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1.
Can J Diabetes ; 46(2): 196-203.e2, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35288040

RESUMO

BACKGROUND: The aim of this study was to estimate the real-world incidence of self-reported non-severe hypoglycemia (NSH) and its related sociodemographic and clinical risk factors in a general population of Canadian adults with type 2 diabetes mellitus (T2DM) taking insulin and/or secretagogues. METHODS: Data for this study were obtained from the InHypo-DM Study. Self-reported data on the frequency of NSH (past 30 days) as well as sociodemographic and clinical characteristics were collected through an online questionnaire. Risk factors for any, daytime and nocturnal NSH were identified using multivariable negative binomial regression with backward selection. RESULTS: Among 432 adults with T2DM (43.8% female, mean age of 53.1 years), 53.9% (95% confidence interval [CI], 49.2% to 58.6%) reported ≥1 event of any (i.e. daytime or nocturnal) NSH in the past 30 days. The 30-day incidence rate of any NSH was 2.3 events per 30 person-days (95% CI, 2.1 to 2.4). Risk factors associated with the increased rate of any NSH were younger age, lower annual household income, being employed, longer duration of diabetes, higher glycated hemoglobin and presence of comorbidity. Risk factors were generally similar for daytime NSH (except for the exclusion of diabetes duration and addition of diabetes medication type) and nocturnal NSH (except for the exclusion of being employed). CONCLUSIONS: This is the largest Canadian investigation to estimate the real-world frequency and distribution of self-reported NSH in T2DM. Events were alarmingly frequent and recurrent. Numerous sociodemographic and clinical risk factors were elucidated. These results highlight the importance of identifying high-risk individuals to minimize future occurrences of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Adulto , Glicemia , Canadá/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Incidência , Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Secretagogos/uso terapêutico
2.
Horm Res Paediatr ; 95(1): 76-81, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35354138

RESUMO

INTRODUCTION: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH secretagogue receptor agonist under development for treatment of pediatric growth hormone deficiency (PGHD). METHODS: The GH response to a single dose of LUM-201 and to other GH secretagogues used for diagnosis of PGHD were compared in 68 pediatric subjects participating in a trial for growth hormone deficiency. RESULTS: LUM-201 elicited greater GH responses than observed in GHD diagnostic tests with arginine, glucagon, clonidine, L-dopa, and insulin-induced hypoglycemia [median and interquartile ranges 15.0 ng/mL (3.5, 49) vs. 5.5 ng/mL (1.8, 7.6) (p < 0.0001)]. The difference between responses was greatest in subjects with higher baseline IGF-I concentrations and higher GH responses to standard GH stimuli. CONCLUSION: LUM-201 elicits greater GH responses than standard stimuli in subjects with higher peak GH in response to conventional testing and is potentially an orally administered treatment alternative to injectable rhGH in a subset of patients with adequate responses to an acute dose of LUM-201.


Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipoglicemia , Criança , Glucagon , Hormônio do Crescimento , Humanos , Fator de Crescimento Insulin-Like I , Secretagogos/efeitos adversos
3.
Psychoneuroendocrinology ; 139: 105716, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35290931

RESUMO

Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.


Assuntos
Óxido Nítrico , Receptores de Grelina , Animais , Grelina/metabolismo , Hipotálamo Posterior , Camundongos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Ratos , Receptores de Grelina/metabolismo , Secretagogos/metabolismo
4.
Clin Pharmacol Ther ; 111(1): 218-226, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34312836

RESUMO

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Insulina/agonistas , Secretagogos/efeitos adversos , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Carbamatos/efeitos adversos , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações Medicamentosas , Feminino , Glipizida/efeitos adversos , Glibureto/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Medicaid , Metformina/efeitos adversos , Pessoa de Meia-Idade , Nateglinida/efeitos adversos , Farmacoepidemiologia , Piperidinas/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Estados Unidos
5.
Chirality ; 34(3): 521-536, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34964164

RESUMO

Polysubstituted tetrahydroquinolines were obtained in moderate to high yields (28% to 92%) and enantiomeric ratios (er 89:11 to 99:1) by a three-component Povarov reaction using a chiral phosphoric acid catalyst. Significantly, post-Povarov functional group interconversions allowed a rapid access to a library of 36 enantioenriched 4-aminotetrahydroquinoline derivatives featuring five points of diversity. Selected analogs were assayed for their ability to function as glucagon-like peptide-1 (GLP-1) secretagogues.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Secretagogos , Catálise , Estereoisomerismo
6.
Nat Commun ; 12(1): 5616, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556670

RESUMO

Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet ß-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.


