The multiple physiological effects of gut hormones in different metabolic tissues make them attractive therapeutic targets for the treatment of metabolic diseases. Currently, only glucagon-like peptide-1 (GLP-1) receptor-based agonists and oral dipeptidyl peptidase-4 inhibitors are available on the market. Despite their positive clinical outcomes across a range of indications, these treatments present several clinical challenges, including high costs, the need for peptide injections, and requirements for repeated administration. These limitations have driven research into improved GLP-1-based therapies, such as oral small-molecule agonists and novel drug delivery strategies based on emerging GLP-1 medicines. This article describes the challenges in clinical application and development of GLP-1-based pharmacotherapies. We review the development of oral small-molecule agonists and various drug delivery technologies, including ultralong-acting injectable technologies, continuous-acting implantable pumps, smart-acting electronic devices, nutrient-induced cell therapies, and noninvasive delivery systems. We discuss the current state of research, challenges to overcome, and opportunities to improve patient compliance and clinical outcomes. Additionally, we explore how endocrinological effects and patient-oriented needs can guide the development of advanced GLP-1 medicines.

Insulin and glucagon are described as having opposing actions on hepatic glycogen metabolism. However, here we showed that their coordinated action promoted glycogen turnover and meal glucose storage. In mice, pharmacological doses of insulin or glucagon failed to alter hepatic glycogen, but the combination produced a robust decrease in glycogen content. Additivity between insulin and glucagon was also seen with the activation of hepatic insulin signaling intermediates. This signaling pathway drove glycogen synthesis, suggesting concurrent actions on glycogen breakdown and repletion. A mixed nutrient meal, which stimulates an increase in both insulin and glucagon, enhanced the incorporation of dietary glucose into hepatic glycogen. This was much more pronounced than the effects of glucose alone, which only stimulated insulin secretion. These findings revealed that glucagon is required for efficient hepatic glucose storage when acting in concert with insulin. Coordinated insulin-glucagon signaling, thus, emerged as a critical mechanism for hepatic glycogen cycling, challenging the classical paradigm that these hormones work in opposition.

Graft failure (GF) following hematopoietic stem cell transplantation (HSCT) remains a major complication particularly in the setting of human leukocyte antigen (HLA)-mismatched grafts where residual host lymphocytes can drive immune-mediated rejection. While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.

Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1rWnt1-/- mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8+ T cells. EC Glp1r deletion in Glp1rTie2-/- mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.

Objectives: Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. Methods: We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. Results: Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone. Conclusions: This represents a novel mechanism for achieving poly-pharmacology to treat obesity.

GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and proapoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in preconstricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.

BACKGROUND:Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide have been shown to induce substantial weight loss and improve cardiometabolic risk factors in patients living with obesity. However, most individuals regain weight after abrupt withdrawal of semaglutide, with reversal of its beneficial cardiometabolic effects. METHODS:We propose a randomized controlled trial to determine whether a gradual dose reduction of semaglutide prior to complete discontinuation is associated with differential changes in weight and cardiometabolic profile as compared to immediate treatment cessation. Individuals living with obesity without preexisting cardiovascular disease who are receiving semaglutide for weight management and have achieved prior weight reduction of at least 10% with no further weight loss over past 12 weeks will be randomized to either gradual dose reduction over 16 weeks or abrupt treatment discontinuation. The primary outcome will be the difference in body weight change (%) between the study groups. Secondary outcomes will include 24-hour ambulatory blood pressure and fasting ghrelin levels. DISCUSSION:We hypothesize that gradual reduction of semaglutide will be associated with less weight regain and cardiometabolic deterioration compared with immediate cessation. This study addresses an important real-world problem regarding treatment discontinuation strategies and may inform future approaches for long-term obesity management. TRIAL REGISTRATION:NCT07294950 (ClinicalTrials.gov).

Glucagon-like peptide-1 medicines are being prescribed to growing numbers of patients worldwide, for type 2 diabetes, obesity and associated comorbidities, including cardiovascular disease, peripheral artery disease and obstructive sleep apnea, and are revolutionizing public health strategies for these conditions. These medicines improve health through reduction of blood glucose and body weight, by attenuation of inflammation and via direct activation of receptors in target tissues. New, more effective molecules with optimized pharmacokinetics produce greater weight loss and some may be more effective for various metabolic disorders, through incorporation of one or more additional peptide epitopes. Parallel efforts are exploring new indications, including neurodegenerative and substance use disorders, metabolic liver disease, arthritis, type 1 diabetes and inflammatory bowel disease. Here we highlight data informing the safety, efficacy, and potential utility of new and emerging glucagon-like peptide-1 medicines. We outline new mechanistic concepts, future therapeutic opportunities, potential for differentiation from currently available medicines and areas of uncertainty requiring additional investigation.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear, largely because of its limited access to pancreatic b-cells. Here, we used D-allulose, a non-metabolizable zero-calorie rare sugar, as a GLP-1 secretagogue. We show that D-allulose–induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left–sided vagal afferents forming the common hepatic branch, but not right–sided afferents. AIGS–enhanced insulin action required both GLP-1 receptors and insulin receptor substrate 2 in these neurons. Remarkably, in db/db mice exhibiting severe insulin resistance, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extra-pancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies.

