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1.
PLoS One ; 15(12): e0241349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33347462

RESUMO

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 µM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 µM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 µM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 µM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 µM), decreased ROS production (IC50 = 14.63 ± 3.18 µM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 µM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.


Assuntos
Benzopiranos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/farmacologia , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Óxido Nítrico/biossíntese , Ratos , Espécies Reativas de Oxigênio/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-33377427

RESUMO

Type 1 diabetes (T1D) is an autoimmune disorder caused by the destruction of insulin-secreting ß-cells.T1D is on the rise around the world. Exposure to polycyclic aromatic hydrocarbons (PAHs) including 2-aminoanthracene (2AA) is considered a contributor to TID increase. The contribution of the ingestion of 2AA toward T1D vulnerability is examined. 2AA is found in a variety of household products. Juvenile male Sprague Dawley rats ingested various amounts of 2AA contaminated diet for 12 weeks. Results showed marginal reduction in body weight gain for the 100 mg/kg treated animals. Glucose tolerance test (GTT) indicated no changes at six weeks. However, at week 12, both treated groups had higher levels of blood glucose than the control group. Serum insulin concentration was elevated in the 50 mg/kg group while reduced in the 100 mg/kg animals. Serum lactate dehydrogenase activity was elevated in treated groups. Evaluation of pancreatic inflammatory cytokines revealed overexpression of IL-1B, IL-6, and IL-7. Apoptotic genes in the pancreas of exposed rats were overly expressed. Histopathology and insulin immunohistochemistry data showed the presence of mesenteric vessels surrounded by lymphocyte and enlarged size of islet cells respectively in the high dose group. These results suggest 2AA ingestion may enhance T1D development.


Assuntos
Antracenos/toxicidade , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Exposição Dietética/análise , Poluentes Ambientais/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Interleucinas/genética , Masculino , Ratos , Ratos Sprague-Dawley , Risco
3.
N Engl J Med ; 383(21): 2007-2017, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33207093

RESUMO

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Área Sob a Curva , Peptídeo C/metabolismo , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Proinsulina/metabolismo , Adulto Jovem
4.
PLoS One ; 15(10): e0229430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33104727

RESUMO

Many compounds have the potential to harm pancreatic beta-cells; organochlorine pollutants belong to those compounds. In this work, we aimed to find markers of acute toxicity of p,p'-DDT exposure among proteins expressed in NES2Y human pancreatic beta-cells employing 2-D electrophoresis. We exposed NES2Y cells to a high concentration (150 µM, LC96 after 72 hours) of p,p'-DDT for 24 and 30 hours and determined proteins with changed expression using 2-D electrophoresis. We have found 22 proteins that changed their expression. They included proteins involved in ER stress (GRP78, and endoplasmin), mitochondrial proteins (GRP75, ECHM, IDH3A, NDUS1, and NDUS3), proteins involved in the maintenance of the cell morphology (EFHD2, TCPA, NDRG1, and ezrin), and some other proteins (HNRPF, HNRH1, K2C8, vimentin, PBDC1, EF2, PCNA, biliverdin reductase, G3BP1, FRIL, and HSP27). The proteins we have identified may serve as indicators of p,p'-DDT toxicity in beta-cells in future studies, including long-term exposure to environmentally relevant concentrations.


Assuntos
Biomarcadores/metabolismo , DDT/toxicidade , Células Secretoras de Insulina/citologia , Proteômica/métodos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eletroforese em Gel Bidimensional , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Espectrometria de Massas
5.
Sci Rep ; 10(1): 16497, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020504

RESUMO

The expression of short chain fatty acid receptors FFA2 and FFA3 in pancreatic islets raised interest in using them as drug targets for treating hyperglycemia in humans. This study aims to examine the efficacy of synthetic FFA2- and FFA3-ligands to modulate glucose-stimulated insulin secretion (GSIS) in human pseudoislets which display intact glucose responsiveness. The FFA2-agonists 4-CMTB and TUG-1375 inhibited GSIS, an effect reversed by the FFA2-antagonist CATPB. GSIS itself was not augmented by CATPB. The FFA3-agonists FHQC and 1-MCPC did not affect GSIS in human pseudoislets. For further drug evaluation we used mouse islets. The CATPB-sensitive inhibitory effect of 100 µM 4-CMTB on GSIS was recapitulated. The inhibition was partially sensitive to the Gi/o-protein inhibitor pertussis toxin. A previously described FFA2-dependent increase of GSIS was observed with lower concentrations of 4-CMTB (10 and 30 µM). The stimulatory effect of 4-CMTB on secretion was prevented by the Gq-protein inhibitor FR900359. As in human pseudoislets, in mouse islets relative mRNA levels were FFAR2 > FFAR3 and FFA3-agonists did not affect GSIS. The FFA3-agonists, however, inhibited GSIS in a pertussis toxin-sensitive manner in INS-1E cells and this correlated with relative mRNA levels of Ffar3 > > Ffar2. Thus, in humans, when FFA2-activation impedes GSIS, FFA2-antagonism may reduce glycemia.


