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1.
Bioorg Med Chem ; 100: 117630, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38330849

RESUMO

Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Receptores dos Hormônios Gastrointestinais , Animais , Cães , Humanos , Camundongos , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/uso terapêutico
2.
Peptides ; 174: 171168, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38320643

RESUMO

The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.


Assuntos
Diabetes Mellitus Tipo 2 , Incretinas , Receptores dos Hormônios Gastrointestinais , Humanos , Incretinas/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Glicemia/metabolismo , Duodeno/metabolismo , Peptídeos/uso terapêutico , Células Enteroendócrinas/metabolismo , Receptores Acoplados a Proteínas G , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo
3.
Endocrinol Metab (Seoul) ; 39(1): 12-22, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356208

RESUMO

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Receptores dos Hormônios Gastrointestinais , Humanos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptores de Glucagon/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/farmacologia , Polipeptídeo Inibidor Gástrico/fisiologia , Polipeptídeo Inibidor Gástrico/uso terapêutico , Obesidade/tratamento farmacológico , Redução de Peso , Receptores Acoplados a Proteínas G , Glucose , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como Assunto
4.
Nucl Med Biol ; 128-129: 108876, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38241936

RESUMO

BACKGROUND: The beneficial role of glucose-dependent insulinotropic polypeptide receptor (GIPR) in weight control and maintaining glucose levels has led to the development of several multi-agonistic peptide drug candidates, targeting GIPR and glucagon like peptide 1 receptor (GLP1R) and/or the glucagon receptor (GCGR). The in vivo quantification of target occupancy by these drugs would accelerate the development of new drug candidates. The aim of this study was to evaluate a novel peptide (GIP1234), based on previously reported ligand DOTA-GIP-C803, modified with a fatty acid moiety to prolong its blood circulation. It would allow higher target tissue exposure and consequently improved peptide uptake as well as in vivo PET imaging and quantification of GIPR occupancy by novel drugs of interest. METHOD: A 40 amino acid residue peptide (GIP1234) was synthesized based on DOTA-GIP-C803, in turn based on the sequences of endogenous GIP and Exendin-4 with specific amino acid modifications to obtain GIPR selectivity. A palmitoyl fatty acid chain was furthermore added at Lys14 via a glutamic acid linker to prolong its blood circulation time by the interaction with albumin. GIP1234 was conjugated with a DOTA chelator at the C-terminal cysteine residue to achieve 68Ga radiolabeling. The resulting PET probe, [68Ga]Ga-DOTA-GIP1234 was evaluated for receptor binding specificity and selectivity using HEK293 cells transfected with human GIPR, GLP1R, or GCGR. Blocking experiments with tirzepatide (2 µM) were conducted using huGIPR HEK293 cells to investigate binding specificity. Ex vivo and in vivo organ distribution of [68Ga]Ga-DOTA-GIP1234 was studied in rats and a pig in comparison to [68Ga]Ga-DOTA-C803-GIP. Binding of [68Ga]Ga-DOTA-GIP1234 to albumin was assessed in situ using polyacrylamide gel electrophoresis (PAGE). The stability was tested in formulation buffer and rat blood plasma. RESULTS: [68Ga]Ga-DOTA-GIP1234 was synthesized with non-decay corrected radiochemical yield of 88 ± 3.7 % and radiochemical purity of 97.8 ± 0.8 %. The molar activity for the radiotracer was 8.1 ± 1.1 MBq/nmol. [68Ga]Ga-DOTA-GIP1234 was stable and maintained affinity to huGIPR HEK293 cells (dissociation constant (Kd) = 40 ± 12.5 nM). The binding of [68Ga]Ga-DOTA-GIP1234 to huGCGR and huGLP1R cells was insignificant. Pre-incubation of huGIPR HEK293 cell sections with tirzepatide resulted in the decrease of [68Ga]Ga-DOTA-GIP1234 binding by close to 90 %. [68Ga]Ga-DOTA-GIP1234 displayed slow blood clearance in pigs with SUV = 3.5 after 60 min. Blood retention of the tracer in rat was 2-fold higher than that of [68Ga]Ga-DOTA-C803-GIP. [68Ga]Ga-DOTA-GIP1234 also demonstrated strong liver uptake in both pig and rat combined with decreased renal excretion. The concentration dependent binding of [68Ga]Ga-DOTA-GIP1234 to albumin was confirmed in situ by PAGE. CONCLUSION: [68Ga]Ga-DOTA-GIP1234 demonstrated nanomolar affinity and selectivity for huGIPR in vitro. Addition of a fatty acid moiety prolonged blood circulation time and tissue exposure in both rat and pig in vivo. However, the liver uptake was also increased which may make PET imaging of abdominal tissues such as pancreas challenging. The investigation of the influence of fatty acid moiety on the biological performance of the peptide ligand paved the way for further rational design of GIPR ligand analogues with improved characteristics.


