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1.
Anat Sci Int ; 95(4): 523-539, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32476103

RESUMO

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ß-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic ß-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous ß-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost ß-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.


Assuntos
Polpa Dentária/citologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Pâncreas/fisiologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Movimento Celular , Sobrevivência Celular , Modelos Animais de Doenças , Transportador de Glucose Tipo 2/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Ratos , Ratos Sprague-Dawley , Regeneração , Estreptozocina
2.
J Pharmacol Sci ; 143(3): 188-198, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414691

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that causes morbidity associated with metabolic syndrome. NAFLD is a worldwide problem and represents a major cause of liver injury, which can lead to liver cell death. We investigated the effects of nonivamide (pelargonic acid vanillylamide, PAVA; 1 mg/kg) and rosuvastatin (RSV; 10 mg/kg) on hepatic steatosis induced by a high-fat diet (HFD). Male Sprague-Dawley rats were fed a HFD for 16 weeks then received PAVA or RSV for 4 additional weeks. We examined the metabolic parameters, function, fat content, histological alterations, reactive oxygen species production, and apoptotic cell death of the liver, in addition to the expression of the following important molecules: transient receptor potential cation channel subfamily V member 1 (TRPV1) phosphorylation of sterol regulatory element binding protein (pSREBP-1c/SREBP-1c), total and membrane glucose transporter 2 (GLUT2), 4-hydroxynonenal (4-HNE), and cleaved caspase-3. HFD-induced hepatic steatosis was associated with significantly increased morphological disorganization, injury markers, oxidative stress, lipid peroxidation, and apoptosis. However, metabolic dysfunction and hepatic injury were reduced by RSV and PAVA treatment. PAVA regulated lipid deposition, improved insulin resistance, and decreased oxidative stress and apoptotic cell death. Therefore, PAVA represents a promising therapeutic approach for treating metabolic disorders in patients with NAFLD.


Assuntos
Capsaicina/análogos & derivados , Capsicum/química , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Fitoterapia , Aldeídos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Capsaicina/administração & dosagem , Capsaicina/isolamento & purificação , Capsaicina/farmacologia , Caspase 3/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Canais de Cátion TRPV/metabolismo
3.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R96-R105, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459971

RESUMO

The rectal gland of the spiny dogfish Squalus acanthias secretes a salt solution isosmotic with plasma that maintains the salt homeostasis of the fish. It secretes salt against an electrochemical gradient that requires the expenditure of energy. Isolated rectal glands perfused without glucose secrete salt, albeit at a rate about 30% of glands perfused with 5 mM glucose. Gradually reducing the glucose concentration is associated with a progressive decrease in the secretion of chloride. The apparent Km for the exogenous glucose-dependent chloride secretion is around 2 mM. Phloretin and cytochalasin B, agents that inhibit facilitated glucose carriers of the solute carrier 2 (Slc2) family such as glucose transporter 2 (GLUT2), do not inhibit the secretion of chloride by the perfused rectal glands. Phloridzin, which inhibits Slc5 family of glucose symporters, or α-methyl-d-glucoside, which competitively inhibits the uptake of glucose through Slc5 symporters, inhibit the secretion of chloride. Thus the movement of glucose into the rectal gland cells appears to be mediated by a sodium-glucose symporter. Sodium-glucose cotransporter 1 (SGLT1), the first member of the Slc5 family of sodium-linked glucose symporters, was cloned from the rectal gland. No evidence of GLUT2 was found. The persistence of secretion of chloride in the absence of glucose in the perfusate suggests that there is an additional source of energy within the cells. The use of 2-mercapto-acetate did not result in any change in the secretion of chloride, suggesting that the oxidation of fatty acids is not the source of energy for the secretion of chloride. Perfusion of isolated glands with KCN in the absence of glucose further reduces the secretion of chloride but does not abolish it, again suggesting that there is another source of energy within the cells. Glucose was measured in the rectal gland cells and found to be at concentrations in the range of that in the perfusate. Glycogen measurements indicated that there are significant stores of glucose in the rectal gland. Moreover, glycogen synthase was partially cloned from rectal gland cells. The open reading frame of glycogen phosphorylase was also cloned from rectal gland cells. Measurements of glycogen phosphorylase showed that the enzyme is mostly in its active form in the cells. The cells of the rectal gland of the spiny dogfish require exogenous glucose to fully support the active secretion of salt. They have the means to transport glucose into the cells in the form of SGLT1. The cells also have an endogenous supply of glucose as glycogen and have the necessary elements to synthesize, store, and hydrolyze it.


