RESUMO
Contrast-induced nephropathy (CIN) is a common complication with adverse outcome after iodinated-contrast injection, yet still lacking effective medication. Heme oxygenase-1 (HO-1) has been reported to play an important role against renal injuries. Hemin, a HO-1 inducer and anti-porphyria medicine, may have a promising effect against CIN. In this study, we aim to investigate the effect of hemin on CIN model and the underlying molecular mechanisms in human proximal tubule epithelial cells (HK-2). To mimic a common condition in percutaneous coronary intervention (PCI) patients, CIN was induced by intravenous iopromide in high-fat fed diabetic rats. We found hemin, given right before iopromide, mitigated CIN with enhanced antioxidative capacity and reduced oxidative stress. HK-2 cells insulted by iopromide demonstrated decreased cell vitality and rising reactive oxygen species (ROS), which could also be inhibited by hemin. The effects of hemin involved a key molecule in ferroptosis, glutathione peroxidase (GPX4), whose down-expression by small interfering RNA (siRNA) reversed the effect of hemin on HK-2 cells. Furthermore, hemin's induction of GPX4 involved HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2). Either HO-1 or Nrf2 inhibitor prevented hemin's effect on GPX4 to a comparable extent, and over-expression of Nrf2 increased GPX4 expression. Moreover, intervention of ferroptosis inhibitor liproxstatin-1 also alleviated CIN in vivo. Therefore, we showed hemin mitigated CIN, inhibiting oxidative stress and ferroptosis, by upregulation of GPX4 via activation of HO-1/Nrf2. Hemin, as a clinical medicine, has a translational significance in treating CIN, and anti-ferroptosis is a potential therapeutic strategy for CIN.
Assuntos
Meios de Contraste , Células Epiteliais , Ferroptose , Fármacos Hematológicos , Hemina , Nefropatias , Animais , Células Cultivadas , Meios de Contraste/efeitos adversos , Diabetes Mellitus Experimental/etiologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Ferroptose/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Fármacos Hematológicos/farmacologia , Heme Oxigenase-1/metabolismo , Hemina/farmacologia , Humanos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/prevenção & controle , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/fisiopatologia , Fator 2 Relacionado a NF-E2/metabolismo , Intervenção Coronária Percutânea , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , RNA Interferente Pequeno/genética , Ratos , Transdução de SinaisRESUMO
Amelioration of hyperinsulinemia and insulin resistance associated with obesity is a cardinal target for therapeutics. Therefore, we investigated the relation of Fibrilln-1 (FBN1) mRNA expression and hepatic phosphoenolpyruvate caboxykinase (PEPCK) enzyme to the ameliorative impact of oxytocin on obesity-induced diabetes, suggesting glycogenolysis markers in diabetic models. Four groups of forty male Wistar rats were formed (n = 10): a control group fed basal diet and intraperitoneal injections of saline; an oxytocin-injected group; a diet-induced obese group fed a high-fat/high-sugar diet and injected with saline; a diet-induced obese group injected with oxytocin. Depending on blood glucose levels, obese groups were further sub-grouped into prediabetic, and diabetic rats, with 5 rats each, at the ninth and the 16th week of the feeding period, respectively. FBN1 expression and PEPCK activity were determined using the qPCR technique and some biochemical parameters (glycemic, lipid profile, kidney, and liver functions) were determined using kits. Obese groups showed an elevation of brain FBN1 expression, high serum lipid profile, high glucose level, and a deleterious impact on liver and kidney functions. Obese groups showed the stimulator effect of the PEPCK enzyme and time-dependent pathological changes in renal and hepatic tissues. The motor activities were negatively correlated with FBN1 gene expression in prediabetic and diabetic rats. In addition to our previous review of the crucial role of asprosin, here we showed that oxytocin could ameliorate obesity-induced diabetes and decrease FBN1 gene expression centrally to block appetite. Oxytocin caused decreases in PEPCK enzyme activity as well as glycogenolysis in the liver. Therefore, oxytocin has a potential effect on FBN1 expression and PEPCK enzyme activity in the obesity-induced diabetic-rat model.
