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1.
Diabetes Obes Metab ; 23 Suppl 3: 40-52, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34519400

RESUMO

Since the first glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) was approved in 2005 (exenatide twice daily) for type 2 diabetes (T2D), the class has developed with newer compounds having more pronounced effects on glycaemic control and body weight. Also, administration regimes have become more convenient with once weekly injections, and recently an oral administration has become available. Large-scale randomized controlled cardiovascular (CV) outcome trials (CVOTs) have shown that GLP-1RA therapy can reduce the risk of CV disease (CVD) in high-risk individuals with T2D. In addition, GLP-1RAs may have renal benefits driven by new-onset macroalbuminuria, although no effect on hard renal endpoints has been found. Subsequently, the place for GLP-1RA therapy has changed over recent years, with most societies endorsing GLP-1RA therapy in patients with established or high risk of CVD independently of glycaemia. Initiation of GLP-1RA therapy can be complex due to differences in efficacy, side effects and safety profiles as well as administration forms within the class. Implementing guideline recommendations into ideal patient selection may be challenging both in specialty and non-specialty settings. To ensure adequate and proactive use of modern glucose-lowering medications in the treatment of T2D, it is essential to recognize patients with high risk or documented CVD. The present review provides an overview of the efficacy and benefits of the currently available GLP-1RA compounds. Furthermore, we review the results from recent large-scale CVOTs in a clinical context and suggest improving the implementation of GLP-1RA therapy across specialties to improve overall patient selection.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/efeitos adversos , Seleção de Pacientes
2.
J Coll Physicians Surg Pak ; 31(9): 1035-1039, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34500517

RESUMO

OBJECTIVE: The purpose of the present study was to determine the effects of exenatide treatment on platelet function in type 2 diabetes mellitus (DM) patients. STUDY DESIGN: Case-control observational study. PLACE AND DURATION OF STUDY: University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara from October 2016 to October 2018. METHODOLOGY: This study included 50 patients with type 2 DM, who had started exenatide therapy; and age-gender matched 54 control subjects. The biochemical data and BMI of the patients were analysed at the time of admission and after six months of exenatide treatment. RESULTS: PDW (platelet distribution width) and MPV (mean platelet volume) were higher in the diabetic patient group than in the control group (p <0.01 and p=0.036, respectively). Significant positive correlations were determined between PDW and BMI (p<0.001), FPG (p <0.001), and HbA1c (p<0.001). After six months of exenatide treatment, PDW (p = 0.015) values and platelet count (p = 0.003) were significantly decreased. CONCLUSIONS: Exenatide causes a decrease in PDW value and platelet count independent of its positive effect on lipid profile, glycemic regulation, and weight loss, which contributes to explain the effect of treatment on the cardiovascular system through a different mechanism. Key Words: Exenatide, Type 2 diabetes mellitus, Platelet count, Platelet distribution width, Mean platelet volume.


Assuntos
Diabetes Mellitus Tipo 2 , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida , Humanos , Volume Plaquetário Médio , Contagem de Plaquetas
3.
Nutrients ; 13(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34444712

RESUMO

Glucagon-like peptide 1 (GLP-1) and PAS kinase (PASK) control glucose and energy homeostasis according to nutritional status. Thus, both glucose availability and GLP-1 lead to hepatic glycogen synthesis or degradation. We used a murine model to discover whether PASK mediates the effect of exendin-4 (GLP-1 analogue) in the adaptation of hepatic glycogen metabolism to nutritional status. The results indicate that both exendin-4 and fasting block the Pask expression, and PASK deficiency disrupts the physiological levels of blood GLP1 and the expression of hepatic GLP1 receptors after fasting. Under a non-fasted state, exendin-4 treatment blocks AKT activation, whereby Glucokinase and Sterol Regulatory Element-Binding Protein-1c (Srebp1c) expressions were inhibited. Furthermore, the expression of certain lipogenic genes was impaired, while increasing Glucose Transporter 2 (GLUT2) and Glycogen Synthase (GYS). Moreover, exendin-4 treatment under fasted conditions avoided Glucose 6-Phosphatase (G6pase) expression, while maintaining high GYS and its activation state. These results lead to an abnormal glycogen accumulation in the liver under fasting, both in PASK-deficient mice and in exendin-4 treated wild-type mice. In short, exendin-4 and PASK both regulate glucose transport and glycogen storage, and some of the exendin-4 effects could therefore be due to the blocking of the Pask expression.