Assuntos
Cloretos/metabolismo , Glucose/metabolismo , Glândula de Sal/metabolismo , Squalus/metabolismo , Animais , Sequência de Bases , Glucose/farmacologia , Transportador de Glucose Tipo 2/metabolismo , Glicogênio/metabolismo , Glicogênio Fosforilase/metabolismo , Glicogênio Sintase/metabolismo , Homeostase , Técnicas In Vitro , Cianeto de Potássio/farmacologia , Glândula de Sal/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo
4.
Biomed Res Int ; 2020: 7103053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051828

RESUMO

Mesenchymal stem cells (MSCs) can be differentiated in vitro to form insulin-producing cells (IPCs). However, the proportion of induced cells is modest. Extracts from injured pancreata of rodents promoted this differentiation, and three upregulated proteins were identified in these extracts. The aim of this study was to evaluate the potential benefits of adding these proteins to the differentiation medium alone or in combination. Our results indicate that the proportion of IPCs among the protein(s)-supplemented samples was significantly higher than that in the samples with no added proteins. The yield from samples supplemented with PRDX6 alone was 4-fold higher than that from samples without added protein. These findings were also supported by the results of fluorophotometry. Gene expression profiles revealed higher levels among protein-supplemented samples. Significantly higher levels of GGT, SST, Glut-2, and MafB expression were noted among PRDX6-treated samples. There was a stepwise increase in the release of insulin and c-peptide, as a function of increasing glucose concentrations, indicating that the differentiated cells were glucose sensitive and insulin responsive. PRDX6 exerts its beneficial effects as a result of its biological antioxidant properties. Considering its ease of use as a single protein, PRDX6 is now routinely used in our differentiation protocols.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Insulina/biossíntese , Células-Tronco Mesenquimais/metabolismo , Peroxirredoxina VI/metabolismo , Peroxirredoxina VI/farmacologia , Peptídeo C/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Fator de Transcrição MafB/metabolismo , Peroxirredoxina VI/genética , Somatostatina/metabolismo , Transcriptoma , gama-Glutamiltransferase/metabolismo
5.
Biochem Biophys Res Commun ; 522(1): 14-20, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31735337

RESUMO

Diabetes mellitus is a metabolic disease characterized by an increase in blood glucose levels due to lack of insulin secretion. Previous studies have confirmed that PICK1 is critical for both ß-cell function and glucose homeostasis. The aim of this study was to investigate the role of PICK1 in response to high glucose-induced ß-cell dysfunction and the molecular mechanism of regulation of PICK1. We found that overexpression of PICK1 in db/db diabetic mice significantly improved glucose tolerance and increased insulin release. High glucose treatment of Min6 cells inhibited PICK1 expression, and overexpression of PICK1 protected against high glucose-induced pancreatic cell dysfunction. Activation of the PI3K/Akt pathway by PICK1 in Min6 cells resulted in increased GLUT2 expression and this increase was abolished by treatment with a PI3K-specific inhibitor. Further, we showed that expression of PICK1 is negatively regulated by miR-139-5p through directly targeting its 3'UTR. These data suggested that PICK1 may participate in the functional protection of pancreatic ß-cells through PI3K/Akt signaling, promote insulin secretion, and delay the progression of diabetes, and is negatively regulated by miR-139-5p, further clarifying the regulation of pancreatic ß-cell function.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Morte Celular , Glucose/metabolismo , Células Secretoras de Insulina/citologia , MicroRNAs/genética , Transdução de Sinais , Animais , Linhagem Celular , Dieta Hiperlipídica , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 2/metabolismo , Homeostase , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
J Biochem Mol Toxicol ; 34(1): e22419, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31702098

