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1.
Arch Physiol Biochem ; : 1-7, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291135

RESUMO

Context: Sodium glucose co-transporter 1 (SGLT1) triggers low glucose-induced glucagon-like peptide-1 (GLP-1) secretion. We reported that a two-week administration of 3-deoxyglucosone (3DG), an independent factor associated with the development of pre-diabetes, reduces basal GLP-1 secretion in rats. Objective: This study investigated the effects of 3DG on GLP-1 secretion and SGLT1 pathway under low-glucose conditions in STC-1 cells. Methods: STC-1 cells were incubated with phloridzin or 3DG at 5.6 mM glucose. SGLT1 expression (by western blotting), GLP-1 and cyclic adenosine monophosphate (cAMP) levels (by ELISA), and intracellular Ca2+ concentration (by Fluo-3/AM) were measured. Results: Phloridzin inhibited GLP-1 secretion. SGLT1 protein expression in STC-1 cells cultured in 5.6 mM glucose is higher than that in 25 mM glucose. Exposure to 3DG for 6 h reduced GLP-1 secretion, SGLT1 protein expression, and intracellular concentrations of cAMP and Ca2+. Conclusions: 3DG reduces low glucose-induced GLP-1 secretion in part through reduction of SGLT1 expression.

2.
Mol Biol Rep ; 46(5): 4799-4808, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31228040

RESUMO

Maintenance of glucose homeostasis is reciprocally regulated by insulin and glucagon-like peptide-1 (GLP-1). We previously reported that GLP-1 secretion in response to an oral glucose load was impaired following an administration of 3-deoxyglucosone (3DG), an independent factor associated with the development of pre-diabetes. Here we investigated the effects of 3DG on insulin signaling and insulin-induced GLP-1 secretion under high-glucose conditions in the enteroendocrine L cell line STC-1. STC-1 cells were exposed to 3DG (80, 300, and 1000 ng/ml) in the presence of 10-7 M insulin and 25 mM glucose. GLP-1 secretion was determined by ELISA, glucose uptake was monitored with 2-NBDG (2-(N(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose), glucose consumption was detected by glucoseoxidase, and protein expression of insulin signaling molecules was examined by western blot. Results showed a decrease in insulin-induced GLP-1 secretion and insulin receptor phosphorylation after 3DG treatment. Concomitantly, 3DG treatment inhibited insulin-induced phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway activation. In the presence, but not absence, of insulin, 3DG treatment decreased insulin-stimulated glucose consumption. Inhibition of PI3K with Wortmannin attenuated insulin-induced increment in glucose transporter 2 (GLUT2) expression and 2-NBDG uptake. Accordingly, insulin-induced increase in GLUT2 expression and 2-NBGD uptake was significantly inhibited by 3DG treatment. 3DG-mediated reduction in GLUT2 expression contributes to the attenuation of insulin-induced GLP-1 secretion under high-glucose conditions in part through the insulin-PI3K/Akt/GLUT2 pathway in STC-1 cells. We conclude that 3DG interferes with insulin signaling and attenuates insulin action on glucose-induced GLP-1 secretion in STC-1 cells.

3.
Mol Med Rep ; 19(6): 5015-5022, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059088

RESUMO

Sweet taste receptors (STRs) expressed on ß­cells stimulate insulin secretion in response to an increase in the circulating level of glucose, maintaining glucose homeostasis. 3­Deoxyglucosone (3DG), a highly reactive α­dicarbonyl compound, has been previously described as an independent factor associate with the development of prediabetes. In our previous study, pathological plasma levels of 3DG were induced in normal rats with a single intravenous injection of 50 mg/kg 3DG, and an acute rise in circulating 3DG induced glucose intolerance by impairing the function of pancreatic ß­cells. The present study aimed to investigate whether the deleterious effects of pathological plasma levels of 3DG on ß­cell function and insulin secretion were associated with STRs. INS­1 cells, an in vitro model to study rat ß­cells, were treated with various concentrations of 3DG (1.85, 30.84 and 61.68 mM) or lactisole (5 mM). Pancreatic islets were collected from rats 2 h after a single intravenous injection of 50 mg/kg 3DG + 0.5 g/kg glucose. The insulin concentration was measured by ELISA. The protein expression levels of components of the STR signaling pathways were determined by western blot analysis. Treatment with 3DG and 25.5 mM glucose for 1 h significantly reduced insulin secretion by INS­1 cells, which was consistent with the phenotype observed in INS­1 cells treated with the STR inhibitor lactisole. Accordingly, islets isolated from rats treated with 3DG exhibited a significant reduction in insulin secretion following treatment with 25.5 mM glucose. Furthermore, acute exposure of INS­1 cells to 3DG following treatment with 25.5 mM glucose for 1 h significantly reduced the protein expression level of the STR subunit taste 1 receptor member 3 and its downstream factors, transient receptor potential cation channel subfamily M member 5 and glucose transporter 2. Notably, islet tissues collected from rats treated with 3DG exhibited a similar downregulation of these factors. The present results suggested that acute exposure to pathologically relevant levels of 3DG in presence of high physiological levels of glucose decreased insulin secretion from ß­cells by, at least in part, downregulating the STR signaling pathway.


Assuntos
Desoxiglucose/análogos & derivados , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Derivados de Benzeno/farmacologia , Células Cultivadas , Desoxiglucose/farmacologia , Regulação para Baixo/efeitos dos fármacos , Transportador de Glucose Tipo 2/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo
4.
Arch Physiol Biochem ; 124(5): 430-435, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29277113

RESUMO

CONTEXT: Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion. OBJECTIVE: This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion. METHODS: STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels. RESULTS: Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reduction of intracellular cAMP levels. CONCLUSION: 3DG attenuates high glucose-stimulated GLP-1 secretion by reducing STR subunit expression and downstream signaling components.

5.
Mol Med Rep ; 16(3): 2976-2984, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28656301

RESUMO

ß­cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2­dicarbonyl compounds, such as 3­deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair ß­cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre­diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing ß­cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose­stimulated insulin secretion in cultured pancreas islets and INS­1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin­PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ∆Ins30­0/∆G30­0. In 3DG­treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased ß­cell function. This idea was further supported by these results that non­cytotoxic 3DG concentration obviously decreased glucose­stimulated insulin secretion in cultured pancreas islets and INS­1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS­1, PI3K­p85 and Akt in high glucose­induced INS­1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from ß­cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing ß­cell dysfunction, at least in part, through impairing IRS­1/PI3K/GLUT2 signaling.


Assuntos
Desoxiglucose/análogos & derivados , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Animais , Glicemia/metabolismo , Linhagem Celular , Desoxiglucose/administração & dosagem , Desoxiglucose/sangue , Desoxiglucose/farmacologia , Jejum/sangue , Teste de Tolerância a Glucose , Insulina/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
Exp Clin Endocrinol Diabetes ; 125(1): 4-11, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27658000

RESUMO

Secretion of glucagon-like peptide-1 has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. 3-Deoxyglucosone, a dietary composition, has been suggested as an independent factor for the development of prediabetes. A-pathophysiological very high condition of 3DG concentrations administered i. v. induced acute glucose intolerance in rats. In this study, to examine the acute effects of single intragastric administration of 3DG at dose of potentially single-meal intake on plasma glucose, insulin, glucagon, total GLP-1 and total GIP levels in response to a glucose load, OGTT was performed immediately in normal Kunming mice or Sprague-Dawleys rats after 3DG administration. GLP-1 secretion, intracellular cAMP levels and 2-NBDG uptake were examined in STC-1 cells exposured to 3DG. In rats, 20 mg/kg 3DG i.g. (3DG-20 i.g.) impaired glucose tolerance (P<0.05) with increased AUC (1 070±105.2 vs. 918.0±91.20, P<0.05). The mice treated with 3DG-20 i.g. exhibited a similar effect, independent of the effect of plasma 3DG concentration. 3DG-20 i.g. treatment reduced plasma insulin concentrations with decreased AUC (3 552±300.2 vs. 4 715±420.5, P<0.05) in rats whereas plasma glucagon levels were not significantly different. These changes occurred in conjunction with decreased plasma GLP-1 and GIP levels (P<0.05). Furthermore, non-cytotoxic 3DG concentrations directly reduced GLP-1 secretion in STC-1, at least in part, by decreasing intracellular cAMP level and glucose uptake. We demonstrated for the first time that single intragastric administration of 3DG resulted in acute reduction of incretin effect and glucose intolerance, which was associated with a decrease in the biological function of GLP-1 by decreasing GLP-1 secretion.


Assuntos
Desoxiglucose/análogos & derivados , Intolerância à Glucose/sangue , Incretinas/farmacologia , Estado Pré-Diabético/sangue , Animais , AMP Cíclico/metabolismo , Desoxiglucose/efeitos adversos , Desoxiglucose/farmacologia , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Intolerância à Glucose/induzido quimicamente , Insulina/sangue , Masculino , Camundongos , Estado Pré-Diabético/induzido quimicamente , Ratos
7.
Diabetol Metab Syndr ; 8: 78, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27956941

RESUMO

BACKGROUND: Our recent findings support the idea that 3-deoxyglucosone (3DG), a dietary composition, has been suggested as an independent factor for the development of prediabetes. Secretion of glucagon-like peptide-1 (GLP-1) has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. Since low oral bioavailability of 3DG has been indicated in a single administration study, in the present study we examined if 3DG is capable of accumulating in intestinal tissue of rats after 2-week administration of 3DG, and the 3DG treatment affects GLP-1 secretion and glucose tolerance. METHODS: Rats were administered by gastric gavage for 2 weeks. We measured 3DG contents of intestinal tissues (by HPLC), plasma levels of total GLP-1 (by ELISA), insulin and glucagon (both by radioimmunoassay) and blood glucose concentrations. The expressions of the sweet receptor subunits (TAS1R2, TAS1R3) and its downstream molecule TRPM5 in duodenum and colon tissues of rats were quantified by WB. We examined GLP-1 secretion in enteroendocrine STC-1 cells exposured to 3DG. RESULTS: 3DG treatment for 2 weeks increased 3DG content of intestinal tissues, fasting blood glucose concentration, and reduced plasma concentrations of GLP-1 and insulin at fasting and 15 and 180 min after the glucose load and oral glucose tolerance in conjunction with increased plasma glucagon concentrations. The expressions of TAS1R2, TAS1R3 and TRPM5 were shown to be reduced whereas 3DG treatment did not affect plasma dipeptidyl peptidase-4 activity, indicating an impaired GLP-1 secretion in 3DG-treated rats. This idea was further supported by the fact that exposure to 3DG directly decrease GLP-1 secretion in STC-1. CONCLUSION: It is the first demonstration that 3DG was capable of accumulating in intestinal tissue and thereby decreased secretion of GLP-1 and insulin in a similar manner. 3DG-treated rats developed impaired glucose regulation (IGR) with obviously pancreatic islet cell dysfunction. It is further concluded that a decrease in the biological function of GLP-1 resulting from the decreased GLP-1 secretion is the most likely mechanism for the impaired insulin secretion, which ultimately promoted the development of IGR. These results will also contribute to a better understanding of the significance for restoring physiological GLP-1 secretion.

8.
Mol Med Rep ; 13(5): 4506-12, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27052187

RESUMO

3-Deoxyglucosone (3DG), a highly reactive dicarbonyl intermediate generated during glycation, has been confirmed to be markedly elevated in the plasma of patients with diabetes. Our previous study found that there is an association between increasing accumulation of plasma 3DG and impaired glucose regulation in non-diabetic seniors (females, >50 years old; males, >55 years old). It was also found that 3DG led to impaired plasma glucose homeostasis in healthy mice, however, the mechanisms underlying the deleterious effect of 3DG in diabetes remain to be fully elucidated. The present study aimed to investigate the ability of 3DG to cause hepatic insulin resistance in a cell model by assessing glucose uptake and glycogen content. In addition, the molecular signaling events, including the phosphoinositide 3­kinase (PI3K)/AKT/glucose transporter 2 (GLUT2) and PI3K/AKT/glycogen synthase kinase­3 (GSK­3) pathways, which affect hepatic insulin resistance, were further investigated using Western blot analysis. The results showed that 3DG (10­300 ng/ml) had no significant effect on HepG2 cell viability, however, the viability of the HepG2 cells decreased with exposure to concentrations of 500 and 1,000 ng/ml. Treatment with non­cytotoxic 3DG concentrations resulted in decreased uptake of glucose and glycogen content with insulin stimulation, but not under basal conditions. The insulin­induced expression of GLUT2 and p­GSK­3 were eliminated by 3DG (80 and 300 ng/ml), in addition to inhibiting the phosphorylation of downstream effectors of the insulin signaling pathway, including insulin receptor substrate 1, PI3K and AKT. In conclusion, the findings of the present study indicated that the addition of exogenous 3DG directly contributed to the induction of insulin resistance by impairing insulin signaling in the HepG2 cells, which suggested that 3DG may be involved in worsening of the diabetic condition.


Assuntos
Desoxiglucose/análogos & derivados , Resistência à Insulina , Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Feminino , Células Hep G2 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
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