Assuntos
Radioisótopos de Gálio , Peptídeos , Receptores dos Hormônios Gastrointestinais , Ratos , Humanos , Animais , Suínos , Células HEK293 , Ligantes , Radioisótopos de Gálio/química , Meia-Vida , Peptídeos/química , Albuminas , Aminoácidos
6.
Diabetes ; 73(2): 292-305, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37934926

RESUMO

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time.


Assuntos
Resistência à Insulina , Receptores dos Hormônios Gastrointestinais , Tiazolidinedionas , Camundongos , Animais , Insulina/metabolismo , Resistência à Insulina/fisiologia , Rosiglitazona/uso terapêutico , Obesidade/metabolismo , Tiazolidinedionas/uso terapêutico , Receptores dos Hormônios Gastrointestinais/metabolismo , Aumento de Peso , Insulina Regular Humana/uso terapêutico , Hiperfagia , Polipeptídeo Inibidor Gástrico/farmacologia
7.
J Diabetes Investig ; 15(3): 282-284, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38140849

RESUMO

The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose-dependent insulinotropic polypeptide receptor (GIPR) in the brainstem and hypothalamus. The chemogenetic activation of the brainstem GIPR neurons and that of the hypothalamic GIPR neurons showed different feeding and behavior responses. The brainstem GIPR neurons projected to the paraventricular hypothalamus and lateral parabrachial nucleus. Fluorescent-labeled, stabilized peptide GIPR agonist (GIPRA), peripherally injected, localized to the area postrema, nucleus tractus solitarius, median eminence and arcuate hypothalamus. This report showed the role of brainstem GIPR neurons in receiving GIPRA to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and the brainstem GIPR pathways will also be discussed.


Assuntos
Hipotálamo , Receptores dos Hormônios Gastrointestinais , Humanos , Tronco Encefálico , Neurônios
8.
Proc Natl Acad Sci U S A ; 120(41): e2306145120, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37792509

RESUMO

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, ß-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated ß-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor).


Assuntos
Polipeptídeo Inibidor Gástrico , Receptores dos Hormônios Gastrointestinais , Humanos , Polipeptídeo Inibidor Gástrico/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Ligantes , Microscopia Crioeletrônica , Células HEK293 , Transdução de Sinais/fisiologia , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/química , Receptores dos Hormônios Gastrointestinais/metabolismo , Peptídeos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo
9.
Curr Opin Cardiol ; 38(6): 539-545, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37792556

RESUMO

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection. RECENT FINDINGS: Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D. SUMMARY: GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.


Assuntos
Diabetes Mellitus Tipo 2 , Receptores dos Hormônios Gastrointestinais , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico
10.
Eur J Pharmacol ; 955: 175912, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37454968

RESUMO

The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR. The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks. While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptores dos Hormônios Gastrointestinais , Animais , Camundongos , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas
11.
Int J Mol Sci ; 24(11)2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37298217

RESUMO

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In this work, we aimed to evaluate whether locus-specific changes in DNA methylation patterns could contribute to this phenomenon. By cloning bisulfite-sequencing PCR, we compared the methylation pattern of the GIPR locus in GIPR-positive (GIPR+) and GIPR-negative (GIPR-) GH-PAs. Then, to assess the correlation between Gipr expression and locus methylation, we induced global DNA methylation changes by treating the lactosomatotroph GH3 cells with 5-aza-2'-deoxycytidine. Differences in methylation levels were observed between GIPR+ and GIPR- GH-PAs, both within the promoter (31.9% vs. 68.2%, p < 0.05) and at two gene body regions (GB_1 20.7% vs. 9.1%; GB_2 51.2% vs. 65.8%, p < 0.05). GH3 cells treated with 5-aza-2'-deoxycytidine showed a ~75% reduction in Gipr steady-state level, possibly associated with the observed decrease in CpGs methylation. These results indicate that epigenetic regulation affects GIPR expression in GH-PAs, even though this possibly represents only a part of a much more complex regulatory mechanism.


Assuntos
Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Receptores dos Hormônios Gastrointestinais , Humanos , Adenoma/genética , Adenoma/metabolismo , Decitabina , Metilação de DNA , Epigênese Genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Receptores dos Hormônios Gastrointestinais/metabolismo
12.
JCI Insight ; 8(10)2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-37212283

RESUMO

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.


