, with injecting insulin and fighting obesity being the most recent. Current research is focused on designing drug candidates that would simultaneously address different mechanisms of high glucose in an individual and contribute to satiation, body weight control and patient convenience. Amylin is a hormone that is, similar to insulin, secreted by the pancreas. Its clinical use is currently limited to a single product, known as pramlintide, which is approved as an adjunct therapy in persons with insulin-treated diabetes. While the use of amylin is efficient, patients have to inject it with each meal and in a separate injection from insulin. Consequently, improving amylin-based medicines focuses on enabling longer action, resulting in weekly use, possibly even oral use and, most importantly, combining the functions of more than one hormone known for being involved in glucose control and the promotion of satiety. Similarly to other medicines primarily used in persons with diabetes, amylin-based medicines might eventually be used to address different diseases of the metabolic spectrum, namely obesity and its complications.

Topics & Concepts