RESUMO

Ionic liquids (ILs) as green alternatives for volatile organic solvents are increasingly used in commercial applications. It is necessary to explore the cytotoxic mechanism of ILs to reduce the risk to human health. For this purpose, cell viability, apoptosis, cytochrome P450 3A4 (CYP3A4), glucose transporter type 2 (GLUT2), and microRNA-122 (miR-122) gene expression in HepG2 cells was evaluated after IL exposure. The results showed that ILs reduced the viability of HepG2 cells through apoptotic cell death. Moreover, ILs markedly upregulated the transcription and protein levels of CYP3A4, but did not affect the expression of GLUT2 in either messenger RNA level or protein level. Finally, ILs increased the expression of miR-122 and inhibition of miR-122 with miR-122 inhibitor blocked ILs-induced apoptosis in HepG2 cells. This finding may contribute to an increased understanding of the in vitro molecular toxicity mechanism of ILs to further understand IL-related human health risks.


Assuntos
Apoptose/efeitos dos fármacos , Brometos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Imidazóis/farmacologia , MicroRNAs/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Células Hep G2 , Humanos
7.
Biochem Biophys Res Commun ; 522(4): 1022-1029, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31813547

RESUMO

Genome wide association study for type 2 diabetes discovered TMEM163 as a risk locus. Perturbations in TMEM163 expression was reported to be associated with impaired intracellular zinc homeostasis. Physiological concentration of zinc is instrumental to maintain insulin storage and functionality in pancreatic ß cells. We found abundant TMEM163 expression in human pancreas, both at transcriptional and translational levels. Knockdown of endogenous Tmem163 in MIN6 cells resulted in increased intracellular zinc and total insulin content, coupled with compromised insulin secretion at high glucose stimuli. Furthermore, Tmem163 knockdown led to enhanced cellular glucose uptake. Upon next generation sequencing, one-third of the studied T2D patients were found to have a novel missense variant in TMEM163 gene. Study participants harboring this missense variant displayed a trend of higher glycemic indices. This is the first report on exploring the biological role of TMEM163 in relation to T2D pathophysiology.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Insulina/metabolismo , Proteínas de Membrana/metabolismo , Zinco/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Éxons/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Índia , Espaço Intracelular/metabolismo , Mutação com Perda de Função/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética
8.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R245-R255, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31746628

RESUMO

The mucosal-to-serosal flux of 14C 3-O-methyl-d-glucose was compared against the electrogenic transport of d-glucose across ex vivo intestinal segments of Nile tilapia, rainbow trout, and pig in Ussing chambers. The difference in affinities (Km "fingerprints") between pig flux and electrogenic transport of glucose, and the absence of this difference in tilapia and trout, suggest two absorptive pathways in the pig and one in the fish species examined. More specifically, the total mucosal-to-serosal flux revealed a super high-affinity, high-capacity (sHa/Hc) total glucose transport system in tilapia; a super high-affinity, low-capacity (sHa/Lc) total glucose transport system in trout and a low-affinity, low-capacity (La/Lc) total glucose transport system in pig. Comparatively, electrogenic glucose absorption revealed similar Km in both fish species, with a super high-affinity, high capacity (sHa/Hc) system in tilapia; a super high-affinity/super low-capacity (sHa/sLc) system in trout; but a different Km fingerprint in the pig, with a high-affinity, low-capacity (Ha/Lc) system. This was supported by different responses to inhibitors of sodium-dependent glucose transporters (SGLTs) and glucose transporter type 2 (GLUT2) administered on the apical side between species. More specifically, tilapia flux was inhibited by SGLT inhibitors, but not the GLUT2 inhibitor, whereas trout lacked response to inhibitors. In contrast, the pig responded to inhibition by both SGLT and GLUT2 inhibitors with a higher expression of GLUT2. Altogether, it would appear that two pathways are working together in the pig, allowing it to have continued absorption at high glucose concentrations, whereas this is not present in both tilapia and trout.


Assuntos
3-O-Metilglucose/metabolismo , Proteínas de Peixes/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Animais , Ciclídeos , Feminino , Transportador de Glucose Tipo 2/genética , Potenciais da Membrana , Oncorhynchus mykiss , Proteínas de Transporte de Sódio-Glucose/genética , Especificidade da Espécie , Sus scrofa
9.
J Trace Elem Med Biol ; 58: 126434, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31778961

RESUMO

BACKGROUND: Chromium picolinate (CrPic) is commonly used to reduce muscle fatigue after exercise. We aimed to elucidate the effects of CrPic on glucose and lipid metabolism and the expression of glucose transporters in exercised rats. METHODS: Forty-two male Wistar rats (8-week-old) were distributed into six groups (n = 7) as follows: Control, CrPic, Chronic Exercise (CEx), CEx + CrPic, Acute Exercise (AEx), and AEx + CrPic. CEx consists of 30 m/min, 30 min/day, and 5 days/week for 6 weeks. CrPic was supplemented at 400 µg elemental Cr/kg of diet for 6 weeks. In the AEx groups, animals were run on the treadmill at 30 m/min until exhaustion. RESULTS: CEx significantly lowered blood glucose (BG), total cholesterol (TC) and triglyceride (TG) levels, but elevated insulin concentration (IC), compared with control (P < 0.05). CEx significantly decreased the level of malondialdehyde (MDA) in the serum, liver, and muscle while AEx elevated it (P < 0.001 for all). CrPic significantly decreased BG, TC, TG levels, and increased IC with a remarkable effect in CEx rats (P < 0.01). CrPic also significantly reduced serum, liver, and muscle MDA levels (P < 0.001). Both AEx and CEx increased the expression of liver glucose transporter 2 (GLUT-2) and muscle GLUT-4 with the highest level in CEx rats (P < 0.05). Moreover, CrPic supplementation significantly elevated GLUT-2 and GLUT-4 expressions in the liver and muscle of sedentary and exercise-treated rats (P < 0.05). CONCLUSION: CrPic improves various metabolic parameters and reduces oxidative stress in CEx and AEx rats by decreasing BG, TC, TG, MDA levels in serum and elevating GLUT-2 and GLUT-4 expression in the liver and muscle samples. The efficacy of CrPic was more pronounced in CEx rats.


Assuntos
Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Condicionamento Físico Animal , Ácidos Picolínicos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Ratos Wistar
10.
Ann Clin Lab Sci ; 49(6): 785-793, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31882430

RESUMO

Diabetes-induced hyperglycemia has a direct damaging effect on ovarian function. Despite its deadly impact on ovaries, the mechanism of this condition has not been fully elucidated. Glucose transporters are involved in glucose uptake and utilization. Many transporters have been detected in the ovaries, but their roles in diabetes-induced ovarian impairment are still unclear. In this study, the goal is to analyze glucose transporter expression in the ovarian follicles of type 1 diabetes mellitus patients and determine their roles within ovarian function impairment. The ovarian function of a mouse model of type 1 diabetes mellitus was evaluated by observing its estrus cycle, follicular development, and ovulation. Subtypes of the glucose transporter (GLUT2, GLUT3, GLUT4, SGLT1, and SGLT2), adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK (Thr172) were found to be simultaneously present in follicle cells. Compared with nondiabetic control mice, the diabetic mice showed a dysregulated estrus cycle and a significantly higher number of abnormal ova. Furthermore, the expression of multiple glucose transporters was lower than that of phosphorylated AMPK. Phosphorylated AMPK possessed more follicular granulosa cells and oocytes of diabetic mice than in those of the control mice. These results suggest that diabetes-induced hyperglycemia reduces the capability of ovarian follicle cells by downregulating glucose transporter expression, causing decreased glucose uptake and energy deprivation. This impact can potentially impair egg maturation and ovulation.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperglicemia/fisiopatologia , Folículo Ovariano/metabolismo , Ovário/fisiopatologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Feminino , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos Endogâmicos ICR , Ovário/metabolismo , Ovulação , Fosforilação , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
11.
Biomed Res Int ; 2019: 4568039, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781615

