Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.
Drucker Daniel J
Cell metabolism
Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.
10.1016/j.cmet.2018.03.001
GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.
Science (New York, N.Y.)
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMH neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMH neurons selectively during eating behavior. We further identified that an intricate interplay between DMH neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARC neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.
10.1126/science.adj2537
GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review.
EClinicalMedicine
Obesity and type 2 diabetes mellitus (T2DM) present major global health challenges, with an increasing prevalence worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a pivotal treatment option for both conditions, demonstrating efficacy in blood glucose management, weight reduction, cardiovascular disease prevention, and kidney health improvement. GLP-1, an incretin hormone, plays a crucial role in glucose metabolism and appetite regulation, influencing insulin secretion, insulin sensitivity, and gastric emptying. The therapeutic use of GLP-1RAs has evolved significantly, offering various formulations that provide different efficacy, routes of administration, and flexibility in dosing. These agents reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects, making them an integral component of T2DM and obesity management. This review will discuss the currently approved medication for T2DM and obesity, and will also highlight the advent of novel agents which are dual and triple hormonal agonists which represent the future direction of incretin-based therapy. Funding:National Institutes of HealthNIDDKU24 DK132733 (FCS), UE5 DK137285 (FCS), and P30 DK040561 (FCS).
10.1016/j.eclinm.2024.102782
GLP-1 physiology informs the pharmacotherapy of obesity.
Drucker Daniel J
Molecular metabolism
BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity. SCOPE OF REVIEW:Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted. MAJOR CONCLUSIONS:The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.
10.1016/j.molmet.2021.101351