Assuntos
Depsipeptídeos/farmacologia , Glucose/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Receptores de Superfície Celular/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Adulto , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Ácidos Graxos Voláteis/agonistas , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Insulina , Células Secretoras de Insulina/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Ratos , Transdução de Sinais
6.
J Med Chem ; 63(21): 12666-12681, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33124824

RESUMO

The field of bioactive lipids is ever expanding with discoveries of novel lipid molecules that promote human health. Adopting a lipidomic-assisted approach, two new families of previously unrecognized saturated hydroxy fatty acids (SHFAs), namely, hydroxystearic and hydroxypalmitic acids, consisting of isomers with the hydroxyl group at different positions, were identified in milk. Among the various regio-isomers synthesized, those carrying the hydroxyl at the 7- and 9-positions presented growth inhibitory activities against various human cancer cell lines, including A549, Caco-2, and SF268 cells. In addition, 7- and 9-hydroxystearic acids were able to suppress ß-cell apoptosis induced by proinflammatory cytokines, increasing the possibility that they can be beneficial in countering autoimmune diseases, such as type 1 diabetes. 7-(R)-Hydroxystearic acid exhibited the highest potency both in cell growth inhibition and in suppressing ß-cell death. We propose that such naturally occurring SHFAs may play a role in the promotion and protection of human health.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Citocinas/farmacologia , Ácidos Graxos/síntese química , Ácidos Graxos/química , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Leite/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ácidos Esteáricos/farmacologia , Estereoisomerismo , Espectrometria de Massas em Tandem
7.
Am J Physiol Endocrinol Metab ; 319(6): E1074-E1083, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044845

RESUMO

This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major ß-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/veterinária , Doenças do Cão/metabolismo , Glucagon/farmacologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemiantes , Insulina , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Cães , Epinefrina/sangue , Células Secretoras de Glucagon/efeitos dos fármacos , Técnica Clamp de Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Norepinefrina/sangue , Polipeptídeo Pancreático/metabolismo
8.
J Med Chem ; 63(21): 12595-12613, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33125843

RESUMO

Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving ß-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases ß-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life (t1/2) is short, and its body weight reducing activity is limited. Here, we report the discovery of a series of novel GLP-1R/CCK-2R dual agonists. Starting from Xenopus GLP-1, dual cysteine mutation was conducted followed by covalent side chain stapling and albumin binder incorporation, resulting in a stabilized secondary structure, increased agonist potency, and improved stability. Further C-terminal conjugation of gastrin-6 generated GLP-1R/CCK-2R dual agonists, among which 6a and 6b showed higher stability and hypoglycemic activity than liraglutide and ZP3022. Desirably, 6a and 6b exhibited prominent metabolic benefits in diet-induced obesity mice without causing nausea responses and exerted considerable effects on ß-cell restoration in db/db mice. These preclinical studies suggest the potential role of GLP-1R/CCK-2R dual agonists as effective agents for treating diabetes and related metabolic disorders.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/química , Receptor de Colecistocinina B/agonistas , Proteínas de Xenopus/agonistas , Xenopus laevis/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Meia-Vida , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Obesidade/metabolismo , Obesidade/patologia , Peptídeos/síntese química , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-Atividade , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo
9.
Nutr Metab Cardiovasc Dis ; 30(11): 1870-1881, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32994121