Assuntos
Hipotálamo , Receptores dos Hormônios Gastrointestinais , Peso Corporal , Tronco Encefálico/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Comportamento Alimentar , Animais
13.
Atherosclerosis ; 372: 19-31, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37015151

RESUMO

BACKGROUND AND AIMS: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity and with or without type 2 diabetes mellitus. As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and lipid handling, two crucial players in atherosclerosis development, here we aimed to investigate the effects of combined GIPR/GLP1R agonism in APOE*3-Leiden.CETP mice, a well-established mouse model for human-like lipoprotein metabolism and atherosclerosis development. METHODS: Female APOE*3-Leiden.CETP mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) to induce dyslipidemia, and received subcutaneous injections with either vehicle, a GIPR agonist (GIPFA-085), a GLP1R agonist (GLP-140) or both agonists. In the aortic root area, atherosclerosis development was assessed. RESULTS: Combined GIPR/GLP1R agonism attenuated the development of severe atherosclerotic lesions, while single treatments only showed non-significant improvements. Mechanistically, combined GIPR/GLP1R agonism decreased markers of systemic low-grade inflammation. In addition, combined GIPR/GLP1R agonism markedly lowered plasma triglyceride (TG) levels as explained by reduced hepatic very-low-density lipoprotein (VLDL)-TG production as well as increased TG-derived fatty acid uptake by brown and white adipose tissue which was coupled to enhanced hepatic uptake of core VLDL remnants. CONCLUSIONS: Combined GIPR/GLP1R agonism attenuates atherosclerosis severity by diminishing inflammation and increasing VLDL turnover. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to lower cardiometabolic risk in humans.


Assuntos
Aterosclerose , Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptores dos Hormônios Gastrointestinais , Animais , Feminino , Humanos , Camundongos , Apolipoproteína E3 , Aterosclerose/tratamento farmacológico , Proteínas de Transferência de Ésteres de Colesterol , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Inflamação , Receptores dos Hormônios Gastrointestinais/agonistas
14.
Sci Adv ; 9(11): eade9020, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36921049

RESUMO

Motilin is an endogenous peptide hormone almost exclusively expressed in the human gastrointestinal (GI) tract. It activates the motilin receptor (MTLR), a class A G protein-coupled receptor (GPCR), and stimulates GI motility. To our knowledge, MTLR is the first GPCR reported to be activated by macrolide antibiotics, such as erythromycin. It has attracted extensive attention as a potential drug target for GI disorders. We report two structures of Gq-coupled human MTLR bound to motilin and erythromycin. Our structures reveal the recognition mechanism of both ligands and explain the specificity of motilin and ghrelin, a related gut peptide hormone, for their respective receptors. These structures also provide the basis for understanding the different recognition modes of erythromycin by MTLR and ribosome. These findings provide a framework for understanding the physiological regulation of MTLR and guiding drug design targeting MTLR for the treatment of GI motility disorders.


Assuntos
Motilina , Receptores dos Hormônios Gastrointestinais , Humanos , Motilina/metabolismo , Eritromicina/farmacologia , Eritromicina/metabolismo , Receptores dos Hormônios Gastrointestinais/química , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/metabolismo
16.
BMC Med Genomics ; 16(1): 44, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36882778

RESUMO

INTRODUCTION: Gastric inhibitory polypeptide receptor (GIPR) encodes a G-protein coupled receptor for gastric inhibitory polypeptide (GIP), which was demonstrated to stimulate insulin secretion. Relation of GIPR gene variation to impaired insulin response has been suggested in previous studies. However, little information is available regarding GIPR polymorphisms and type 2 diabetes mellitus (T2DM). Hence, the aim of the study was to investigate single nucleotide polymorphisms (SNPs) in the promoter and coding regions of GIPR in Iranian T2DM patients. MATERIALS AND METHODS: Two hundred subjects including 100 healthy and 100 T2DM patients were recruited in the study. Genotypes and allele frequency of rs34125392, rs4380143 and rs1800437 in the promoter, 5' UTR and coding region of GIPR were investigated by RFLP-PCR and Nested-PCR. RESULTS: Our finding indicated that rs34125392 genotype distribution was statistically different between T2DM and healthy groups (P = 0.043). In addition, distribution of T/- + -/- versus TT was significantly different between the both groups (P = 0.021). Moreover, rs34125392 T/- genotype increased the risk of T2DM (OR = 2.68, 95%CI = 1.203-5.653, P = 0.015). However, allele frequency and genotype distributions of rs4380143 and rs1800437 were not statistically different between the groups (P > 0.05). Multivariate analysis showed that the tested polymorphisms had no effect on biochemical variables. CONCLUSION: We concluded that GIPR gene polymorphism is associated with T2DM. In addition; rs34125392 heterozygote genotype may increase the risk of T2DM. More studies with large sample size in other populations are recommended to show the ethnical relation of these polymorphisms to T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Receptores dos Hormônios Gastrointestinais , Humanos , Diabetes Mellitus Tipo 2/genética , Genótipo , Irã (Geográfico) , Polimorfismo de Nucleotídeo Único , Receptores dos Hormônios Gastrointestinais/genética
17.
Endocrinology ; 164(5)2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36774542

