RESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic ß-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
Asunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Péptido 1 Similar al Glucagón , Agonistas Receptor de Péptidos Similares al Glucagón , Receptores de la Hormona Gastrointestinal , Animales , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Inhibidor Gástrico/uso terapéutico , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al Glucagón/farmacología , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Incretinas/uso terapéutico , Incretinas/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismoAsunto(s)
Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/uso terapéutico , Receptores de la Hormona Gastrointestinal/agonistas , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/administración & dosificación , Pérdida de Peso/efectos de los fármacos , Animales , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Polipéptido Inhibidor Gástrico/uso terapéutico , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-ß (Aß), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aß, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.
Asunto(s)
Enfermedad de Alzheimer , Glucosa , Fármacos Neuroprotectores , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Fármacos Neuroprotectores/farmacología , Glucosa/metabolismo , Modelos Animales de Enfermedad , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones Transgénicos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Masculino , Péptidos beta-Amiloides/metabolismo , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Factor de Transcripción Activador 4RESUMEN
The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.
Asunto(s)
Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Simulación de Dinámica Molecular , Obesidad , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Animales , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Masculino , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Péptidos/química , Péptidos/farmacología , Receptor del Péptido 2 Similar al Glucagón , Polipéptido Inhibidor GástricoRESUMEN
Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment.
Asunto(s)
Antiinflamatorios , Receptor del Péptido 1 Similar al Glucagón , Incretinas , Fármacos Neuroprotectores , Humanos , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Incretinas/farmacología , Ratones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/química , Línea Celular , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Exenatida/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Línea Celular Tumoral , Péptidos/farmacología , Péptidos/química , Receptores de Glucagón/agonistas , Receptores de Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/agonistasRESUMEN
Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic ß-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice.
Asunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/metabolismo , Animales , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/química , Receptores de la Hormona Gastrointestinal/metabolismoRESUMEN
Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Incretinas , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Animales , Resultado del Tratamiento , Incretinas/uso terapéutico , Incretinas/efectos adversos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Transducción de Señal/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/efectos adversos , Biomarcadores/sangre , Medición de Riesgo , Receptor del Péptido 2 Similar al Glucagón , Polipéptido Inhibidor GástricoRESUMEN
INTRODUCTION: One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified. AREAS COVERED: This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of 'biased agonism' wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction. EXPERT OPINION: Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.
Asunto(s)
Fármacos Antiobesidad , Polipéptido Inhibidor Gástrico , Obesidad , Receptores de la Hormona Gastrointestinal , Pérdida de Peso , Humanos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Animales , Polipéptido Inhibidor Gástrico/farmacología , Polipéptido Inhibidor Gástrico/metabolismo , Fármacos Antiobesidad/farmacología , Pérdida de Peso/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Drogas en Investigación/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Incretinas/farmacología , Desarrollo de Medicamentos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismoRESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.
Asunto(s)
Diabetes Mellitus Tipo 2 , Metabolismo Energético , Incretinas , Humanos , Incretinas/uso terapéutico , Incretinas/farmacología , Incretinas/metabolismo , Metabolismo Energético/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Corazón/efectos de los fármacos , Enfermedades Cardiovasculares/metabolismo , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Péptido 1 Similar al Glucagón/metabolismo , Miocardio/metabolismoRESUMEN
Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
Asunto(s)
Fenotipo , Receptores de la Hormona Gastrointestinal , beta-Arrestinas , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Animales , Ratones , Humanos , beta-Arrestinas/metabolismo , Variación Genética , Arrestina beta 2/metabolismo , Arrestina beta 2/genética , Transducción de Señal , Polipéptido Inhibidor Gástrico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Obesidad/metabolismo , Obesidad/genética , Masculino , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genéticaRESUMEN
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.
Asunto(s)
Adipocitos , Polipéptido Inhibidor Gástrico , Receptores de la Hormona Gastrointestinal , Animales , Humanos , Masculino , Ratones , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Polipéptido Inhibidor Gástrico/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 2 Similar al Glucagón , Glucosa/metabolismo , Insulina/metabolismo , Lipólisis/efectos de los fármacos , Ratones Endogámicos C57BL , Nutrientes/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Transducción de Señal/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.
Asunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Receptor del Péptido 1 Similar al Glucagón , Receptores de la Hormona Gastrointestinal , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Receptor del Péptido 1 Similar al Glucagón/agonistas , Polipéptido Inhibidor Gástrico/uso terapéutico , Hipoglucemiantes/uso terapéutico , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 2 Similar al GlucagónRESUMEN
Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.
Asunto(s)
Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Receptores de la Hormona Gastrointestinal , Humanos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Receptores de la Hormona Gastrointestinal/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Animales , Polipéptido Inhibidor Gástrico/agonistas , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Receptor del Péptido 2 Similar al GlucagónRESUMEN
Motilin (MLN) is a peptide hormone originally isolated from the mucosa of the porcine intestine. Its orthologs have been identified in various vertebrates. Although MLN regulates gastrointestinal motility in tetrapods from amphibians to mammals, recent studies indicate that MLN is not involved in the regulation of isolated intestinal motility in zebrafish, at least in vitro. To determine the unknown function of MLN in teleosts, we examined the expression of MLN and the MLN receptor (MLNR) at the cellular level in Japanese medaka (Oryzias latipes). Quantitative PCR revealed that mln mRNA was limitedly expressed in the gut, whereas mlnr mRNA was not detected in the gut but was expressed in the brain and kidney. By in situ hybridization and immunohistochemistry, mlnr mRNA was detected in the dopaminergic neurons of the area postrema in the brain and the noradrenaline-producing cells in the interrenal gland of the kidney. Furthermore, we observed efferent projections of mlnr-expressing dopaminergic neurons in the lobus vagi (XL) and nucleus motorius nervi vagi (NXm) of the medulla oblongata by establishing a transgenic medaka expressing the enhanced green fluorescence protein driven by the mlnr promoter. The expression of dopamine receptor mRNAs in the XL and cholinergic neurons in NXm was confirmed by in situ hybridization. These results indicate novel sites of MLN activity other than the gastrointestinal tract. MLN may exert central and peripheral actions through the regulation of catecholamine release in medaka.
Asunto(s)
Motilina , Oryzias , Receptores de la Hormona Gastrointestinal , Animales , Oryzias/metabolismo , Oryzias/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/genética , Motilina/metabolismo , Receptores de Neuropéptido/metabolismo , Receptores de Neuropéptido/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Animales Modificados Genéticamente , Neuronas Dopaminérgicas/metabolismo , Encéfalo/metabolismoRESUMEN
Unimolecular co-agonists at the GLP-1/GIP receptors have recently achieved remarkable anti-obesogenic feats; yet, in a recent Phase 1 clinical trial, Véniant and colleagues report astounding body-weight loss, and an appreciable safety profile, in participants with obesity using the GLP-1R agonist/GIPR antagonist AMG 133.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Obesidad , Receptores de la Hormona Gastrointestinal , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Receptores de la Hormona Gastrointestinal/metabolismo , Obesidad/metabolismo , Péptidos/farmacología , Animales , Pérdida de Peso/efectos de los fármacos , Receptores de Glucagón/metabolismo , Receptores de Glucagón/antagonistas & inhibidoresRESUMEN
The development of oligomeric glucagon-like peptide-1 (GLP-1) and GLP-1-containing coagonists holds promise for enhancing the therapeutic potential of the GLP-1-based drugs for treating type 2 diabetes mellitus (T2DM). Here, we report a facile, efficient, and customizable strategy based on genetically encoded SpyCatcher-SpyTag chemistry and an inducible, cleavable self-aggregating tag (icSAT) scheme. icSAT-tagged SpyTag-fused GLP-1 and the dimeric or trimeric SpyCatcher scaffold were designed for dimeric or trimeric GLP-1, while icSAT-tagged SpyCatcher-fused GLP-1 and the icSAT-tagged SpyTag-fused GIP were designed for dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. These SpyCatcher- and SpyTag-fused protein pairs were spontaneously ligated directly from the cell lysates. The subsequent icSAT scheme, coupled with a two-step standard column purification, resulted in target proteins with authentic N-termini, with yields ranging from 35 to 65 mg/L and purities exceeding 99%. In vitro assays revealed 3.0- to 4.1-fold increased activities for dimeric and trimeric GLP-1 compared to mono-GLP-1. The dual GLP-1/GIP receptor agonist exhibited balanced activity toward the GLP-1 receptor or the GIP receptor. All the proteins exhibited 1.8- to 3.0-fold prolonged half-lives in human serum compared to mono-GLP-1 or GIP. This study provides a generally applicable click biochemistry strategy for developing oligomeric or dual peptide/protein-based drug candidates.
Asunto(s)
Química Clic , Péptido 1 Similar al Glucagón , Péptido 1 Similar al Glucagón/química , Humanos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/metabolismo , Diseño de Fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/química , Polipéptido Inhibidor Gástrico/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistasRESUMEN
Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expressing the prototypic secretin receptor (SecR) to gain insights into secretin binding to homo-dimeric and monomeric SecR. Spatial proximity between peptide and receptor residues, probed by disulfide bond formation, demonstrates that the secretin N-terminus moves from adjacent to extracellular loop 3 (ECL3) at wild type SecR toward ECL2 in non-dimerizing mutants. Analysis of fluorescent secretin analogs demonstrates stable engagement of the secretin C-terminal region within the receptor extracellular domain (ECD) for both dimeric and monomeric receptors, while the mid-region exhibits lower mobility while docked at the monomer. Moreover, decoupling of G protein interaction reduces mobility of the peptide mid-region at wild type receptor to levels similar to the mutant, whereas it has no further impact on the monomer. These data support a model of peptide engagement whereby the ability of SecR to dimerize promotes higher conformational dynamics of the peptide-bound receptor ECD and ECLs that likely facilitates more efficient G protein recruitment and activation, consistent with the higher observed functional potency of secretin at wild type SecR relative to the monomeric mutant receptor.
Asunto(s)
Unión Proteica , Multimerización de Proteína , Receptores Acoplados a Proteínas G , Receptores de la Hormona Gastrointestinal , Secretina , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Secretina/metabolismo , Secretina/química , Secretina/genética , Ligandos , Animales , Humanos , Cricetulus , Células CHO , Mutación , Células HEK293RESUMEN
Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic ß cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity.NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Incretinas , Ratones Endogámicos C57BL , Obesidad , Animales , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Masculino , Incretinas/farmacología , Incretinas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Control Glucémico/métodos , Ratones Obesos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Humanos , Dieta Alta en Grasa/efectos adversos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Insulina/metabolismo , Exenatida/farmacología , Transducción de Señal/efectos de los fármacos , AMP Cíclico/metabolismoRESUMEN
Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas and MrgD receptor antagonist, prevented the anxiolytic effects induced by this peptide. However, its effects were not altered by the selective Mas receptor antagonist, A779. In conclusion, our data indicates that alamandine, through MrgD, attenuates anxiety-like behavior in male TGR(ASrAOGEN)680, which reinforces the importance of the counter-regulatory RAS axis as promising target for the treatment of neuropsychiatric disorders.