RESUMO

AIMS: Diabetes mellitus (DM) is a disorder of heterogeneous etiology marked by persistent hyperglycemia. Exogenous insulin is the only treatment for type 1 diabetes (T1D). Islet transplantation is a potential long cure for T1D but is disapproved due to the possibility of immune rejection in the later stage. The approaches used for treating type 2 diabetes (T2D) include diet restrictions, weight management and pharmacological interventions. These procedures have not been able to boost the quality of life for diabetic patients owing to the complexity of the disorder. DATA SYNTHESIS: Hence, research has embarked on permanent ways of managing, or even curing the disease. One of the possible approaches to restore the pancreas with new glucose-responsive ß-cells is by their regeneration. Regeneration of ß-cells include islet neogenesis, dedifferentiation, and trans-differentiation of the already differentiated cells. CONCLUSIONS: This review briefly describes the islet development, functions of ß-cells, mechanism and factors involved in ß-cell death. It further elaborates on the potential of the existing and possible therapeutic modalities involved in the in-vivo replenishment of ß-cells with a focus on exercise, diet, hormones, small molecules, and phytochemicals.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Comportamento de Redução do Risco , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Dieta Saudável , Exercício Físico , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Recuperação de Função Fisiológica
10.
PLoS One ; 15(9): e0236081, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960890

RESUMO

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of ß cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of ß cells. The purpose of this study was to assess whether an analogue of FR258900 can influence ß cell function. BF142 (Meso-Dimethyl 2,3-bis[(E)-3-(4-acetoxyphenyl)prop-2-enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence ß cell function and can support the insulin producing ability of ß cells.


Assuntos
Cinamatos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutaratos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ácido Succínico/farmacologia , Animais , Linhagem Celular Tumoral , Cinamatos/química , Inibidores Enzimáticos/química , Glucose/metabolismo , Glutaratos/química , Glicogênio Fosforilase/metabolismo , Glicólise/efeitos dos fármacos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Metilação , Camundongos , Ácido Succínico/química
11.
Life Sci ; 263: 118490, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32979357

RESUMO

AIMS: The development of type 1 diabetes is associated with inflammatory lesion of the pancreatic islets, known as insulitis. In this study, we focused on the protective effects of acarbose against insulitis in streptozotocin (STZ)-induced diabetic mice and the underlying mechanisms. MAIN METHODS: The mouse models were established via intraperitoneal injection of multiple low-dose STZ. Blood glucose level and body weight were measured. The severity of insulitis and inflammatory parameters in pancreatic tissues were evaluated. Insulin levels in pancreas and serum were also assessed. In vitro, MIN6 ß cells were exposed to pro-inflammatory cytokines to assess the protective effects of acarbose. Cell function and apoptosis were evaluated. KEY FINDINGS: We found that acarbose administration by gavage reduced the severity of insulitis and improved insulin levels in the experimental diabetic mice. ELISA revealed decreased levels of the inflammatory response markers IL-1ß and TNF-α in mouse pancreatic tissues following acarbose treatment. In vitro, acarbose increased cell viability, decreased cell apoptosis, and improved GSIS in MIN6 ß cells exposed to pro-inflammatory cytokines. In addition, caspase-3 level and p-p53/p53 ratio in ß cells were reduced by acarbose treatment. SIGNIFICANCE: Taken together, these results revealed a novel function of acarbose in attenuating insulitis. The protective effects of acarbose elicited in vitro and in vivo were shown to be mediated, at least in part, through its anti-inflammatory action.


Assuntos
Acarbose/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Relação Dose-Resposta a Droga , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Am J Physiol Cell Physiol ; 319(5): C922-C932, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32936698

RESUMO

The role of hypoxia-inducible factor (HIF)-1 in pancreatic ß-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), ß-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic ß-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in ß-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in ß-HIF-1-/- mice. IH-evoked ß-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic ß-cell dysfunction.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia/genética , NADPH Oxidase 4/genética , Oxigênio/farmacologia , Apneia Obstrutiva do Sono/genética , Animais , Digoxina/farmacologia , Modelos Animais de Doenças , Glucose/metabolismo , Heterozigoto , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Hipóxia/metabolismo , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Ativação Transcricional
13.
PLoS One ; 15(8): e0237669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810137

RESUMO

Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sobrevivência Celular/genética , Células Secretoras de Insulina/patologia , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Ratos , Estreptozocina/toxicidade , Tunicamicina/toxicidade
14.
Ecotoxicol Environ Saf ; 205: 111154, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810643

RESUMO

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Gestacional/induzido quimicamente , Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Proteína Forkhead Box M1/metabolismo , Exposição Materna/efeitos adversos , Fator de Transcrição STAT1/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Fosforilação , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT1/genética , Transdução de Sinais
15.
Life Sci ; 259: 118268, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32800830

RESUMO

AIM: Cadmium is a persistent ubiquitous environmental toxicant that elicits several biological defects on delicate body organs. Growing evidence suggests that cadmium (Cd) may perturb signaling pathways to induce oxidative pancreatitis. Thus, we explored whether hesperidin, a flavonone, could mitigate Cd-induced oxidative stress-mediated inflammation and pancreatitis in Wistar rats. MAIN METHODS: Forty (40) rats randomly assigned to 5 groups (n = 8) were administered normal saline or hesperidin (Hsp) followed by Cd intoxication for 28 days. KEY FINDINGS: Cadmium accumulated in the pancreas of rats, and markedly decreased insulin, pancreatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and glutathione (GSH) level. Cadmium considerably increased malondialdehyde (MDA), serum lipase and amylase activities. Cadmium induced pancreatic pro-inflammation via over-expression of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-κB), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), along with histopathological alterations. Hesperidin prominently decreased serum amylase and lipase activities, and markedly increased insulin level, pancreatic antioxidant defense mechanism, whereas iNOS, NF-κB, IL-6 and TNF-α levels significantly decreased. Changes in histology confirmed our biochemical findings. SIGNIFICANCE: Our findings suggest that Cd induced pancreatitis via pro-inflammation and oxidative stress; Hsp, thus, protects against Cd-induced pancreatitis via attenuation of oxidative stress and proinflammatory responses in pancreas.


Assuntos
Hesperidina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Cádmio/toxicidade , Catalase/metabolismo , Glutationa/metabolismo , Hesperidina/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/fisiologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/metabolismo , Substâncias Protetoras , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
16.
Toxicol Appl Pharmacol ; 404: 115181, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758488

RESUMO

Exposure to ambient fine particulate matter (PM2.5) elicits various abnormalities in glycaemic control and thus correlates with type 2 diabetes. Intermittent fasting is an emerging treatment for type 2 diabetes. This study, therefore, tested whether intermittent fasting ameliorates PM2.5 exposure-induced abnormalities in glycaemic control. To this end, C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 16 weeks and concurrently subject to ad libitum feeding or intermittent fasting. The food intake assessment showed that CAP exposure transiently reduced food intake in ad libitum fed mice, but persistently reduced food intake in intermittently fasted mice. In contrast, CAP exposure persistently promoted mouse weight gain in ad libitum fed mice, while intermittent fasting blocked this CAP exposure-induced weight gain. The glucose homeostasis assessments revealed that CAP exposure elicited insulin resistance and glucose intolerance and meanwhile increased glucose-induced insulin secretion (GIIS). The insulin resistance and glucose intolerance, but not the increase in GIIS, induced by CAP exposure were blocked by intermittent fasting. Analysis of Akt phosphorylation, the indicator of local insulin signaling, showed that CAP exposure reduced insulin signaling in the liver and adipose tissues but not in the skeletal muscle. Intermittent fasting blocked CAP exposure-induced insulin resistance in the liver but not in the adipose tissues. The present study demonstrates that intermittent fasting ameliorates PM2.5 exposure-induced insulin resistance and glucose intolerance, strongly supporting that it may be used to prevent type 2 diabetes due to exposure to PM2.5.


Assuntos
Glicemia/efeitos dos fármacos , Privação de Alimentos , Material Particulado/toxicidade , Animais , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo
17.
Toxicol Appl Pharmacol ; 406: 115189, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800772

RESUMO

The potential therapeutic effect of histone deacetylase 3 (HDAC3) pharmacologic inhibition on diabetes has been focused recently. RGFP966, as a highly-selective HDAC3 inhibitor, its possible roles and underlying mechanism in the treatment of diabetes needs to be clarified. In this study, low-dose streptozotocin (STZ)-induced pre-diabetic mice were used to test the regulatory ability of RGFP966 in blood glucose and insulin. We isolated the islets both from normal C57BL/6 J mice and KKAy mice with spontaneous type 2 diabetes to determine the potency of RGFP966 on glucose-stimulated insulin secretion. NIT-1 pancreatic ß-cells induced by sodium palmitate (PA) were applied to identify the protective effects of RGFP966 against ß-cell apoptosis. The results showed that administration of RGFP966 in the pre-diabetic mice not only significantly reduced hyperglycemia, promoted phase I insulin secretion, improved morphology of islets, but also increased glucose infusion rate (GIR) during hyperglycemic clamp test. When treated in vitro, RGFP966 enhanced insulin secretion and synthesis in islets of normal C57BL/6J mice and diabetic KKAy mice. In addition, it partially attenuated PA-induced apoptosis in NIT-1 cells. Therefore, our research suggests that RGFP966, probably through selective inhibition of HDAC3, might serve as a novel potential preventive and therapeutic candidate for diabetes.


Assuntos
Acrilamidas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Hipoglicemiantes/uso terapêutico , Fenilenodiaminas/uso terapêutico , Acrilamidas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Fenilenodiaminas/farmacologia
18.
Chem Biol Interact ; 328: 109197, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32710900

RESUMO

The present study was undertaken to assess the effect of imatinib mesylate; a tyrosine kinase inhibitor and a well-known anticancer with numerous medical benefits on blood sugar levels, insulin, and glucagon secretion in an experimental model of STZ-induced diabetes mellitus. Type 1 diabetes mellitus (T1DM) was induced by a single I.P. injection of Streptozotocin (STZ) (50 mg/kg) in male Sprague-Dawley rats. Daily oral imatinib (10 mg/kg) and (20 mg/kg) for 4 weeks induced a significant attenuation in signs of DM in rats reflected in their assessed lab values. Biomarkers of cell injury, tissue necrosis, and apoptosis; caspase-3 were significantly reduced with imatinib treatment. Furthermore, pancreatic antioxidants defenses of which; superoxide dismutase (SOD) and catalase activities, reduced glutathione (GSH) concentration, and total antioxidant capacity have significantly improved with a simultaneous reduction in malondialdehyde (MDA) content. Histopathologically, imatinib treatment was associated with a minimal pancreatic injury and marked restoration of insulin content in ß-cells. Moreover, imatinib treatment revealed a significant reduction in the infiltration of macrophages in ß-cells. Imatinib's ameliorative impact on DM may be attributed to it's mediated protection and preservation of pancreatic ß-cells function and the improvement in serum insulin levels and hence the improvement of blood glucose and overall glycemic control.


Assuntos
Diabetes Mellitus Experimental/patologia , Mesilato de Imatinib/farmacologia , Células Secretoras de Insulina/metabolismo , Administração Oral , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antioxidantes/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Catalase/metabolismo , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Glucagon/sangue , Glutationa/metabolismo , Insulina/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Estreptozocina , Superóxido Dismutase/metabolismo
19.
PLoS One ; 15(7): e0236603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706828

RESUMO

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.


Assuntos
Biomarcadores/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proinsulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
20.
J Pharmacol Exp Ther ; 375(1): 10-20, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32665318

RESUMO

The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion. This study investigates how different key points of the stimulus-secretion coupling in mouse islets and ß-cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca2+]c in islets at a concentration of 100 µM along with a stimulating glucose concentration. DXO and DXM increased insulin secretion approximately 30-fold at a substimulatory glucose concentration (3 mM). Patch-clamp experiments revealed that 100 µM DXM directly inhibited KATP channels by about 70%. Of note, DXM decreased the current through L-type Ca2+ channels about 25%, leading to a transient reduction in Ca2+ action potentials. This interaction might explain why elevating DXM to 500 µM drastically decreased insulin release. DXO inhibited KATP channels almost equally. In islets of KATP channel-deficient sulfonylurea receptor 1 knockout mice, the elevating effects of 100 µM DXM on [Ca2+]c and insulin release were completely lost. By contrast, 100 µM DXO still increased glucose-stimulated insulin release around 60%. In summary, DXM-induced alterations in stimulus-secretion coupling of wild-type islets result from a direct block of KATP channels and are partly counteracted by inhibition of L-type Ca2+ channels. The stimulatory effect of DXO seems to be based on a combined antagonism on KATP channels and NMDA receptors and already occurs under resting conditions. Consequently, both compounds seem not to be suitable candidates for treatment of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the use of dextromethorphan as an antidiabetic drug can cause unpredictable alterations in insulin secretion by direct interaction with KATP and L-type Ca2+ channels besides its actual target, the NMDA receptor.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Dextrometorfano/farmacologia , Dextrorfano/farmacologia , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Canais KATP/antagonistas & inibidores , Animais , Células Cultivadas , Feminino , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Canais KATP/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Receptores Sulfonilureia/genética
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