Assuntos
Berberina/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Hiperglicemia/metabolismo , Secreção de Insulina/efeitos dos fármacos , Secretagogos/farmacologia , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Estudos Cross-Over , Dieta Hiperlipídica/efeitos adversos , Canais de Potássio Éter-A-Go-Go/genética , Células HEK293 , Humanos , Hiperglicemia/etiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Adulto Jovem
7.
Rapid Commun Mass Spectrom ; 35(23): e9201, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34542924

RESUMO

RATIONALE: Interest in growth hormone secretagogues has intensified during the past several years based on capable, ever-widening investigational applications of recombinant growth hormone in animals and humans. Ibutamoren is a potent, long-acting, selective and orally active non-peptide growth hormone secretagogue, which has a great potential for abuse as a performance-enhancing agent in sports. METHODS: To support drug metabolism and pharmacokinetic studies of chiral pharmaceuticals, it is necessary to combine the resolving power of high-performance liquid chromatography with the sensitivity of mass spectrometric techniques. This paper describes the metabolic conversion of ibutamoren using equine liver microsomes and metabolite characterization using a QExactive high-resolution mass spectrometer. RESULTS: A total of 32 metabolites for ibutamoren (20 phase I and 12 phase II) were detected. The important findings of the current research are as follows: (1) the growth hormone secretagogue ibutamoren was prone to oxidation, resulting in corresponding hydroxylated metabolites; (2) in ibutamoren, the dissociation of the phenyl ring and 2-amino-2-methylpropanamide side chain was also observed; (3) the glucuronic acid conjugates of mono-, di- and trihydroxylated analogues were detected; and (4) no sulfonic acid conjugated metabolites were observed in this study of ibutamoren. CONCLUSIONS: The reported data help in the speedy detection of the growth hormone secretagogue ibutamoren and reveal its illegal use in competitive sports.


Assuntos
Indóis , Microssomos Hepáticos/metabolismo , Secretagogos , Compostos de Espiro , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Doping nos Esportes , Cavalos , Indóis/análise , Indóis/química , Indóis/metabolismo , Secretagogos/análise , Secretagogos/química , Secretagogos/metabolismo , Compostos de Espiro/análise , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas
8.
Fish Shellfish Immunol ; 119: 508-515, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34592474

RESUMO

Growth Hormone-Releasing Peptide 6 (GHRP-6) (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2) is an agonist of the growth hormone secretagogue receptor. GHRP-6 mimics the effect of ghrelin. The present study focuses on the immunomodulatory effects of GHRP-6 in tilapia with and without the presence of Pseudomonas aeruginosa infection. GHRP-6 up-regulated the transcription levels of three piscidin-like antimicrobial peptides (Oreochromicins I, II, and III) and granzyme in a tissue-dependent manner. Antimicrobial activity stimulation in serum (lysozyme and anti-protease activity) was also confirmed. Besides, GHRP-6 enhanced the in vitro antimicrobial activity against P. aeruginosa in tilapia gills mucus and serum samples and decreased the bacterial load in vivo after infection with this Gram-negative bacterium. Our results evidenced, for the first time, a direct link between a growth hormone secretagogue ghrelin mimetic in fish and the enhancement of antimicrobial peptides transcription, which suggests that this secretagogue is capable to lead the activation of microbicidal activity in tilapia. Thus, these results open new possibilities for GHRP-6 application in aquaculture to stimulate the teleost immune system as an alternative treatment against opportunistic bacteria.