Assuntos
Adaptação Fisiológica , Jejum , Glicogênio Hepático/metabolismo , Fígado/metabolismo , Estado Nutricional , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Exenatida/metabolismo , Exenatida/farmacologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucoquinase/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação para Cima , Perda de Peso
4.
Epilepsy Behav ; 123: 108246, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34385055

RESUMO

AIM: Epilepsy is a neurological condition affecting millions of people worldwide. Glucagon-like peptide-1 (GLP-1) is a gut hormone, and its neuroprotective effect was investigated in previous studies. In this study, the effects of exendin-4, a GLP-1 receptor agonist, were studied in genetic absence epileptic Wistar Albino Glaxo/Rijswijk rats (WAG/Rij). WAG/Rij rat is a genetic model of the absence epilepsy and depression-like comorbidity. METHOD: We examined the effects of exendin-4 (10, 50 and 100 µg/kg) on the absence seizures (Electrocorticography [ECoG] recordings), anxiety level (open-field test [OF]), and depression-like levels (forced swimming test [FST]) in the WAG/Rij rats. Basal ECoG recording was performed for all rats. Then, exendin-4 (10, 50 or 100 µg/kg) was administered intraperitoneally and ECoG recording was made for 180 min. After ECoG recording, forced swimming test and open-field test were applied. RESULTS: Administration of 10, 50, or 100 µg/kg exendin-4 increased the duration and number of spike-wave discharges (SWDs) considerably without changing the amplitude. The 100 µg/kg dose of exendin-4 was the most effective in increasing the total duration of SWDs. Additionally, all exendin-4 doses increased anxiety level in OF and depression-like level in FST. CONCLUSION: Our results showed that exendin-4 increased SWD incidence and anxiety- and depression-like behaviors in the WAG/Rij rats. Besides, it was also found that high doses caused the most proabsence effect.


Assuntos
Epilepsia Tipo Ausência , Animais , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Exenatida/uso terapêutico , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico
5.
Molecules ; 26(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299526

RESUMO

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (DM) of 3.3. The 2D 1H-13C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1H, 15 ppb for 13C and 98% peaks with equivalent peak height. Finally, 2D 1H-15N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.


Assuntos
Peptídeos/química , Preparações Farmacêuticas/química , Proteínas/química , Calcitonina/química , Exenatida/química , Insulina Glargina/química , Liraglutida/química , Ressonância Magnética Nuclear Biomolecular/métodos , Conformação Proteica , Rituximab/química , Teriparatida/química
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 1073-1078, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308859

RESUMO

OBJECTIVE: To investigate the effect of exendin-4 on lipid deposition in hepatocytes and explore its possible mechanism for treatment of nonalcoholic fatty liver disease (NAFLD). METHODS: Human normal hepatocyte line LO2 and hepatoma cell line HepG2 were treated with palmitic acid (PA) to mimic hepatocyte steatosis or with combined treatments with PA+exendin-4 or PA+exendin-4+3BDO. Lipid deposition and proliferation of the two cell lines following treatment with PA or PA+exendin-4 were detected using Oil Red O staining and CCK8 assay, and the expression of p-mTOR, m-TOR, p-AKT, AKT and autophagy-related proteins LC3-Ⅰ/Ⅱ and p62 were detected with Western blotting; the expression of GLP-1R was detected with both Western blotting and immunofluorescence assay. The expression of LC3-Ⅰ/Ⅱ and p62 in the cells following treatment with PA+exendin-4 and PA+exendin-4+3BDO was detected with Western blotting. RESULTS: Lipid deposition in the two cell lines increased significantly after PA treatment, but was alleviated by co-treatment with exendin-4. PA treatment significantly inhibited the proliferation of the two cell lines (P < 0.01), and this inhibitory effect was obviously attenuated by exendin-4 (P < 0.05). Immunofluorescence assay showed that both LO2 and HepG2 cells expressed GLP-1R. The expression of p-mTOR was significantly lower and that of p-AKT was higher in cells treated with PA+exendin-4 than in PA-treated cells. Exendin-4 also down-regulated the autophagy-associated protein p62 and up-regulated the expression of LC3-Ⅱ in PA-treated cells, and this effect was obviously reversed by 3BDO. CONCLUSION: Exendin-4 may activate the AKT-mTOR signal pathway to promote autophagy via its direct action on GLP-1R. Exendin-4 can also alleviate lipid deposition and promote proliferation of PA-treated hepatocytes, suggesting its important role in PA-induced lipid deposition in hepatocytes.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Autofagia , Exenatida/farmacologia , Humanos , Ácido Palmítico/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
7.
BMJ Open ; 11(7): e045663, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285005

