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1.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
2.
PLoS Med ; 16(10): e1002942, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589609

RESUMO

BACKGROUND: Disparities in type 2 diabetes (T2D) care provision and clinical outcomes have been reported in the last 2 decades in the UK. Since then, a number of initiatives have attempted to address this imbalance. The aim was to evaluate contemporary data as to whether disparities exist in glycaemic control, monitoring, and prescribing in people with T2D. METHODS AND FINDINGS: A T2D cohort was identified from the Royal College of General Practitioners Research and Surveillance Centre dataset: a nationally representative sample of 164 primary care practices (general practices) across England. Diabetes healthcare provision and glucose-lowering medication use between 1 January 2012 and 31 December 2016 were studied. Healthcare provision included annual HbA1c, renal function (estimated glomerular filtration rate [eGFR]), blood pressure (BP), retinopathy, and neuropathy testing. Variables potentially associated with disparity outcomes were assessed using mixed effects logistic and linear regression, adjusted for age, sex, ethnicity, and socioeconomic status (SES) using the Index of Multiple Deprivation (IMD), and nested using random effects within general practices. Ethnicity was defined using the Office for National Statistics ethnicity categories: White, Mixed, Asian, Black, and Other (including Arab people and other groups not classified elsewhere). From the primary care adult population (n = 1,238,909), we identified a cohort of 84,452 (5.29%) adults with T2D. The mean age of people with T2D in the included cohort at 31 December 2016 was 68.7 ± 12.6 years; 21,656 (43.9%) were female. The mean body mass index was 30.7 ± SD 6.4 kg/m2. The most deprived groups (IMD quintiles 1 and 2) showed poorer HbA1c than the least deprived (IMD quintile 5). People of Black ethnicity had worse HbA1c than those of White ethnicity. Asian individuals were less likely than White individuals to be prescribed insulin (odds ratio [OR] 0.86, 95% CI 0.79-0.95; p < 0.01), sodium-glucose cotransporter-2 (SGLT2) inhibitors (OR 0.68, 95% CI 0.58-0.79; p < 0.001), and glucagon-like peptide-1 (GLP-1) agonists (OR 0.37, 95% CI 0.31-0.44; p < 0.001). Black individuals were less likely than White individuals to be prescribed SGLT2 inhibitors (OR 0.50, 95% CI 0.39-0.65; p < 0.001) and GLP-1 agonists (OR 0.45, 95% CI 0.35-0.57; p < 0.001). Individuals in IMD quintile 5 were more likely than those in the other IMD quintiles to have annual testing for HbA1c, BP, eGFR, retinopathy, and neuropathy. Black individuals were less likely than White individuals to have annual testing for HbA1c (OR 0.89, 95% CI 0.79-0.99; p = 0.04) and retinopathy (OR 0.82, 95% CI 0.70-0.96; p = 0.011). Asian individuals were more likely than White individuals to have monitoring for HbA1c (OR 1.10, 95% CI 1.01-1.20; p = 0.023) and eGFR (OR 1.09, 95% CI 1.00-1.19; p = 0.048), but less likely for retinopathy (OR 0.88, 95% CI 0.79-0.97; p = 0.01) and neuropathy (OR 0.88, 95% CI 0.80-0.97; p = 0.01). The study is limited by the nature of being observational and defined using retrospectively collected data. Disparities in diabetes care may show regional variation, which was not part of this evaluation. CONCLUSIONS: Our findings suggest that disparity in glycaemic control, diabetes-related monitoring, and prescription of newer therapies remains a challenge in diabetes care. Both SES and ethnicity were important determinants of inequality. Disparities in glycaemic control and other areas of care may lead to higher rates of complications and adverse outcomes for some groups.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Disparidades em Assistência à Saúde , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Diabetes Mellitus Tipo 2/etnologia , Inglaterra/epidemiologia , Grupo com Ancestrais do Continente Europeu , Feminino , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hemoglobina A Glicada/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/etnologia , Hiperglicemia/terapia , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do Tratamento
3.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540136