RESUMO

Chemical structures derived from marine foods are highly diverse and pharmacologically promising. In particular, chitooligosaccharides (COS) present a safe pharmacokinetic profile and a great source of new bioactive polymers. This review describes the antioxidant, anti-inflammatory, and antidiabetic properties of COS from recent publications. Thus, COS constitute an effective agent against oxidative stress, cellular damage, and inflammatory pathogenesis. The mechanisms of action and targeted therapeutic pathways of COS are summarized and discussed. COS may act as antioxidants via their radical scavenging activity and by decreasing oxidative stress markers. The mechanism of COS antidiabetic effect is characterized by an acceleration of pancreatic islets proliferation, an increase in insulin secretion and sensitivity, a reduction of postprandial glucose, and an improvement of glucose uptake. COS upregulate the GLUT2 and inhibit digestive enzyme and glucose transporters. Furthermore, they resulted in reduction of gluconeogenesis and promotion of glucose conversion. On the other hand, the COS decrease inflammatory mediators, suppress the activation of NF-κB, increase the phosphorylation of kinase, and stimulate the proliferation of lymphocytes. Overall, this review brings evidence from experimental data about protective effect of COS.


Assuntos
Anti-Inflamatórios , Quitina/análogos & derivados , Depuradores de Radicais Livres , Hipoglicemiantes , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Quitina/farmacocinética , Quitina/uso terapêutico , Depuradores de Radicais Livres/farmacocinética , Depuradores de Radicais Livres/uso terapêutico , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico
12.
Curr Pharm Des ; 25(32): 3418-3433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613724

RESUMO

BACKGROUND: Glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium- dependent glucose transporter (SGLT1) and the facilitated-transporter glucose transporter (GLUT2). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2. METHODS: Phenolic inhibition of intestinal glucose transport has been examined using brush border membrane vesicles from rats, pigs or rabbits, Xenopus oocytes and more recently Caco-2 cells, which are the most promising for harmonizing in vitro experiments. RESULTS: Phenolic concentrations above 100 µM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2, while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1. Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2. CONCLUSION: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition, and also the inhibition of phenolic acids remains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters. A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interactions is also included.


Assuntos
Glucose/metabolismo , Mucosa Intestinal/metabolismo , Fenóis/metabolismo , Animais , Transporte Biológico , Células CACO-2 , Transportador de Glucose Tipo 2/metabolismo , Humanos , Coelhos , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Suínos
13.
Phytomedicine ; 65: 153101, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31648126

RESUMO

BACKGROUND: Oestrogen deficiency leads to metabolic disturbances such as insulin resistance and impairment of adipose tissue or lipid metabolism. Marantodes pumilum (Blume) Kuntze (Primulaceae) is believed to have phytoestrogenic properties and is claimed to have beneficial effects in the treatment of diabetes mellitus (DM), but the mechanism behind its phytoestrogenic effects on estrogen-deficient diabetic condition have not been fully examined. PURPOSE: The present study investigated the effects of oral treatment with M. pumilum var. alata (MPA) extracts on the estrogen receptor, metabolic characteristics and insulin signaling pathway in pancreas and liver of ovariectomised nicotidamide streptozotocin-induced diabetes in female rats. MATERIALS AND METHODS: Ovariectomised diabetic (OVXS) Sprague-Dawley rats were orally administered with either aqueous leaf extract and ethanol (50%) stem-root extract of MPA (50 or 100 mg/kg) respectively for 28 days. Metabolic parameters were evaluated by measuring fasting blood glucose, serum insulin, oral glucose and insulin tolerance test. Distribution and expression level of insulin, oxidative stress and inflammatory marker in the pancreatic islets and liver were evaluated by immunohistochemistry and western blot, respectively. RESULTS: Oral treatment with aqueous leaf and ethanol (50%) stem-root extracts of MPA (100 mg/kg) significantly reversed the elevated fasting blood glucose, impaired glucose and insulin tolerance. The protein expression of insulin, glucose transporter (GLUT-2 and GLUT-4) increased in the pancreatic islets and liver. Furthermore, marked improvement in the tissue morphology following treatment with MPA was observed. Similarly, the western blots analysis denotes improved insulin signaling in the liver and decreased reactive oxygen species producing enzymes, inflammatory and pro-apoptotic molecules with MPA treatment. CONCLUSIONS: Taken together, this work demonstrate that 100 mg/kg of aqueous leaf extract and ethanol (50%) stem-root extract of MPA improves ß-cell function and insulin signaling in postmenopausal diabetes through attenuation of oxidative stress and partially mediated by oestrogen receptor stimulation.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Extratos Vegetais/farmacologia , Primulaceae/química , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Células Secretoras de Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Extratos Vegetais/administração & dosagem , Pós-Menopausa , Ratos Sprague-Dawley , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Genes (Basel) ; 10(9)2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540540