RESUMO

INTRODUCTION: The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. METHODS AND ANALYSIS: 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). ETHICS AND DISSEMINATION: This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. TRIAL SPONSOR: University of Liverpool. TRIAL REGISTRATION NUMBER: ISRCTN 52028580; EUDRACT number 2015-005242-60.


Assuntos
Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos , Glicemia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Exenatida , Glucosídeos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
8.
Intern Med J ; 51(9): 1463-1472, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34142743

RESUMO

BACKGROUND: Diabetes is 3-4 times more prevalent in Indigenous Australians with blood glucose levels often above target range. Once weekly formulations of exenatide(exenatide-LAR) have demonstrated significantly greater improvements in glycaemic management with no increased risk of hypoglycaemia and with reductions in bodyweight but have not been studied in Indigenous Australians. AIMS: To assess the feasibility and metabolic effects of once weekly supervised injection of exenatide-LAR in addition to standard care in Indigenous Australians with type 2 diabetes. METHODS: Two communities in Central Australia with longstanding specialist clinical outreach services were allocated by random coin toss to receive once-weekly exenatide-LAR injection with weekly nurse review and adjustment of medication for 20 weeks (community with exenatide-LAR) or to weekly nurse review in addition to standard care over 20 weeks (community without exenatide-LAR). The primary outcome was the feasibility of an intensive diabetes management model of care with and without weekly supervised exenatide-LAR. Secondary outcomes included change in HbA1c. RESULTS: Thirteen participants from the community with exenatide-LAR and nine participants from the community without exenatide-LAR were analysed. Eighty-five percent of individuals in the community with exenatide-LAR and 67% in the community without exenatide-LAR attended more than half of clinic visits. Median difference in the change in HbA1c from baseline to final visit, adjusted for baseline HbA1c, between the community with exenatide-LAR and the community without exenatide-LAR was -3.1%, 95% CI (-5.80%, -0.38%; P = 0.03). CONCLUSIONS: Weekly exenatide-LAR combined with weekly nurse review demonstrated greater improvements in HbA1c, highlighting its potential for use in remote communities.


Assuntos
Diabetes Mellitus Tipo 2 , Austrália/epidemiologia , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Exenatida , Estudos de Viabilidade , Hemoglobina A Glicada , Humanos , Hipoglicemiantes , Peptídeos , Peçonhas
9.
Am J Physiol Cell Physiol ; 321(1): C187-C198, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34106786

RESUMO

Ca2+ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca2+ regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca2+ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca2+-insulin and insulin-Ca2+ signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca2+ release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca2+ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca2+ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca2+ release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca2+ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca2+ signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.


Assuntos
Síndrome de Alstrom/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Síndrome de Alstrom/metabolismo , Síndrome de Alstrom/patologia , Animais , Glicemia/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/metabolismo , Fura-2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Obesidade/patologia , Ácido Palmítico/farmacologia
10.
J Transl Med ; 19(1): 235, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078383

RESUMO

BACKGROUND AND AIMS: The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro. METHODS: Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs. RESULTS: We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-ß, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways. CONCLUSION: Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.


Assuntos
Hepatopatia Gordurosa não Alcoólica , RNA Longo não Codificante , Exenatida/farmacologia , Células Hep G2 , Humanos , Fígado , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , RNA Longo não Codificante/genética
11.
Commun Biol ; 4(1): 656, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079050

RESUMO

Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by systemic glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer's disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.


Assuntos
Encéfalo/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Neuroglia/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Doença de Alzheimer/genética , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Exenatida/farmacologia , Estudos de Viabilidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Neuroglia/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
12.
Biomaterials ; 275: 120944, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34153783

RESUMO

The oral administration route is popular with T2DM patients because they need convenience in lifelong medication. At present, oral Exenatide is not available on the market and therefore the relevant studies are valuable. Herein, we constructed a novel dual cholic acid-functionalized nanoparticle for oral delivery of Exenatide, which was based on the functionalized materials of deoxycholic acid-low molecular weight protamine and glycocholic acid-poly (ethylene glycol)-b-polysialic acid. The hydrophobic deoxycholic acid strengthened the nanoparticles and the hydrophilic glycolic acid targeted to specific transporter. We first condensed Exenatide-Zn2+ complex with deoxycholic acid-low molecular weight protamine to prepare nanocomplexes with ζ-potentials of +8 mV and sizes of 95 nm. Then, we used glycocholic acid-poly (ethylene glycol)-b-polysialic acid copolymers masking the positive charge of nanocomplexes to prepare nanoparticles with negative charges of -22 mV and homogeneous sizes of 140 nm. As a result, this dual cholic acid-functionalized nanoparticle demonstrated enhanced uptake and transport of Exenatide, and a special targeting to apical sodium-dependent cholic acid transporter in vitro. Moreover, in vivo studies showed that the nanoparticle effectively accumulated in distal ileum, raised the plasma concentration of Exenatide, prolonged hypoglycemic effect, reduced blood lipid levels, and lightened organ lesions.


Assuntos
Diabetes Mellitus , Exenatida/administração & dosagem , Hipoglicemiantes , Administração Oral , Preparações de Ação Retardada/administração & dosagem , Ácido Desoxicólico , Diabetes Mellitus/tratamento farmacológico , Ácido Glicocólico , Humanos , Íleo , Nanopartículas , Zinco
13.
J Pharm Biomed Anal ; 203: 114136, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087552

RESUMO

Exenatide is a peptide based anti-diabetic prescription medication. Until now, the literature has lacked a comprehensive atom-specific molecular characterization for this complex large peptide by NMR spectroscopy that can be effortlessly and rapidly utilized for biopharmaceutical structural veracity. Peptide structure verification by NMR is challenging and cumbersome when reliant on traditional proton-based methodology (through-bond and through-space proton connectivity) alone due to increasing complexity, low signal dispersion, and overlap. These challenges are overcome by using 2D heteronuclear (1H-13C and 1H-15N) maps that not only allow unambiguous signal assignment, but also condense the structural verification information within simplified peptide amide and carbon fingerprint maps. Here we report such simplified amide and carbon fingerprint maps for exenatide; made possible by the first ever comprehensive heteronuclear (1H,13C, and 15N) atom specific assignment of exenatide. These heteronuclear assignments were obtained without any isotopic enrichments i.e. at natural abundance, and hence are easily deployable as routine procedures. Furthermore, we compare the 2D heteronuclear maps of exenatide to a chemically identical peptide differing only in the isomerism of the Cα position of the first amino acid, [dHis1]-exenatide, to demonstrate the uniqueness of these maps. We show that despite deliberate changes in pH, temperature, and concentrations, the differences between the amide maps of exenatide and [dHis1]-exenatide are retained. The work presented here not only provides a facilitated structure verification of exenatide but also a framework for heteronuclear NMR data acquisition and signal assignment of large peptides, at natural abundance, in creating their respective unique 2D fingerprint maps.


Assuntos
Produtos Biológicos , Exenatida , Espectroscopia de Ressonância Magnética , Ressonância Magnética Nuclear Biomolecular , Peptídeos
14.
Expert Rev Clin Pharmacol ; 14(9): 1081-1089, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34015974

RESUMO

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer a unique opportunity to simultaneously address various comorbid associated conditions and phenotypic presentations of polycystic ovary syndrome (PCOS) as these agents improve insulin sensitivity, reduce cardiovascular disease (CVD) risk, result in weight loss, and improve nonalcoholic fatty liver disease.Areas covered: The authors describe trials conducted during the last 5 years and provide an update on exenatide and liraglutide use in PCOS women. Information from the studies investigating GLP-1 RAs effects on reducing CVD risk in PCOS is also presented.Expert opinion: Exenatide and liraglutide are good options for the treatment of PCOS when used alone or in combination with metformin. Especially strong consideration should be given to GLP-1 RAs when developing treatment strategies for PCOS women who are overweight or obese, glucose intolerant, have CVD or its attendant risk factors, and/or are seeking treatment for infertility.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Exenatida/administração & dosagem , Exenatida/farmacologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Fatores de Risco de Doenças Cardíacas , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Liraglutida/administração & dosagem , Liraglutida/farmacologia , Metformina/administração & dosagem , Metformina/farmacologia , Síndrome do Ovário Policístico/fisiopatologia , Perda de Peso/efeitos dos fármacos
15.
Adv Clin Exp Med ; 30(5): 555-561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33984196

RESUMO

BACKGROUND: Microvascular dysfunction is one of the most serious complications of diabetic retinopathy (DR). As a novel treatment drug for type 2 diabetes, exenatide possesses protective properties against retinal neurodegeneration. Sphingosine-1-phosphate receptor 2 (S1PR2) could regulate blood glucose in diabetes, and inhibition of S1PR2 is involved in the treatment of diabetes. However, the mechanism of exenatide in human retinal vascular endothelial cells (hRVECs) has not been fully defined. OBJECTIVES: We tested the hypothesis that S1PR2 plays a vital role in high glucose (HG)-induced hRVECs, and that exenatide could ameliorate HG-induced hRVEC injury by regulating S1PR2 production. MATERIAL AND METHODS: The hRVECs underwent HG-stimulation. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot were performed to examine the expression of S1PR2. Oxidative stress levels, inflammatory markers and cell apoptosis were detected using reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay (ELISA) kits and TUNEL staining. RESULTS: High glucose increased the level of S1PR2 in hRVECs and reduced the expression of glucagon-like peptide-1 receptor (GLP1R) compared to the control group. Exenatide decreased the level of S1PR2 induced by HG. Sphingosine-1 blocked the effects of exenatide, alleviating the ROS and cell apoptosis induced by HG. JTE-013 treatment protected hRVECs from injury by HG. The inhibitory effects of exenatide on S1PR2 expression lessened HG-induced hRVEC injury. CONCLUSIONS: The results demonstrate a possible mechanism of exenatide mediated inhibition of S1PR2 synthesis, and support S1PR2 as a novel target for treating DR.


Assuntos
Diabetes Mellitus Tipo 2 , Células Endoteliais , Apoptose , Exenatida/farmacologia , Glucose , Humanos , Inflamação , Estresse Oxidativo , Espécies Reativas de Oxigênio , Receptores de Esfingosina-1-Fosfato
16.
BMJ Open ; 11(5): e047993, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049922

RESUMO

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. METHODS AND ANALYSIS: This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. ETHICS AND DISSEMINATION: This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. TRIAL REGISTRATION NUMBERS: NCT04232969, ISRCTN14552789.


Assuntos
Doença de Parkinson , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Exenatida , Humanos , Estudos Multicêntricos como Assunto , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Chem Commun (Camb) ; 57(47): 5814-5817, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34002181

RESUMO

We report the design and evaluation of pH responsive luminescent europium(iii) probes that allow conjugation to targeting vectors to monitor receptor internalisation in cells. The approach adopted here can be used to tag proteins selectively and to monitor uptake into more acidic organelles, thereby enhancing the performance of time-resolved internalisation assays that require pH monitoring in real time.


Assuntos
Complexos de Coordenação/química , Európio/química , Receptor do Peptídeo Semelhante ao Glucagon 1/análise , Substâncias Luminescentes/química , Complexos de Coordenação/síntese química , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Substâncias Luminescentes/síntese química , Medições Luminescentes , Imagem Óptica
18.
Endocr Pract ; 27(8): 790-797, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33831552