RESUMO

Insulin resistance and diabetes are both associated with chronic hepatitis C virus (HCV) infection, and the glucagon-like peptide-1(GLP-1) receptor agonist, liraglutide, is a common therapy for diabetes. Our aim was to investigate whether liraglutide treatment can inhibit HCV replication. A cell culture-produced HCV infectious system was generated by transfection of in vitro-transcribed genomic JFH-1 ribonucleic acid (RNA) into Huh-7.5 cells. Total RNA samples were extracted to determine the efficiency of HCV replication. The Ava5 cells were treated with liraglutide and cell viability was calculated. A Western blot analysis of the protein expression was performed. The immunoreactive blot signals were also detected. Liraglutide activated GLP-1 receptors in the HCV infectious system, and inhibited subgenomic HCV RNA replication in the HuH-7.5 cells. The Western blot analysis revealed both HCV protein and replicon RNA were reduced after treatment with liraglutide in a dose-dependent manner. Liraglutide decreased the cell viability of HCV RNA at an optimum concentration of 120 µg/mL, activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and the phosphorylated- transducer of regulated cyclic adenosine monophosphate (CAMP) response element-binding protein 2 (TORC2), thereby decreasing the cell viability of phosphoenolpyruvate carboxykinase (PEPCK) and G6pase RNA Therefore, we conclude that liraglutide can inhibit HCV replication via an AMPK/TORC2-dependent pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hepacivirus/efeitos dos fármacos , Hepatócitos/enzimologia , Liraglutida/farmacologia , Replicação Viral/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hepacivirus/fisiologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
PLoS Biol ; 17(8): e3000097, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31430273

RESUMO

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Células CHO , Membrana Celular/metabolismo , Análise por Conglomerados , Cricetulus , AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2 , Endocitose/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Células HEK293 , Humanos , Insulina/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Lipoilação , Transdução de Sinais/efeitos dos fármacos
5.
Med Hypotheses ; 131: 109308, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443779

RESUMO

Adiposity is a chronic disease and one of the major modifiable risk factors for the development of type 2 diabetes mellitus (T2DM). Its prevalence in the world could be considered epidemic with 80% of patients with T2DM being obese. Novel antidiabetic drugs, such as glucagone-like peptide-1 (GLP-1) agonists have demonstrated benefitial effect on weight reduction. Nevertheless, in the last decades the need for new therapeutic strategies in the management of adiposity have emerged. Both adiposity and T2DM have negative effect on hypothalamic-pituitary-gonadal axis. Conversely, it has been known that sex hormone replacement therapy improves metabolic parameters in hypogonadal subjects. Recent research has found potential therapeutic effect of combination therapies with sex hormones and GLP-1 agonists in reducing body weight. Based on the aforementioned, we hypothesize that there is a possible synergistic effect of GLP-1 agonists and sex hormones on body mass reduction in patients with type 2 diabetes. The possible additional effect of sex hormones on weight loss could contribute to more effective treatment of T2DM and its complications.


Assuntos
Adiposidade/fisiologia , Fármacos Antiobesidade/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hormônios Esteroides Gonadais/farmacologia , Hipoglicemiantes/farmacologia , Modelos Biológicos , Perda de Peso , Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/farmacologia , Depressores do Apetite/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Sinergismo Farmacológico , Estradiol/sangue , Feminino , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Ciclo Menstrual/fisiologia , Sobrepeso/sangue , Sobrepeso/tratamento farmacológico , Sobrepeso/epidemiologia , Pâncreas/efeitos dos fármacos , Pâncreas/embriologia , Fatores de Risco , Taxa Secretória/efeitos dos fármacos , Testosterona/sangue , Perda de Peso/efeitos dos fármacos
6.
Diabetes Metab Syndr ; 13(4): 2489-2494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405666

RESUMO

AIMS: GLP-1 analogues decrease food intake and have great promise for the fight against obesity. Little is known about their effects on food hedonic sensations and taste perception in poor controlled patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Eighteen T2D patients with BMI ≥25 kg/m2 and poor controlled glycemia were studied before and after 3 months of treatment with Liraglutide. Detection thresholds for salty, sweet and bitter tastes, optimal preferences, olfactory liking, wanting and recalled liking for several food items were assessed. Subjects also answered questionnaires to measure their attitudes to food. RESULTS: T2D patients had a significant decrease in bodyweight and HbA1c after treatment with Liraglutide. Liraglutide improved gustative detection threshold of sweet flavors, and decreased wanting for sweet foods and recalled liking for fatty foods. It also led to a decrease in feelings of hunger. CONCLUSIONS: Liraglutide increases sensitivity to sweet tastes and decreases pleasure responses for fatty foods in poor controlled T2D patients, and is of particular interest in the understanding of the mechanisms of weight loss. CLINICAL TRIAL: NCT02674893.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Preferências Alimentares/psicologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Liraglutida/uso terapêutico , Rememoração Mental , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Comportamento de Escolha , Diabetes Mellitus Tipo 2/psicologia , Feminino , Seguimentos , Humanos , Fome/fisiologia , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/prevenção & controle , Prognóstico , Paladar/fisiologia , Adulto Jovem
7.
Metabolism ; 98: 104-111, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31255662