Assuntos
Anti-Infecciosos , Ciclídeos , Tilápia , Animais , Grelina , Hormônio do Crescimento , Secretagogos
10.
Mol Metab ; 53: 101327, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34428557

RESUMO

OBJECTIVE: The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. METHODS: We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. RESULTS: LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2-119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. CONCLUSIONS: LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed a high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake. Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Grelina/análogos & derivados , Secretagogos/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/deficiência , Peptídeos Catiônicos Antimicrobianos/genética , Dieta Hiperlipídica/efeitos adversos , Feminino , Grelina/administração & dosagem , Grelina/metabolismo , Hormônio do Crescimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
J Steroid Biochem Mol Biol ; 212: 105925, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34089834

RESUMO

There is some evidence for ameliorating effect of vitamin D on glycemic and lipidemic status which are likely to be mediated through other molecules including adiponectin. However, the overall results have been controversial. This study was conducted to evaluate the effect of vitamin D supplementation on serum adiponectin concentration. MEDLINE, PubMed, Embase, Cochrane Library, and Google Scholar were searched and 402 studies were found in a preliminary search. After screening of titles and abstracts nine studies were selected. Pooled data showed no significant effect on adiponectin concentrations (mean difference (MD) 0.37, 95 % CI: -0.1 to 0.87). However, there was a significant effect in a subgroup of participants who had diabetes (MD: 0.03, 95 % CI: 0.00 to 0.05, p = 0.029). The treatment effect on adiponectin concentrations was significant in those trials that used supplementation on a daily basis (MD: 0.03, 95 % CI: 0.00 to 0.05, p = 0.028) and vitamin D plus calcium (MD: 0.04, 95 % CI: 0.01 to 0.07, p = 0.014). The meta-regression revealed a significant association between BMI and age of participants at baseline and the treatment effect (B, -0.144, 95 % CI: -0.276 to -0.011, p = 0.033 and B, -0.043, 95 % CI: -0.075 to -0.012, p = 0.006). The results of this meta-analysis study indicates that vitamin D may be considered an adiponectin secretagogue in subjects with diabetes and this effect may be potentiated if vitamin D intake is on daily basis and in combination with calcium but can be weakened by increasing BMI.


Assuntos
Adiponectina/sangue , Secretagogos/farmacologia , Vitamina D/farmacologia , Vitaminas/farmacologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Transl Psychiatry ; 11(1): 230, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879778

RESUMO

Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.


Assuntos
Receptores de Grelina , Área Tegmentar Ventral , Animais , Grelina , Masculino , Camundongos , Camundongos Knockout , Motivação , Receptores de Grelina/metabolismo , Secretagogos , Área Tegmentar Ventral/metabolismo
13.
J Clin Gastroenterol ; 55(6): 512-519, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569031

RESUMO

GOALS: To assess short-term and long-term effects of lubiprostone, a type-2 chloride channel activator, on electrolyte homeostasis. BACKGROUND: Conventional laxatives are associated with electrolyte imbalances. Lubiprostone is a type-2 chloride channel activator approved for treating chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and constipation-predominant irritable bowel syndrome in women. It induces intestinal fluid secretion, possibly affecting water and electrolyte homeostasis. We investigated short-term and long-term effects of lubiprostone on electrolyte, blood urea nitrogen (BUN), and creatinine levels using pooled data from CIC and OIC patients. STUDY: Data were pooled from 10 CIC and OIC studies-6 double-blind, randomized, placebo-controlled studies and 4 open-label, long-term studies. Total duration of lubiprostone exposure was from 3 weeks (short-term: CIC, 3 to 4 wk; OIC, placebo-controlled, 12 wk) to 48 weeks (long-term: CIC, 24 to 48 wk; OIC, 48 wk). Sodium, chloride, potassium, magnesium, BUN, and creatinine levels were examined at baseline and final assessment. RESULTS: Overall, 3209 patients were assessed. In the double-blind, placebo-controlled studies, there were no clinically meaningful differences in levels of electrolytes, BUN, and creatinine between lubiprostone and placebo groups, and in changes from baseline levels with long-term use of lubiprostone. Analyses of shifts in laboratory values (low/normal/high) at baseline and final assessment showed minimal effects on electrolytes, BUN, and creatinine. CONCLUSIONS: Lubiprostone did not cause clinically meaningful electrolyte imbalances or affect markers of renal function in either the short-term or long-term treatment of CIC or OIC.


