The global rise in type 2 diabetes (T2D), obesity, and metabolic dysfunction‑associated steatotic liver disease has prompted rapid changes in pharmacotherapeutic strategies. While insulin and metformin remain foundational for diabetes care, the introduction and clinical success of gut peptide analogues have initiated a paradigm shift. This review focuses on non‑insulin, gut–pancreatic peptide signalling‑based therapies that are clinically approved or under investigation, emphasizing the therapeutic convergence among T2D, obesity, and associated liver disease.
Several gut and pancreatic peptides are highlighted for their therapeutic potential. Chief among these are glucagon‑like peptide‑1 (GLP‑1) receptor agonists, which have delivered multifaceted metabolic benefits and reshaped treatment approaches for both T2D and obesity. Other peptides under active consideration include glucose‑dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY). Each peptide exerts distinct physiological effects on insulin secretion, glucagon suppression, appetite regulation, gastric motility, adipose biology, and hepatic metabolism; these diverse actions form the pharmacological rationale for mono‑, dual‑, and multi‑agonist therapies.
Mono‑agonism at the GLP‑1 receptor predominantly engages Gαs signalling, increasing intracellular cAMP and activating downstream effectors such as protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), PI3K/AKT, and AMP‑activated protein kinase (AMPK). These pathways enhance glucose‑stimulated insulin secretion (GSIS), suppress glucagon release, promote satiety through hypothalamic circuits (NPY/AgRP and POMC/CART), and delay gastric emptying. Indirectly, GLP‑1 receptor activation can improve hepatic glucose and lipid homeostasis. Clinically, GLP‑1 receptor agonists have improved glycaemic control and induced weight loss, establishing them as a transformative class for T2D and obesity management.
Dual GLP‑1/GIP agonists extend incretin signalling by incorporating GIP‑mediated inputs into the signalling network. GIP also activates Gαs‑cAMP‑PKA/EPAC, PI3K/AKT, and AMPK pathways, and dual agonism may modify GLP‑1 receptor behaviour by reducing β‑arrestin recruitment and receptor internalisation, consistent with biased signalling. The combined signalling repertoire is proposed to augment β‑cell insulinotropic activity, improve insulin sensitivity, and promote adipose nutrient partitioning and lipid storage with reduced ectopic fat deposition. These mechanistic additions provide a basis for potentially greater metabolic efficacy — in glycaemic control and weight management — compared with GLP‑1 mono‑agonism alone.
Triple agonists that target GLP‑1, GIP, and glucagon further broaden receptor signalling by recruiting glucagon receptor (GCGR)‑mediated pathways. Glucagon receptor activation engages both Gαs and Gαq signalling, incorporating AC/cAMP and PLC/IP3/Ca2+ cascades. These additional signals confer direct hepatic actions that increase amino acid catabolism, hepatic glucose production, lipid mobilisation, and fatty acid oxidation, and may increase energy expenditure. In parallel, triple agonism can potentiate insulin secretion and reinforce gut–brain–liver satiety signalling and gastric emptying delays. The progressive recruitment of complementary metabolic pathways underlies the mechanistic rationale for additive or synergistic benefits of dual and triple agonists on glycaemic control, weight loss, and metabolic steatohepatitis.
Beyond incretins, amylin and PYY are gut‑pancreatic peptides of clinical interest due to their specific contributions to appetite regulation and postprandial metabolism. Amylin acts in gut–brain circuits to reduce food intake and modulate postprandial glucose handling. PYY similarly influences satiety pathways and slows gastric emptying, affecting postprandial nutrient flux. Both peptides are being developed as potential adjuncts or components of combination peptide therapies to enhance weight loss and metabolic control when used with incretin‑based agents.
The review presents a critical narrative of mechanisms, efficacy, and limitations for peptide‑based therapies. Clinically proven benefits have been most robust for GLP‑1 receptor agonists, which have shown glycaemic improvement and weight reduction in people with T2D and obesity. Dual and triple agonists carry a mechanistic rationale for broader metabolic effects—improved insulin secretion, enhanced insulin sensitivity, adipose nutrient partitioning, reduced ectopic fat, hepatic metabolic actions, and increased energy expenditure—but their full clinical potential, safety profile, and long‑term outcomes continue to be defined in clinical investigations. The text emphasizes the need to evaluate limitations such as receptor desensitisation, tolerability, and the balance between hepatic glucose production and increased energy expenditure with glucagon activity. Details on specific trial results, approval status, and comparative efficacy were discussed in the source review; readers should consult the full text for data and trial references.
The field is actively exploring novel peptide constructs and multi‑agonist designs to optimise efficacy and safety across T2D, obesity, and associated liver disease. Strategies include engineering biased agonism to favour beneficial intracellular signalling, combining peptides to recruit complementary pathways, and designing molecules with favourable pharmacokinetics and receptor engagement profiles to limit adverse effects and receptor internalisation. Development efforts are converging on therapeutics that can simultaneously address glycaemia, body weight, adipose biology, and hepatic steatosis, reflecting the interconnected pathophysiology of metabolic disorders.
Non‑insulin gut–pancreatic peptide therapies now occupy a central role in the expanding pharmacotherapeutic landscape for T2D, obesity, and related liver disease. GLP‑1 receptor agonists have led this transformation; interest in GIP, glucagon, amylin, and PYY has produced a pipeline of dual and multi‑agonists grounded in complementary signalling biology. The progressive recruitment of additive metabolic pathways provides a mechanistic basis for improved outcomes, but ongoing clinical investigation is required to define optimal combinations, long‑term efficacy, and safety. This review synthesises the mechanisms of action, therapeutic potential, limitations, and development status of these peptide‑based approaches and outlines future directions in the management of interconnected metabolic disorders.