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.

Keywords: Adjunct non-insulin-based therapies; Amylin; Amylin receptor agonists; Cagrisema; Incretin; Obesity; Postprandial hyperglycemia; Pramlintide; Type 1 diabetes mellitus; Type 2 diabetes mellitus.

Fig. 1

Position of amylin in diabetes: multi-hormonal dysregulation in different subtypes of diabetes, informing personalized therapeutic avenues according to diabetes phenotype. Achieving near-normoglycemia warrants a comprehensive understanding of the complex interplay of amylin deficiency, insulin deficiency or resistance and glucagon suppression. Personalized therapeutic approaches must address broader hormonal and gastrointestinal dysregulation characteristic of glucoregulation and accompanying metabolic disorders, namely obesity

Fig. 2

Organ-specific physiological actions of amylin. Amylin, a neuroendocrine hormone that is co-secreted with insulin, plays a role in glucose regulation, with further potential cardiovascular and neuroprotective functions in addition to a well-characterized influence on appetite and weight control. ↑ increase, ↓ decrease, CNS central nervous system

Fig. 3

Amylin-based therapies—present and future. Diverse strategies are being pursued to deliver enhanced stability, potency and patient convenience, resulting in oral or weekly subcutaneous formulations. While amylin is the core molecule of interest, synthetic peptides—amylin mimetics are represented by the currently approved amylin receptor agonist (RA) pramlintide. Selective amylin agonists are designed to provide for a longer duration of action and less frequent dosing. Similarly, the non-selective receptor agonists termed dual amylin/calcitonin receptor agonists (DACRAs) achieve their long-acting dual activity through conformational flexibility. Furthermore, cagrilintide, a nonselective agonist of the entire calcitonin receptor family, exhibits a distinct pharmacological profile compared to that of other DACRAs, while being administered once weekly. The combination of amylin RA with other incretin-based agents, such as the GLP-1/glucagon dual RA is also being investigated, with the aim to achieve enhanced weight loss and end-organ protection via triple mechanism effect. GLP-1R Glucagon-like peptide-1 receptor

Fig. 4

Amylin-based therapies in the pipeline. Pramlintide (trade name Symlin [pramlintide acetate]) injection is approved as an adjunct treatment in patients with type 1 and type 2 diabetes who use mealtime insulin and have not achieved desired glycemic control despite optimal insulin therapy. Further product candidates (amylin receptor agonists in development) are listed according to their corresponding status in Clinical Trials databases and companies’ pipelines. GLP-1 Glucagon-like peptide-1