Assuntos
Constipação Induzida por Opioides , Secretagogos , Analgésicos Opioides , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Feminino , Homeostase , Humanos , Lubiprostona
14.
Assay Drug Dev Technol ; 19(1): 27-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164547

RESUMO

Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.2/SUR1 complex. To characterize hit compounds, we developed an assay to quantify endogenous potassium channel activity in INS-1E cells. We quantified ligand-regulated potassium channel activity in INS-1E cells using fluorescence imaging and thallium flux. Potassium channel activity was metabolically regulated and coupled to insulin secretion. The pharmacology of channel opening agents (diazoxide) and closing agents (sulfonylureas) was used to validate the applicability of the assay. A precise high-throughput assay was enabled, and phenotypic screening hits were triaged to enable a higher likelihood of discovering chemical matter with novel and useful mechanisms of action.


Assuntos
Diazóxido/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Secretagogos/farmacologia , Compostos de Sulfonilureia/farmacologia , Receptores de Sulfonilureias/metabolismo , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Imagem Óptica , Fenótipo
15.
Front Immunol ; 11: 564953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281812

RESUMO

A hallmark of enteroaggregative Escherichia coli (EAEC) infection is the formation of an intestinal biofilm, which comprises a mucus layer with immersed bacteria. Pic is an autotransporter secreted by EAEC, and other E. coli pathotypes, and has been involved in two apparently contradictory phenotypes, as a mucus secretagogue and as a mucinase. Here, we investigated this Pic dual activity, mucus secretagogue capability and mucinolytic activity, in human goblet cells that secrete MUC2 and MUC5AC. Pic induced mucus hypersecretion directly in the goblet cells, without other intestinal cell types involved. At the same time, Pic exhibited strong proteolytic activity on the secreted mucins. These activities were independent since a mutation in the serine protease motif (PicS258I) abolished mucin degradation while maintaining the mucus secretagogue activity intact. Furthermore, deoxycholic acid (DCA)-induced mucins were proteolytically degraded when goblet cells were co-incubated with DCA/Pic, while co-incubation with DCA/PicS258I induced a synergistic effect on mucus hypersecretion. Pic was more efficient degrading MUC5AC than MUC2, but no degradation was detected with Pic inactivated at the active site by mutation or pharmacological inhibition. Remarkably, Pic cleaved MUC2 and MUC5AC in the C-terminal domain, leaving N-terminal subproducts, impacting the feature of gel-forming mucins and allowing mucus layer penetration by EAEC. Astonishingly, Pic stimulated rapid mucin secretion in goblet-like cells by activating the intracellular calcium pathway resulting from the PLC signal transduction pathway, leading to the production of DAG and releasing IP3, a second messenger of calcium signaling. Therefore, the dual activity of Pic, as a mucus secretagogue and a mucinase, is relevant in the context of carbon source generation and mucus layer penetration, allowing EAEC to live within the layer of mucus but also access epithelial cells.


Assuntos
Infecções por Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Muco/metabolismo , Polissacarídeo-Liases/metabolismo , Secretagogos/metabolismo , Serina Endopeptidases/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Domínio Catalítico , Linhagem Celular , Infecções por Escherichia coli/microbiologia , Células Caliciformes/metabolismo , Células Caliciformes/microbiologia , Humanos , Mucina-5AC/metabolismo , Mucina-2/metabolismo
16.
Life Sci ; 262: 118504, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32991877

RESUMO

Of the three groups of innate lymphoid cells, the type 3 innate lymphoid cell(s) (ILC3) include the subgroup of enteric ILC3 that participates in many physiological functions of the organism, such as promoting the repair of damaged mucosa, maintaining the homeostasis of gut symbiotic microorganisms, and presenting specific antigens. ILC3 also includes splenic and decidual ILC3. Like other physiological processes in the organism, enteric ILC3 functions are precisely regulated at the endogenous and exogenous levels. However, there has been no review on the physiological functions and regulatory signals of intestinal ILC3. In this paper, based on the current research on the physiological functions of enteric ILC3 in animals and the human, we summarize the signals that regulate cytokine secretion, antigen presentation and the quantity of ILC3 under normal intestinal conditions. We discuss for the first time the classification of the promoting mechanism of secretagogues of ILC3 into direct and indirect types. We also propose that ILC3 can promote intestinal homeostasis, and intestinal homeostasis can ensure the physiological phenotype of ILC3. If homeostasis is disturbed, ILC3 may participate in intestinal pathological changes. Therefore, regulating ILC3 and maintaining intestinal homeostasis are critical to the body.