The unprecedented broad efficacy of GLP-1 medicines reflects mechanisms beyond weight loss. GLP-1R agonism recruits neural and immune circuits, inter-organ communication, and engages local GLP-1Rs to improve cardiovascular, renal, hepatic, musculoskeletal, and organismal health. Defining dose-response relationships for weight-loss-independent mechanisms will facilitate optimization of the therapeutic potential of GLP-1 medicines.

The constant expansion of the field of metabolic research has led to more nuanced and sophisticated understanding of the complex mechanisms that underlie metabolic functions and diseases. Collaborations with scientists of various fields such as neuroscience, immunology and drug discovery have further enhanced the ability to probe the role of metabolism in physiological processes. However, many behaviours, endocrine and biochemical processes, and the expression of genes, proteins and metabolites have daily ~24-h biological rhythms and thus peak only at specific times of the day. This daily variation can lead to incorrect interpretations, lack of reproducibility across laboratories and challenges in translating preclinical studies to humans. In this Review, we discuss the biological, environmental and experimental factors affecting circadian rhythms in rodents, which can in turn alter their metabolic pathways and the outcomes of experiments. We recommend that these variables be duly considered and suggest best practices for designing, analysing and reporting metabolic experiments in a circadian context. This broad group of authors summarizes the impact of circadian factors on metabolic biology and offers recommendations on how to account for and report biological, environmental and experimental factors affecting circadian rhythms in metabolic studies in rodents.

GLP-1 medicines, initially developed for blood glucose and weight control, improve outcomes in people with cardiovascular, kidney, liver, arthritis, and sleep apnea disorders, actions mediated in part through anti-inflammatory and metabolic pathways, with some benefits partly independent of the degree of weight loss achieved.

Obesity and its related disorders, including type 2 diabetes and liver, kidney, and cardiovascular diseases, are now recognized as chronic inflammatory conditions. Here, we review the mechanisms underlying inflammation in these settings and how they may contribute to pathology. Nutrient excess triggers immune activation through pattern recognition receptors and the NLRP3 inflammasome, leading to interleukin (IL)-1β production and downstream cytokine cascades. Initially adaptive, this inflammation promotes tissue remodeling and metabolic compensation, but chronic activation contributes to insulin resistance, β cell dysfunction, and end-organ damage. We discuss the current therapeutic options, with a focus on glucagon-like peptide-1 (GLP-1) receptor agonists, which, alone or combined with additional bioactive moieties, exert notable anti-inflammatory effects. Some effects of GLP-1 medicines are independent of glucose control or weight loss, and they are attributed to direct signaling via the immune GLP-1 receptor (GLP-1R) and, indirectly, via central nervous system circuits. Understanding these mechanisms may unlock further therapeutic potential in chronic inflammatory diseases.

Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics.

Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep-/-). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgrhep-/- mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction.

Objective: Glucagon-like peptide-1 (GLP-1) reduces systemic and gut inflammation. Here we assessed whether gain or loss of GLP-1 receptor (GLP-1R) signaling modifies the extent of gut injury and inflammation in experimental murine acute graft vs. host disease (aGvHD). Methods: Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/c donors to induce aGvHD in C57BL/6 recipients or vice versa. Chimerism was determined by flow cytometry analysis of immune cell compartments. Inflammation was assessed by histological scoring of gut mucosal damage and by measuring circulating cytokine levels. qPCR was used to quantify gene expression in small intestine immune cells and tissues. The gut microbiome was assessed by 16S rRNA sequencing. Results: Allogeneic chimerism was greater than 90% in peripheral blood and in the gut epithelial compartment. Levels of Glp1r mRNA transcripts were induced in the ileum of both vehicle- and semaglutide-treated allogeneic mice, reflecting that allogeneic T cells homing to the gut express a functional GLP-1R. Nevertheless, semaglutide did not attenuate the severity of systemic cytokine induction, gut injury or inflammation, or the extent of aGvHD in the gut mucosa. Loss of GLP-1R signaling in donor cells had limited effects on overall microbial diversity during acute GvHD, and semaglutide-treated mice exhibited modest changes in proportions of microbial species. Conclusions: Although gut T cells express a functional GLP-1R, GLP-1R signaling has no meaningful impact on systemic or intestinal inflammation or microbiota composition in mice with experimental aGvHD, highlighting that the anti-inflammatory actions of GLP-1 medicines are highly context-dependent.

This Perspective explores recent progress and future directions in glucagon-like peptide-1 medicines.

Background: Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. Scope of Review: In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. Major Conclusions: Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

With therapeutic progress in Alzheimer's disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD.