Beyond GLP-1: functional and therapeutic roles of proglucagon-derived peptides in islet and metabolic regulation

Abstract

The proglucagon gene encodes a family of peptides whose physiological roles remain incompletely understood. While GLP-1 has been extensively characterised as an incretin hormone and validated therapeutic target, several other proglucagon-derived peptides (PGDPs) have long been regarded as biologically inert processing intermediates. This thesis systematically challenges that assumption, demonstrating that multiple PGDPs exert significant insulinotropic, cytoprotective, and anorexigenic effects in vitro and in vivo. Using BRIN-BD11 cells, isolated mouse islets, and multiple murine models of obesity and diabetes, all peptides examined stimulated insulin secretion, elevated intracellular cAMP and Ca²⁺, promoted beta cell proliferation, and attenuated cytokine-induced apoptosis. These effects were mediated primarily through GLP-1 receptors, with peptide-dependent contributions from GIP and glucagon receptors via PKA/PKC signalling. Select PGDPs also improved glucose tolerance and reduced food intake in vivo. Protease-resistant analogues of Intervening Peptide-1 (IP-1) were developed and shown to resist plasma degradation while retaining or enhancing native biological activity. Chronic administration of a lead analogue in obese-diabetic mice reduced body weight, improved glycaemic control, preserved islet architecture, and expanded beta cell mass, effects further potentiated in combination with GLP-1 receptor agonists. These findings redefine multiple PGDPs as physiologically active hormones contributing to the paracrine regulation of islet function and identify enzymatically stabilised IP-1 analogues as a promising therapeutic strategy for obesity and type 2 diabetes.