RESUMO

Feed cost accounts for approximately 65-75% of overall commercial pork production costs. Therefore, improving the feed efficiency of pig production is important. In this study, 12 individuals with either extremely high (HE) or low (LE) feed efficiency were selected from 225 Duroc × (Landrace × Yorkshire) (DLY) pigs. After the pigs were slaughtered, we collected small intestine mucosal tissue. Next, RNA sequencing (RNA-seq) analysis was used to reveal the presence and quantity of genes expressed between these extremely HE- and LE-groups. We found 433 significantly differentially expressed genes (DEGs) between the HE- and LE-groups. Of these, 389 and 44 DEGs were upregulated and downregulated in the HE-group, respectively. An enrichment analysis showed that the DEGs were mainly enriched in functions related to apical plasma membrane composition, transporter activity, transport process and hormone regulation of digestion and absorption. Protein network interaction and gene function analyses revealed that SLC2A2 was an important candidate gene for FE in pigs, which may give us a deeper understanding of the mechanism of feed efficiency. Furthermore, some significant DEGs identified in the current study could be incorporated into artificial selection programs for increased feeding efficiency in pigs.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Suínos/genética , Transcriptoma , Animais , Feminino , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Intestino Delgado/metabolismo , Carne de Porco/normas , Seleção Artificial , Suínos/metabolismo
15.
Food Funct ; 10(10): 6517-6532, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31538163

RESUMO

Pyracantha fortuneana fruits are consumed as a dietary supplement in China and attenuate obesity and metabolic disorders. Obesity is known to be associated with intestinal barrier dysfunction driven by hyperglycemia and gut dysbiosis. However, whether the health benefits of P. fortuneana fruits are linked with the intestinal barrier function (IBF) remains unknown. This study aimed to evaluate the restorative effects of P. fortuneana fruit extract (PFE) on the IBF. Sprague Dawley rats were fed with a chow, a high-fat diet (HFD), or a PFE-supplemented diet for 8 weeks. Results showed that PFE intervention ameliorated HFD-induced intestinal barrier dysfunction by attenuating impaired structural integrity, reducing the elevated lactulose/mannitol ratio, and improving the mRNA and protein expression levels of tight junction proteins in HFD-fed rats. The ameliorations were associated with a beneficial effect on glycolipid homeostasis, as evidenced from the PFE decreasing intestinal absorptive capacity based on the d-xylose excretory rate, lowering the expression of GLUT2 and inhibiting digestive enzyme activities. The proanthocyanidins in the PFE showed greater in vitro inhibition on α-amylase, α-glucosidase, and lipase compared with triterpenoid saponins. Furthermore, the ameliorations on the IBF were also associated with effects on the microbial composition based on 16S rRNA gene sequence analysis. Several bacterial groups, which were linked with gut barrier integrity, were modulated after PFE administration, that is, Actinobacteria, Bacteroidaceae, Corynebacteriaceae, Lactobacillaceae, and S24-7 were elevated and the HFD-induced increase in Clostridia, Ruminococcaceae, Oscillospira, and Flexispira was restored. These data provide evidence for the ameliorative effect of the PFE on diet-induced intestinal barrier functional alternations in association with its capacity to modulate glycolipid digestion and gut microbiota in HFD-fed obese rats.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Glicolipídeos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Pyracantha/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Frutas/química , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Obesidade/genética , Obesidade/metabolismo , Obesidade/microbiologia , Ratos , Ratos Sprague-Dawley
16.
J Food Biochem ; 43(11): e13021, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31441956