RESUMO

Managing type 2 diabetes is complex and necessitates careful consideration of patient factors such as engagement in self-care, comorbidities and costs. Since type 2 diabetes is a progressive disease, many patients will require injectable agents, usually insulin. Recent ADA-EASD guidelines recommend glucagon-like peptide 1 receptor agonists (GLP-1 RAs) as first injectable therapy in most cases. The basis for this recommendation is the similar glycemic efficacy of GLP-1 RAs and insulin, but with GLP-1 RAs promoting weight loss instead of weight gain, at lower hypoglycemia risk, and with cardiovascular benefits in patients with pre-existing cardiovascular disease. GLP-1 RAs also reduce burden of glucose self-monitoring. However, tolerability and costs are important considerations, and notably, rates of drug discontinuation are often higher for GLP-1 RAs than basal insulin. To minimize risk of gastrointestinal symptoms patients should be started on lowest doses of GLP-1 RAs and up-titrated slowly. Overall healthcare costs may be lower with GLP-1 RAs compared to insulin. Though patient-level costs may still be prohibitive, GLP-1 RAs can replace 50-80 units of insulin daily and reduce costs associated with glucose self-monitoring. Decisions regarding initiating injectable therapy should be individualized. This review provides a framework to guide decision-making in the real-world setting.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Animais , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Hipoglicemiantes/efeitos adversos , Injeções , Insulina/efeitos adversos
8.
Drugs ; 79(11): 1187-1197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243696

RESUMO

Obesity, type 2 diabetes, and the numerous associated metabolic co-morbidities are growing global threats to public health. Despite recent progress in pharmacotherapies for metabolic diseases, the current treatment options have limited efficacy and provide mostly symptomatic relief with little or no impact on disease reversal. Thus, improved therapies are urgently needed. As a result, the scientific community has increasingly invested in leveraging new pathophysiological insights into more efficacious pharmacotherapies for metabolic complications. A heightened understanding of the large, interindividual variation in responsiveness to certain metabolic medicines combined with advances in engineering multi-agonist candidates are important steps towards this goal. Additionally, the emerging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. In this review, we summarize recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, and we discuss the recent results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/metabolismo , Doenças Metabólicas/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão , Receptores de Glucagon/metabolismo
9.
Mol Med Rep ; 20(1): 701-708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180545

RESUMO

The pathogenesis of nonalcoholic fatty liver disease non­alcoholic steatohepatitis (NASH) has not been fully elucidated, and there are currently no effective treatments for NASH. The aim of the present study was to explore the therapeutic effects of the glucagon­like peptide­1 (GLP­1) receptor agonist liraglutide (LRG) on NASH and the underlying mechanisms. C57BL6J mice were fed a high­fat diet (HFD) for 8 weeks to induce hepatic steatosis, and then LRG was injected subcutaneously for 4 weeks. The expression of sterol regulatory element­binding protein 1 (SREBP1) and adenosine monophosphate­activated protein kinase (AMPK) as well as the phosphorylation of mechanistic target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6K) were determined by western blot analysis. The intracellular distribution of SREBP1 was assessed by immunofluorescence staining. The results revealed that LRG treatment ameliorated HFD­induced hepatic lipid accumulation and inhibited body weight gain. In addition, LRG treatment significantly suppressed the expression of hepatic SREBP1 as well as the phosphorylation of mTOR and p70S6K; it also increased the phosphorylation of AMPK and acetyl coenzyme A carboxylase. Furthermore, LRG treatment inhibited the hepatic nuclear translocation of SREBP1. It was suggested that the GLP­1 receptor agonist LRG may have ameliorated hepatic steatosis by activating the AMPK/mTOR/SREBP1 signaling pathway as opposed to inhibiting body weight gain.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Liraglutida/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
JAMA ; 321(15): 1466-1480, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30903796

RESUMO

Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02607865.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Administração Oral , Adulto , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fosfato de Sitagliptina/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
11.
Front Biosci (Landmark Ed) ; 24: 688-699, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844705

RESUMO

Numerous micro-organisms naturally reside in the human body assuming a symbiotic, or, at times, even a dysbiotic relationship with the host. These microbial populations are referred to as the human microbiota. Host microbial populations are an important mediator of gastro-intestinal mucosal permeability, bile acid metabolism, short-chain fatty acids synthesis, fermentation of dietary polysaccharides and FXR/TGR5 signaling. Variations in the composition and function of gut microbiota have been observed in type 2 diabetes mellitus, insulin resistance and obesity, as well as in inflammatory bowel diseases. The microbial imbalance induced by such pathological processes is described as dysbiosis. In this review, we describe the pathophysiological links between type 2 diabetes mellitus and gut microbiota, explore the effect of anti-diabetic drugs on gut microbiota and suggest possible therapeutic targets.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Tipo 2/microbiologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Disbiose/induzido quimicamente , Fermentação , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Incretinas/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Metformina/farmacologia , Camundongos , Obesidade/metabolismo , Permeabilidade , Polissacarídeos/metabolismo , Transdução de Sinais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , alfa-Glucosidases/metabolismo
12.
Diabetes Res Clin Pract ; 149: 78-88, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30735771