RESUMO

The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), are prime therapeutic targets for the treatment of type 2 diabetes (T2D) and obesity. They are expressed in pancreatic beta cells where they potentiate insulin release in response to food intake. Despite GIP being the main incretin in healthy individuals, GLP-1R has been favored as a therapeutic target due to blunted GIPR responses in T2D patients and conflicting effects of GIPR agonists and antagonists in improving glucose tolerance and preventing weight gain. There is, however, a recently renewed interest in GIPR biology, following the realization that GIPR responses can be restored after an initial period of blood glucose normalization and the recent development of dual GLP-1R/GIPR agonists with superior capacity for controlling blood glucose levels and weight. The importance of GLP-1R trafficking and subcellular signaling in the control of receptor outputs is well established, but little is known about the pattern of spatiotemporal signaling from the GIPR in beta cells. Here, we have directly compared surface expression, trafficking, and signaling characteristics of both incretin receptors in pancreatic beta cells to identify potential differences that might underlie distinct pharmacological responses associated with each receptor. Our results indicate increased cell surface levels, internalization, degradation, and endosomal vs plasma membrane activity for the GLP-1R, while the GIPR is instead associated with increased plasma membrane recycling, reduced desensitization, and enhanced downstream signal amplification. These differences might have potential implications for the capacity of each incretin receptor to control beta cell function.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Receptores dos Hormônios Gastrointestinais , Humanos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Polipeptídeo Inibidor Gástrico/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Incretinas/metabolismo , Células Secretoras de Insulina/metabolismo , Receptores dos Hormônios Gastrointestinais/genética
18.
Mol Metab ; 66: 101638, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36400403

RESUMO

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. METHODS: We report a structure-activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. RESULTS: We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. CONCLUSIONS: Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptores dos Hormônios Gastrointestinais , Roedores , Animais , Humanos , Camundongos , Polipeptídeo Inibidor Gástrico/antagonistas & inibidores , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos Obesos , Peptídeos/farmacologia , Peptídeos/química , Roedores/metabolismo , Redução de Peso , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores
19.
Genes (Basel) ; 13(9)2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36140702

RESUMO

Single nucleotide variants (SNVs) of the GIPR gene have been associated with BMI and type 2 diabetes (T2D), suggesting the role of the variation in this gene in metabolic health. To increase our understanding of this relationship, we investigated the association of three GIPR SNVs, rs11672660, rs2334255 and rs10423928, with anthropometric measurements, selected metabolic parameters, and the risk of excessive body mass and metabolic syndrome (MS) in the Polish population. Normal-weight subjects (n = 340, control group) and subjects with excessive body mass (n = 600, study group) participated in this study. For all participants, anthropometric measurements and metabolic parameters were collected, and genotyping was performed using the high-resolution melting curve analysis. We did not find a significant association between rs11672660, rs2334255 and rs10423928 variants with the risk of being overweight. Differences in metabolic and anthropometric parameters were found for investigated subgroups. An association between rs11672660 and rs10423928 with MS was identified. Heterozygous CT genotype of rs11672660 and AT genotype of rs10423928 were significantly more frequent in the group with MS (OR = 1.38, 95%CI: 1.03-1.85; p = 0.0304 and OR = 1.4, 95%CI: 1.05-1.87; p = 0.0222, respectively). Moreover, TT genotype of rs10423928 was less frequent in the MS group (OR = 0.72, 95%CI: 0.54-0.95; p = 0.0221).


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Receptores dos Hormônios Gastrointestinais , Alelos , Diabetes Mellitus Tipo 2/epidemiologia , Genótipo , Humanos , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Receptores dos Hormônios Gastrointestinais/genética
20.
Pharmacol Res Perspect ; 10(5): e01013, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36177761

RESUMO

The incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP-1R) are closely related members of the secretin class of G-protein-coupled receptors. As both receptors are expressed on pancreatic ß-cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP-1R heteromerization and the impact of GIPR on GLP-1R-mediated signaling and vice versa in HEK-293 cells. Real-time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP-1R and GIPR form heteromers. Stimulation with 1 µM GLP-1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 µM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP-1 metabolite, GLP-1 (9-36). GIPR expression had no significant effect on mini-Gs recruitment to GLP-1R but significantly inhibited GLP-1 stimulated mini-Gq and arrestin recruitment. In contrast, the presence of GLP-1R improved GIP stimulated mini-Gs and mini-Gq recruitment to GIPR. These data support the hypothesis that GIPR and GLP-1R form heteromers with differential consequences on cell signaling.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptores dos Hormônios Gastrointestinais , Arrestinas/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/farmacologia , Células HEK293 , Humanos , Incretinas , Ligantes , Peptídeos , Receptores Acoplados a Proteínas G/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Secretina/metabolismo , Transdução de Sinais
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