RESUMO

Diabetes, a disease with abnormal production or use of insulin, is a growing concern that affects many individuals globally. Although many attempts have been made, there is no satisfactory treatment for diabetes. Recently, scientists have been exploring a promising treatment of diabetes involving herbal medicine. In this line, we show that Momordica charantia, a tendril-bearing vine belonging to the Cucurbitaceae family, permanently normalizes blood glucose levels comparable to healthy rats. Most importantly, M. charantia increases the expression of Insulin and Pdx1 genes while lowers the expression Glut2. Moreover, the number and size of the pancreatic islets have remarkably increased in treated animals. Liver ALT, AST, and ALP enzyme activities fell into normal range in treated animals suggesting the protective effect of M. charantia. These data indicate that M. Charantia improves the pancreas function by activating pancreatic beta cells and protecting liver tissue. PRACTICAL APPLICATIONS: Owing to the effectiveness of Momordica Charantia extracts in management of diabetes in STZ-induced diabetic rats, we have intention to evaluate the powder of Charantia to discover novel drug for treating diabetes. It is expected that the results could be translated in clinical trials.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Momordica charantia/química , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Transativadores/genética , Transativadores/metabolismo
17.
J Pediatr Gastroenterol Nutr ; 69(5): 611-618, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31261244

RESUMO

OBJECTIVES: In newborn rodents, intestinal maturation involves delayed fructose transporter GLUT5 expression until weaning. In jejunoileal atresia (JIA), distal intestinal segments lack exposure to amniotic fluid-containing carbohydrates. We assessed in human newborns, the impact of intestinal maturation and obstruction on mucosal monosaccharide transporter expression. METHODS: Samples were obtained from 10 newborns operated for small intestinal atresia and from 17 adults undergoing gastroduodenoscopy and/or ileocolonoscopy. mRNA expression of the transporters SGLT1, GLUT1, GLUT2, GLUT5, and GLUT7 was measured in neonate samples proximal and distal of the atresia as well as in adult duodenum, ileum, and colon. Protein expression and localization was assessed using immunofluorescence. RESULTS: Although mRNA expression of monosaccharide transporters did not significantly differ between newborn and adult samples, luminal fructose transporter GLUT5 protein was absent in 0- to 4-day-old neonates, but expressed in adults. The mRNA expression of the 5 tested monosaccharide transporters was unchanged distal from the JIA relative to proximal. Similarly, luminal sodium-dependent glucose transporter SGLT1 and basolateral GLUT2 were expressed proximal and distal to JIA as visualized by immunofluorescence staining. With the exception of glucose transporter GLUT1 that showed highest expression levels in colon, all investigated hexose transporters showed strongest expression in duodenum, lower levels in ileum and lowest in colon. CONCLUSIONS: Human newborns lack small intestinal fructose transporter GLUT5 protein expression and small intestinal atresia does not affect the expression of hexose transporters.


Assuntos
Atresia Intestinal/metabolismo , Intestino Delgado/anormalidades , Jejuno/anormalidades , Proteínas de Transporte de Monossacarídeos/metabolismo , Adulto , Idoso , Feminino , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Humanos , Recém-Nascido , Intestino Delgado/metabolismo , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , RNA Mensageiro/análise , Transportador 1 de Glucose-Sódio/metabolismo
18.
Food Funct ; 10(8): 4566-4576, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31314039

RESUMO

Intake of fructose-containing sugars is epidemiological and experimentally linked to metabolic syndrome (MS). We recently verified that the dietary polyphenol chrysin was able to abolish some of the metabolic changes induced by fructose-feeding in the rat. Because the role of the intestine upon fructose-induced MS is poorly understood, we decided to investigate the influence of fructose, in vivo, on the intestinal environment and the ability of chrysin to interfere with the putative observed changes. For this, adult male Sprague-Dawley rats were treated for 18 weeks as follows: (A) tap water (CONT), (B) tap water and chrysin (100 mg kg-1 day-1) (CHRY), (C) 10% fructose in tap water (FRUCT), and (D) 10% fructose in tap water and chrysin (100 mg kg-1 day-1) (FRUCT + CHRY). Our findings show that the relative expression of SGLT1 and GLUT2 mRNA were not affected by fructose-feeding and/or chrysin. In contrast, GLUT5 mRNA expression was markedly increased in fructose-fed animals, and this effect was reduced by chrysin. However, the apparent permeability to 14C-FRUCT was markedly and similarly decreased in FRUCT, CHRY and FRUCT + CHRY rats. Jejunal villus width and crypt depth were significantly higher in FRUCT and FRUCT + CHRYS rats, respectively. Finally, chrysin did not alter gut microbiota composition, but fructose significantly increased Lactobacillus and E. coli. Moreover, FRUCT + CHRY rats had an increase on the Firmicutes to Bacteroidetes ratio. This is the first report showing that chrysin is able to interfere with the effects of fructose at the intestinal level, which may contribute to the fructose-induced MS features.