RESUMO

Tobacco use disorder (TUD), in particular cigarette smoking, contributes significantly to the macro- and micro-vascular complications of type 2 diabetes mellitus (DM). Persons with DM who regularly use tobacco products are twice as likely to experience mortality and negative health outcomes. Despite these risks, TUD remains prevalent in persons with DM. The objective of this integrative review is to summarize the relationship between TUD and DM based on epidemiological and preclinical biological evidence. We conclude with a review of the literature on the glucagon-like peptide-1 (GLP-1) as a potential treatment target for addressing comorbid TUD in smokers with DM.


Assuntos
Fumar Cigarros/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hipoglicemiantes/farmacologia
13.
Diabetes Res Clin Pract ; 150: 8-16, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30794833

RESUMO

AIM: To assess the effects DPP-4i; SGLT2-i & GLP1-RA on CV death, MI, stroke and hHF. This is probably the first meta-analysis to assess the effects of these drugs on MI and stroke in totality, including non-fatal & fatal MI and stroke. METHODS: Scientific databases were searched for RCTs with pre-specified inclusion criteria and each end-point from the selected 13 studies was reported as an effect size (M H odds ratio) with a 95% confidence interval P value. RESULTS: The pooled analysis of all the 5 available CVOT with DPP-4i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke, CV death and hHF. The pooled analysis of all the 5 available CVOTs with GLP1-RA resulted in a neutral effect on MI. However, there was a statistically significant 12% reduction in CV death (P = 0.01), 13% reduction in stroke (P = 0.02) and 11% reduction the combined end points of MI & Stroke (P = 0.001). The impact of GLP1-RA inhibitors on hHF was neutral. The pooled analysis of all the 3 available CVOTs with SGLT2-i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke and CV death. There was however a statistically significant 28% reduction in hHF (P < 0.001). CONCLUSION: DPP-4i & SGLT-2i are neutral as far as all aspects of CV outcomes are concerned except for hHF which is significantly reduced by the latter. GLP1-RA as a class reduce risk of ASCVD showing a significant reduction in MI and stroke.


Assuntos
Doenças Cardiovasculares/epidemiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Insuficiência Cardíaca/epidemiologia , Hospitalização/estatística & dados numéricos , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Acidente Vascular Cerebral/epidemiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/prevenção & controle , Humanos , Incidência , Infarto do Miocárdio , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/prevenção & controle
14.
Curr Mol Pharmacol ; 12(2): 139-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747091

RESUMO

BACKGROUND: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. METHODS: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). RESULTS: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. CONCLUSION: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.


Assuntos
Bile/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptores de Glucagon/agonistas , Tiroxina/sangue , Tri-Iodotironina/sangue , Animais , Dieta Hiperlipídica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metimazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/etiologia , Obesidade/metabolismo , Propiltiouracila/farmacologia , Receptores de Glucagon/metabolismo , Triglicerídeos/análise
15.
Clin Cardiol ; 42(3): 406-412, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30635924

RESUMO

Patients with type 2 diabetes have a significantly increased risk of cardiovascular disease (CVD) compared to the general population-with CVD accounting for two out of every three deaths in patients with diabetes. In 2008, the FDA suggested that CVD risk should be evaluated for any new antidiabetic therapy, leading to a multitude of large CVD outcome trials to assess CVD risk from these medications. Interestingly, several of these outcome trials with new novel antidiabetic therapies have demonstrated a clear and definite CVD advantage at mid-term follow up in high-risk patients with T2DM. In this review, we discuss two relatively new classes of diabetic drugs, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists, and their efficacy in improving cardiovascular outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/uso terapêutico , Prevenção Secundária/métodos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Saúde Global , Humanos , Incidência , Prognóstico , Taxa de Sobrevida/tendências
16.
Ann Intern Med ; 170(3): 155-163, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30597484

RESUMO

Background: Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture. Objective: To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist. Design: Population-based new-user cohort study. Setting: Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015. Patients: Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist. Measurements: The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR). Results: 79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]). Limitation: Unmeasured confounding, measurement error, and low fracture rate. Conclusion: In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists. Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.