Assuntos
Imunidade Inata/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Animais , Apresentação do Antígeno/imunologia , Citocinas/imunologia , Homeostase/imunologia , Humanos , Secretagogos/imunologia
17.
Nutr Metab Cardiovasc Dis ; 30(10): 1601-1608, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32811736

RESUMO

BACKGROUND AND AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect. METHODS AND RESULTS: A MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH-OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH-OR 1.11 [1.00, 1.23], p = 0.04). CONCLUSIONS: This meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Insulina/sangue , Secretagogos/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
18.
J Pharm Pharmacol ; 72(9): 1221-1231, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32557699

RESUMO

OBJECTIVES: To investigate the inhibitory effects of Kaempferol, a natural flavonol active compound, on pseudo-allergic reactions (in vivo and in vitro), particularly on the mechanism underlying its effect in human mast cells. METHODS: Compound 48/80 (C48/80)-induced immunoglobulin E (IgE)-independent passive cutaneous anaphylaxis (PCA) model and systemic anaphylaxis were applied to investigate the anti-allergic activity of Kaempferol. The degranulation assay, calcium imaging and the secretion of cytokines and chemokines were used to evaluate the inhibitory effect on mast cell activation. Western blot analysis was performed to investigate intracellular calcium fluctuation-related signalling pathways. KEY FINDINGS: Kaempferol dose-dependently attenuated C48/80-induced mice hind paw swelling, dye extravasation and skin mast cell degranulation, and rehabilitated the hypothermia, as well as reduced the serum concentrations of histamine, tryptase, tumour necrosis factor-alpha (TNF-α), interleukin-8 (IL-8) and monocyte chemo-attractant protein-1 (MCP-1). Furthermore, Kaempferol suppressed C48/80-triggered human MC degranulation and calcium fluctuations by inhibiting phospholipase Cγ (PLCγ) phosphorylation and subsequent cytokines synthesis pathways. CONCLUSIONS: The inhibition of the process of PLCγ phosphorylation to Ca2+ mobilization represents a major strategy in Kaempferol-suppressed pseudo-allergic reactions. Thus, Kaempferol could be considered as a therapeutic drug candidate for non-IgE-mediated allergic reactions or inflammations.


Assuntos
Anafilaxia/tratamento farmacológico , Antialérgicos/farmacologia , Cálcio/metabolismo , Quempferóis/farmacologia , Anafilaxia/imunologia , Animais , Antialérgicos/administração & dosagem , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Imunoglobulina E/imunologia , Quempferóis/administração & dosagem , Masculino , Mastócitos , Camundongos , Camundongos Endogâmicos C57BL , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Anafilaxia Cutânea Passiva/imunologia , Secretagogos/imunologia , p-Metoxi-N-metilfenetilamina/imunologia
19.
Eur J Pharmacol ; 880: 173162, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32423868

RESUMO

Na+-K+-2Cl- cotransporter (NKCC) is expressed at exceptionally high levels in gastric parietal cells. Bumetanide, a potent loop diuretic that blocks NKCC, usually causes a decrease in gastric acid secretion. Endotoxaemia causes hypochlorhydria in vivo, in which lipopolysaccharide (LPS) plays an important role. This study aimed to investigate the effect of NKCC2 on gastric acid secretion and its alteration in LPS-treated mice. The scanning ion-selective electrode technique and real-time pH titration combined with RNA interference were used to determine the effects of bumetanide on gastric acid secretion. Immunochemistry and Western blotting were performed to investigate the changes in NKCC2 expression in LPS-treated mice. Immunoreactivity of NKCC1 and NKCC2 was mainly observed near the basolateral and apical membranes of parietal cells, respectively. Pretreatment with bumetanide reduced the histamine-stimulated H+ flux in the mouse gastric mucosa. The apical, but not the basolateral, addition of bumetanide inhibited forskolin- or histamine/3-isobutyl-1-methylxanthine(IBMX)-induced gastric acid secretion. In vivo treatment with NKCC2 siRNA inhibited forskolin-induced acid secretion. Upon histamine stimulation, the majority of NKCC2 was targeted to the apical membrane in the gastric mucosa and in primary cultured parietal cells. The expression of NKCC2 and vesicle-associated membrane protein-2 (VAMP2), but not that of H+/K+-ATPase, was decreased in the gastric mucosa of LPS-treated mice. Blocking apical NKCC2, but not basolateral NKCC1, by bumetanide inhibited secretagogue-induced gastric acid secretion, during which the membrane trafficking of NKCC2 may be necessary. The downregulation of NKCC2 and VAMP2 may be related to the reduced gastric acid secretion induced by LPS.