Assuntos
Flavonoides/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Síndrome Metabólica/tratamento farmacológico , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Frutose/efeitos adversos , Frutose/metabolismo , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Humanos , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo
19.
J Biol Chem ; 294(31): 11728-11740, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31186351

RESUMO

Diabetes is characterized by a loss of ß-cell mass, and a greater understanding of the transcriptional mechanisms governing ß-cell function is required for future therapies. Previously, we reported that a complex of the Islet-1 (Isl1) transcription factor and the co-regulator single-stranded DNA-binding protein 3 (SSBP3) regulates the genes necessary for ß-cell function, but few proteins are known to interact with this complex in ß-cells. To identify additional components, here we performed SSBP3 reverse-cross-linked immunoprecipitation (ReCLIP)- and MS-based experiments with mouse ß-cell extracts and compared the results with those from our previous Isl1 ReCLIP study. Our analysis identified the E3 ubiquitin ligases ring finger protein 20 (RNF20) and RNF40, factors that in nonpancreatic cells regulate transcription through imparting monoubiquitin marks on histone H2B (H2Bub1), a precursor to histone H3 lysine 4 trimethylation (H3K4me3). We hypothesized that RNF20 and RNF40 regulate similar genes as those regulated by Isl1 and SSBP3 and are important for ß-cell function. We observed that Rnf20 and Rnf40 depletion reduces ß-cell H2Bub1 marks and uncovered several target genes, including glucose transporter 2 (Glut2), MAF BZIP transcription factor A (MafA), and uncoupling protein 2 (Ucp2). Strikingly, we also observed that Isl1 and SSBP3 depletion reduces H2Bub1 and H3K4me3 marks, suggesting that they have epigenetic roles. We noted that the RNF complex is required for glucose-stimulated insulin secretion and normal mitochondrial reactive oxygen species levels. These findings indicate that RNF20 and RNF40 regulate ß-cell gene expression and insulin secretion and establish a link between Isl1 complexes and global cellular epigenetics.


Assuntos
Proteínas com Domínio LIM/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Histonas/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Proteínas com Domínio LIM/química , Proteínas com Homeodomínio LIM/antagonistas & inibidores , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Camundongos , Ligação Proteica , Domínios Proteicos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
20.
J Diabetes Res ; 2019: 9536032, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179344

RESUMO

Thyrotropin (TSH) is a modulator of glucose metabolism by binding to its receptor on pancreatic cells. We used thyrotropin receptor (TSHR) knockout mice (Tshr -/-) as a model of TSH deletion to study its function in pancreatic ß cells. Tshr -/- mice had a similar body weight at birth compared with Tshr +/+ mice, but grew at a significantly slower rate until adulthood with adequate thyroxine supplementation. TSH deletion led to lower fasting and postprandial blood glucose, insulin secretion impairment, and atrophy of islets in adult mice. Transcription factors and markers of pancreatic ß cell maturation, Pdx1, Nkx6.1, Glut2, and insulin, together with cell proliferation marker Ki67 showed no differences at the mRNA level between the two groups. However, the Bax/Bcl-2 ratio was remarkably elevated in Tshr -/- mice at both mRNA and protein levels. We hypothesized that pancreatic cell apoptosis, rather than abnormal cell proliferation and maturation, is associated with pancreatic dysfunction and glucose intolerance in the absence of TSH modulation.


Assuntos
Células Secretoras de Insulina/patologia , Tireotropina/fisiologia , Animais , Apoptose , Peso Corporal , Proliferação de Células , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Glucose/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 2/metabolismo , Heterozigoto , Proteínas de Homeodomínio/metabolismo , Homeostase , Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Pâncreas/fisiopatologia , Receptores da Tireotropina/genética , Tiroxina/uso terapêutico , Transativadores/metabolismo
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