Assuntos
Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fraturas Ósseas/etiologia , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Idoso , Feminino , Seguimentos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Medição de Risco
17.
J Atheroscler Thromb ; 26(2): 183-197, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29962378

RESUMO

AIMS: Recently, incretin therapy has attracted increasing attention because of its potential use in tissue-protective therapy. Neuron-derived orphan receptor 1 (NOR1) is a nuclear orphan receptor that regulates vascular smooth muscle cell (VSMC) proliferation. In the present study, we investigated the vascular-protective effect of Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, by inhibiting NOR1 expression in VSMCs. METHODS: We classified 7-week-old male 129X1/SvJ mice into control group and Ex-4 low- and high-dose-treated groups fed normal or high-fat diets, respectively. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by the evaluation of neointima formation at 12 weeks of age. To evaluate VSMC proliferation, bromodeoxyuridine incorporation assay and cell cycle distribution analysis were performed. NOR1 and cell cycle regulators were detected using immunohistochemistry, western blotting, quantitative reverse-transcription polymerase chain reaction, and luciferase assays. RESULTS: Ex-4 treatment reduced vascular injury-induced neointima formation compared with controls. In terms of VSMCs occupying the neointima area, VSMC numbers and NOR1-expressing proliferative cells were significantly decreased by Ex-4 in a dose-dependent manner in both diabetic and non-diabetic mice. In vitro experiments using primary cultured VSMCs revealed that Ex-4 attenuated NOR1 expression by reducing extracellular signal-regulated kinase-mitogen-activated protein kinase and cAMP-responsive element-binding protein phosphorylations. Furthermore, in the cell cycle distribution analysis, serum-induced G1-S phase entry was significantly attenuated by Ex-4 treatment of VSMCs by inhibiting the induction of S-phase kinase-associated protein 2. CONCLUSION: Ex-4 attenuates neointima formation after vascular injury and VSMC proliferation possibly by inhibiting NOR1 expression.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Exenatida/farmacologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptores de Esteroides/antagonistas & inibidores , Receptores dos Hormônios Tireóideos/antagonistas & inibidores , Animais , Células Cultivadas , Masculino , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Neointima/patologia
18.
Am J Med ; 132(1): 16-24, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30201240

RESUMO

Cardiovascular disease is responsible for 205 deaths per 100,000 persons annually and is the leading cause of death worldwide. The public health burden of cardiovascular disease is expected to continue to grow as the prevalence of many cardiovascular risk factors increases. Several novel classes of glucose-lowering, lipid-lowering, and weight-loss therapeutics have shown mortality benefits in outcomes trials. However, a large proportion of subjects in those trials had established cardiovascular disease, so, as a result, the role of these novel therapeutics in primary cardiovascular prevention is controversial. In this review, we highlight recent advances in the pharmacotherapeutic management of the cardiovascular risk factors of hyperglycemia, dyslipidemia, and obesity. We examine key subgroups within recent cardiovascular outcome trials, weigh the risks and benefits of several novel therapeutics, and provide practical insight into the use of these agents. Our article concludes with a look toward the future and provides the practitioner and scientist with an early view of emerging therapeutics that may play an important role in primary cardiovascular prevention.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Anticolesterolemiantes/farmacologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Hipoglicemiantes/farmacologia , Prevenção Primária , Pró-Proteína Convertase 9/antagonistas & inibidores
19.
Am J Med ; 132(4): 408-412, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30472322

RESUMO

On any given night in the United States, an estimated 553,742 people are homeless. Applying a broader definition of homelessness that includes unstably housed people, an estimated 1.5% of Americans experience homelessness in a given year. Rates of diabetes are increasing among individuals experiencing homelessness. The social, psychological, and physical challenges of homelessness not only contribute to the rate of diabetes, but also complicate management. Unstable housing, limited medical resources, food insecurity, and competing priorities are barriers to diabetes care among patients experiencing homelessness. Homeless patients with diabetes more frequently develop specific comorbidities that require special attention, such as cardiovascular disease, substance abuse, depression, and foot wounds. The Affordable Care Act gave states the option to expand Medicaid to those earning up to 138% of the federal poverty level. This addressed a gap in coverage for low-income individuals not eligible for Medicaid or employer-sponsored insurance. With increased insurance coverage, this has increased the variety of medications available to treat hyperglycemia from type 2 diabetes beyond metformin, sulfonylureas, and insulin. Several of the newer classes of medications have advantages for patients experiencing homelessness, but also have special considerations in this vulnerable patient population. This narrative review will provide a review of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide agonists, sodium glucose cotransporter-2 inhibitors, and thiazolidinediones in individuals experiencing homelessness.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Pessoas em Situação de Rua , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico
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