Assuntos
Diabetes Mellitus Experimental , Obesidade , Ocitocina , Estado Pré-Diabético , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Expressão Gênica , Lipídeos , Masculino , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Obesidade/genética , Ocitocina/farmacologia , Fosfoenolpiruvato , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/genética , Ratos , Ratos WistarRESUMO
Obesity is occurring due to continue taken high fat diet; this is the fast-growing problem reaching epidemic proportion globally. Ursolic acid altered the abnormal glucose metabolism in diabetic rats. In this experimental protocol, we examine ursolic acid (UA) anti-obesity effect against streptozotocin (STZ) and high-fat diet-induced obesity in rats. Orally administered the ursolic acid (2.5, 5 and 10 mg/kg) dose to the hyperglycemic rats for 8 weeks and estimated the blood glucose level at different time intervals. Biochemical, hepatic, lipid, renal and antioxidant parameters were estimated. Traf-4, Mapk-8, Traf-6 and genes such as Ins-1, ngn-3 and Pdx-1 mRNA expression were estimated using qRT-PCR to scrutinize the molecular mechanism in MAPK downstream JNK cascade and insulin pathway signalling pathways. Ursolic acid significantly (p<0.001) down-regulated the blood glucose level at dose dependent manner. Its also reduced the plasma insulin level, non-essential fatty acid and increased the level of adiponectin as compared to obese control group rats. Ursolic acid treated group rats reduced the level of total cholesterol and triglycerides. Ursolic-acid-treated rats have been shown to decrease oxidative stress in pancreatic tissue by restoring the free radical effect of scavenging, suppress the Traf-6, Mapk-8 and Traf-4 mRNA expression, enhance the expression of Pdx-1, Ins-1 and Ngn-3 and ensure the regeneration of pancreas ß cells and therefore pancreas insulin. The current result suggested the anti-obese effect of ursolic acid against high fat diet (HFD) induced obese rats via alteration of insulin and JNK signaling pathway.
Assuntos
Fármacos Antiobesidade , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes , Insulina/metabolismo , Obesidade/tratamento farmacológico , Triterpenos/administração & dosagem , Triterpenos/farmacologia , Administração Oral , Animais , Antioxidantes , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Estreptozocina/efeitos adversos , Ácido UrsólicoRESUMO
Type2 diabetes mellitus (T2DM) causes several complications that affect the quality of life and life span of patients. Hyperbaric oxygen therapy (HBOT) has been used to successfully treat several diseases, including carbon monoxide poisoning, ischemia, infections and diabetic foot ulcer, and increases insulin sensitivity in T2DM. The present study aimed to determine the effect of HBOT on ßcell function and hepatic gluconeogenesis in streptozotocin (STZ)induced type2 diabetic mice. To establish a T2DM model, 7weekold male C57BL/6J mice were fed a highfat diet (HFD) and injected once daily with lowdose STZ for 3 days after 1week HFD feeding. At the 14th week, HFD+HBOT and T2DM+HBOT groups received 1h HBOT (2 ATA; 100% pure O2) daily from 5:00 to 6:00 p.m. for 7 days. The HFD and T2DM groups were maintained under normobaric oxygen conditions and used as controls. During HBOT, the 12h nocturnal food intake and body weight were measured daily. Moreover, blood glucose was measured by using a tail vein prick and a glucometer. After the final HBO treatment, all mice were sacrificed to conduct molecular biology experiments. Fasting insulin levels of blood samples of sacrificed mice were measured by an ultrasensitive ELISA kit. Pancreas and liver tissues were stained with hematoxylin and eosin, while immunohistochemistry was performed to determine the effects of HBOT on insulin resistance. TUNEL was used to determine the effects of HBOT on ßcell apoptosis, and immunoblotting was conducted to determine the ßcell apoptosis pathway. HBOT notably reduced fasting blood glucose and improved insulin sensitivity in T2DM mice. After HBOT, ßcell area and ßcell mass in T2DM mice were significantly increased. HBOT significantly decreased the ßcell apoptotic rate in T2DM mice via the pancreatic Bcl2/caspase3/poly(ADPribose) polymerase (PARP) apoptosis pathway. Moreover, HBOT improved the morphology of the liver tissue and increased hepatic glycogen storage in T2DM mice. These findings suggested that HBOT ameliorated the insulin sensitivity of T2DM mice by decreasing the ßcell apoptotic rate via the pancreatic Bcl2/caspase3/PARP apoptosis pathway.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/fisiologia , Oxigenoterapia Hiperbárica/métodos , Células Secretoras de Insulina/metabolismo , Fígado/metabolismo , Animais , Apoptose/fisiologia , Glicemia/metabolismo , Western Blotting , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Jejum/sangue , Teste de Tolerância a Glucose/métodos , Humanos , Insulina/sangue , Células Secretoras de Insulina/citologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic ß-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.