Assuntos
Bumetanida/farmacologia , Ácido Gástrico/metabolismo , Células Parietais Gástricas/efeitos dos fármacos , Secretagogos/farmacologia , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Células Parietais Gástricas/metabolismo , Ratos Sprague-Dawley , Proteína 2 Associada à Membrana da Vesícula/metabolismo
20.
Acta Diabetol ; 57(8): 991-1000, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32206903

RESUMO

AIMS: This study aimed to compare the efficacy and safety of generic exenatide with branded exenatide Byetta® in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues. METHODS: A multicenter, randomized, controlled, non-inferiority trial was performed. A total of 240 patients with T2DM and glycated hemoglobin (HbA1c) ≥ 7% (53 mmol/mol) to ≤ 9.0% (75 mmol/mol) on monotherapy or combination therapy of metformin and insulin secretagogues for at least 3 months were randomized into generic exenatide or branded exenatide groups with a 1:1 ratio for 16 weeks of treatment. The primary endpoint was the change in HbA1c levels from baseline at week 16, with a non-inferiority margin of - 0.35% (- 3.83 mmol/mol) (lower bound of one-sided 95% confidence interval (CI) > - 0.35% (- 3.83 mmol/mol)). Secondary endpoints included the proportion of participants achieving HbA1c < 7% (53 mmol/mol), the changes in fasting plasma glucose (FPG), 2-h postprandial glucose (2hPG) following a standard meal, 7-point self-monitoring blood glucose (SMBG) profiles, body weight change from baseline at week 16 and the change in HbA1c levels from baseline at week 8. Safety issues were also evaluated. RESULTS: After 16 weeks of treatment, HbA1c levels decreased significantly from baseline in the two groups, with a reduction of - 1.10% ± 1.31% (- 12.0 mmol/mol ± 14.3 mmol/mol) in the generic exenatide group and - 1.08% ± 1.11% (- 11.8 mmol/mol ± 12.1 mmol/mol) in the branded exenatide group (both P < 0.001). The least-squares mean difference of HbA1c reduction between the two groups was - 0.03% (- 0.33 mmol/mol), with a lower one-sided 95% CI limit of - 0.27% (- 2.95 mmol/mol), which was higher than the prespecified non-inferiority margin of - 0.35% (- 3.83 mmol/mol). Moreover, there were no significant differences in the proportion of participants achieving HbA1c < 7% (53 mmol/mol) and the changes in FPG, 2hPG, 7-point SMBG profiles and body weight at week 16 and the change in HbA1c levels from baseline at week 8 (all P > 0.05) between the two groups. The incidence of adverse events, including the incidence of hypoglycemia (18.3% and 17.5%, respectively), was similar for the generic and branded exenatide groups (P > 0.05). CONCLUSIONS: In patients with T2DM inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues, add-on treatment with generic exenatide demonstrated non-inferiority to branded exenatide in terms of improvements in HbA1c after 16 weeks of treatment. Furthermore, the two drugs were also similar for other efficacy endpoints and safety profile. Trial registration Chinese Clinical Trial Registry: ChiCTR-IPR-15006558, Date registered May 27, 2015.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Exenatida/efeitos adversos , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , China , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Estudos de Equivalência como Asunto , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Injeções , Insulina/metabolismo , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Secretagogos/administração & dosagem , Secretagogos/efeitos adversos , Resultado do Tratamento
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