RESUMO

OBJECTIVE: Many patients with type 2 diabetes treated with premixed insulin gradually have inadequate glycemic control and switch to a basal-bolus regimen, which raises some concerns for weight gain and increased hypoglycemic risk. Switching to combination use of glp-1 agonist and basal insulin may be an alternative option. METHODS: After a 12-week premixed human insulin 70/30 dosage optimization period, 200 patients with HbA1c of 7.0% to 10.0% were randomized into 24-week treatment groups with exenatide twice a day plus glargine or with aspart 70/30 twice a day. RESULTS: After 24 weeks, the patients receiving exenatide plus glargine (n = 90) had improved HbA1c control compared with those receiving aspart 70/30 (n = 90) (least squares mean change: ‒0.59 vs ‒0.13%; difference [95% CI]: ‒0.45 [‒0.74 to ‒0.17]) in the full analysis set population. Weight decreased 3.5 kg with exenatide and decreased 0.4 kg with aspart 70/30 (P < .001). The insulin dose was reduced 10.7 units/day (95% CI, ‒12.2 to ‒9.2 units; P < .001) with exenatide, and increased 9.7 units/day (95% CI, 8.2 to 11.2 units; P < .001) with aspart 70/30. The most common adverse events were gastrointestinal adverse effects in the exenatide group (nausea [21%], vomiting [16%], diarrhea [13%]). The incidence of hypoglycemia was similar in 2 groups (27% for exenatide and 38% for aspart 70/30; P = .1). CONCLUSION: In premixed human insulin‒treated patients with type 2 diabetes with inadequate glycemic control, switching to exenatide twice a day plus glargine was superior to aspart 70/30 twice a day for glycemic and weight control.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida , Hemoglobina A Glicada/análise , Controle Glicêmico , Humanos , Hipoglicemiantes , Insulina , Insulina Aspart , Insulina Glargina
19.
Am Heart J ; 239: 59-63, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33905751

RESUMO

Cardiovascular (CV) outcome studies of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shifted the paradigm of type 2 diabetes management given their benefits regarding a reduction in major adverse CV events. However, the relationship between GLP-1 RAs and coronary revascularization remains poorly understood. In this EXSCEL post-hoc analysis, we used univariate Cox proportional models and Kaplan Meier survival analysis to evaluate the effect of once-weekly exenatide (EQW) on a composite outcome of hospitalization for acute coronary syndrome (ACS) or coronary revascularization. Similar models were utilized to evaluate the relationship between significant participant characteristics within the entire study population and the composite outcome. Of the 14,736 participants in EXSCEL with complete follow-up data, 1642 (11.1%) experienced an ACS or coronary revascularization event during a median follow-up of 3.3 years (interquartile range, 2.3-4.4). EQW had no effect on hospitalization for ACS or coronary revascularization (HR 1.00, 95% CI 0.91-1.10). Among EXSCEL participants, enrollment in Latin America (HR 0.51, 95% CI 0.43-0.60) and a history of peripheral artery disease (HR 0.79, 95% CI 0.70-0.90) were associated with a reduced risk for coronary revascularization, whereas enrollment in North America (HR 1.92, 95% CI 1.74-2.12), a history of CV disease (HR 3.24, 95% CI 2.78-3.78), and a previous myocardial infarction (HR 1.54, 95% CI 1.39-1.71) were associated with increased risk for study end points. EQW had no association with hospitalization for ACS or coronary revascularization. Participant enrollment location and CV disease burden may play a role in the variable CV efficacy of GLP-1 RAs that has been observed in trials thus far.


Assuntos
Síndrome Coronariana Aguda , Diabetes Mellitus Tipo 2 , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hospitalização/estatística & dados numéricos , Revascularização Miocárdica , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/prevenção & controle , Síndrome Coronariana Aguda/cirurgia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Esquema de Medicação , Exenatida/administração & dosagem , Exenatida/efeitos adversos , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Revascularização Miocárdica/métodos , Revascularização Miocárdica/estatística & dados numéricos , Avaliação de Processos e Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais
20.
J Med Chem ; 64(8): 4947-4959, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33825469

RESUMO

Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. The resulting Ex4-DNP conjugates retained GLP-1 receptor activation potency in vitro and had a similar in vivo acute glucose-lowering effect comparable to that of native Ex4. Pharmacokinetic studies and hypoglycemic duration tests demonstrated that the Ex4-DNP conjugates displayed significantly elongated half-lives and improved long-acting antidiabetic activity in the presence of endogenous anti-DNP antibodies. In chronic treatment studies, once-daily administration of optimal conjugate 7 demonstrated more beneficial effects without prominent toxicity compared with Ex4. This strategy provides a new approach and represents an alternative to the well-established peptide-Fc fusion strategy to improve the peptide half-life and the therapeutic efficacy.


Assuntos
Anticorpos/sangue , Exenatida/química , Haptenos/química , Hipoglicemiantes/síntese química , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/metabolismo , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Dinitrobenzenos/química , Dinitrobenzenos/imunologia , Desenho de Fármacos , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Teste de Tolerância a Glucose , Meia-Vida , Haptenos/imunologia , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL
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