Assuntos
Adiponectina/metabolismo , Curcumina/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Fitoterapia , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/uso terapêutico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina , Regulação para Cima/efeitos dos fármacosRESUMO
Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic ß-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucosídeos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Liraglutida/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tiofenos/farmacologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos ObesosRESUMO
BACKGROUND: The number of patients with diabetes is increasing worldwide. Diabetic testicular damage can cause spermiogenesis disorders and sexual dysfunction. We thus explored the role of miRNAs in diabetic testicular damage, and revealed that they could serve as effective prevention and treatment therapeutic targets. METHODS: Streptozotocin (STZ) was used to generate a rat model of type 2 diabetes. Rat testicular tissues were used for miRNA and mRNA sequencing. Through bioinformatics analysis, we constructed an miRNA-mRNA diabetic testicular damage regulatory network and screened for key miRNAs. We also used Leydig cells to generate a diabetic cell model and detected the downstream target genes of miRNAs, secretion of testosterone, and proliferation and apoptotic levels to elucidate the role and mechanism of the selected miRNAs in diabetic testicular damage. RESULTS: Using second-generation sequencing, we identified 19 differentially expressed miRNAs and 555 mRNAs in the testes of diabetic rats. Based on computational prediction of targets and negative regulation relationships, we constructed a miRNA-mRNA regulatory network, including 12 miRNAs and 215 mRNAs. KEGG enrichment analysis revealed that genes were more concentrated on the survival signalling pathway. Based on this, we screened 2 key miRNAs, miR-504 and miR-935. In vitro, glucose could induce an increase in miR-504 and miR-935, whereas a decrease in MEK5 and MEF2C in a dose-dependent manner. Overexpression of miR-504 and miR-935 led to the decreased expression of MEK5 and MEF2C, decreased proliferation rate of Leydig cells, increased apoptotic rate, and decreased secretion of testosterone. Whereas, knockdown of miR-504 and miR-935 displayed opposite tendencies. CONCLUSIONS: miRNAs play important roles in diabetic testicular damage. miR-504 and miR-935 might regulate testicular damage through the classic survival pathway of MEK5-ERK5-MEF2C. Targeted inhibition of miR-504 and miR-935 could reverse the high-glucose-induced testicular complications, thus posing as a potential therapeutic approach in diabetic testicular injury.
Assuntos
Apoptose/genética , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Células Intersticiais do Testículo/metabolismo , MicroRNAs/genética , Animais , Biologia Computacional/métodos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucose/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Interferência de RNA , Ratos , Transdução de Sinais , Testículo/metabolismo , Testosterona/metabolismo , TranscriptomaRESUMO
Glimepiride (GMP), an oral hypoglycemic agent is extensively employed in the treatment of type 2 diabetes. Transdermal delivery of GMP has been widely investigated as a promising alternative to an oral approach but the delivery of GMP is hindered owing to its low solubility and permeation. The present study was designed to formulate topical nanoemulgel GMP system and previously reported solubility enhanced glimepiride (GMP/ßCD/GEL-44/16) in combination with anti-diabetic oil to enhance the hypoglycemic effect. Nanoemulsions were developed using clove oil, Tween-80, and PEG-400 and were gelled using xanthan gum (3%, w/w) to achieve the final nanoemulgel formulations. All of the formulations were evaluated in terms of particle size, zeta potential, pH, conductivity, viscosity, and in vitro skin permeation studies. In vivo hypoglycemic activity of the optimized nanoemulgel formulations was evaluated using a streptozocin-induced diabetes model. It was found that a synergistic combination of GMP with clove oil improved the overall drug permeation across the skin membrane and the hypoglycemic activity of GMP. The results showed that GMP/ßCD/GEL-44/16-loaded nanoemulgel enhanced the in vitro skin permeation and improved the hypoglycemic activity in comparison with pure and marketed GMP. It is suggested that topical nano emulsion-based GMP gel and GMP/ßCD/GEL-44/16 could be an effective alternative for oral therapy in the treatment of diabetes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Emulsões , Hipoglicemiantes/farmacologia , Nanopartículas/administração & dosagem , Pele/efeitos dos fármacos , Compostos de Sulfonilureia/farmacologia , Administração Cutânea , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Masculino , Nanopartículas/química , Permeabilidade , Ratos , Ratos Wistar , Testes de Irritação da Pele , Solubilidade , ViscosidadeRESUMO
Tumour necrosis factor alpha (TNFα) is essential in neuroinflammatory modulation. Therefore, the goal of this study is to reveal the effects of chronic hyperglycaemia and insulin treatment on TNFα expression in different gut segments and intestinal wall layers. TNFα expression was mapped by fluorescent immunohistochemistry and quantitative immunogold electron microscopy in myenteric ganglia of duodenum, ileum and colon. Tissue TNFα levels were measured by enzyme-linked immunosorbent assays in muscle/myenteric plexus-containing (MUSCLE-MP) and mucosa/submucosa/submucous plexus-containing (MUC-SUBMUC-SP) homogenates. Increasing density of TNFα-labelling gold particles is observed in myenteric ganglia from proximal to distal segments and TNFα tissue levels are much more elevated in MUSCLE-MP homogenates than in MUC-SUBMUC-SP samples in healthy controls. In the diabetics, the number of TNFα gold labels is significantly increased in the duodenum, decreased in the colon and remained unchanged in the ileal ganglia, while insulin does not prevent these diabetes-related TNFα changes. TNFα tissue concentration is also increased in MUSCLE-MP homogenates of diabetic duodenum, while decreased in MUC-SUBMUC-SP samples of diabetic ileum and colon. These findings support that type 1 diabetes has region-specific and intestinal layer-dependent effects on TNFα expression, contributing to the regional damage of myenteric neurons and their intestinal milieu.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Trato Gastrointestinal/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Intestinos/fisiologia , Plexo Mientérico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Intestinos/efeitos dos fármacos , Masculino , Plexo Mientérico/efeitos dos fármacos , Plexo Mientérico/patologia , Ratos , Ratos WistarRESUMO
INTRODUCTION: Primary bile acids (PBAs) are produced and released into human gut as a result of cholesterol catabolism in the liver. A predominant PBA is chenodeoxycholic acid (CDCA), which in a recent study in our laboratory, showed significant excipient-stabilizing effects on microcapsules carrying insulinoma ß-cells, in vitro, resulting in improved cell functions and insulin release, in the hyperglycemic state. Hence, this study aimed to investigate the applications of CDCA in bio-encapsulation and transplantation of primary healthy viable islets, preclinically, in type 1 diabetes. METHODS: Healthy islets were harvested from balb/c mice, encapsulated in CDCA microcapsules, and transplanted into the epididymal tissues of 6 syngeneic diabetic mice, post diabetes confirmation. Pre-transplantation, the microcapsules' morphology, size, CDCA-deep layer distribution, and physical features such as swelling ratio and mechanical strength were analyzed. Post-transplantation, animals' weight, bile acids', and proinflammatory biomarkers' concentrations were analyzed. The control group was diabetic mice that were transplanted encapsulated islets (without PBA). RESULTS AND CONCLUSION: Islet encapsulation by PBA microcapsules did not compromise the microcapsules' morphology or features. Furthermore, the PBA-graft performed better in terms of glycemic control and resulted in modulation of the bile acid profile in the brain. This is suggestive that the improved glycemic control was mediated via brain-related effects. However, the improvement in graft insulin delivery and glycemic control was short-term.
Assuntos
Cápsulas/administração & dosagem , Ácido Quenodesoxicólico/farmacologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Células Secretoras de Insulina/citologia , Transplante das Ilhotas Pancreáticas/métodos , Animais , Biotecnologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Fármacos Gastrointestinais/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Sargassum fusiforme alginate (SF-Alg) possess many pharmacological activities, including hypoglycemic and hypolipidemic. However, the hypoglycemic mechanisms of SF-Alg remain unclear due to its low bioavailability. In this study, we evaluated the therapeutic effect of SF-Alg on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. SF-Alg intervention was found to significantly reduce fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC), while increasing high-density lipoprotein cholesterol (HDL-c) and improving glucose tolerance. In addition, administrating SF-Alg to diabetic mice moderately attenuated pathological changes in adipose, hepatic, and heart tissues as well as skeletal muscle, and diminished oxidative stress. To probe the underlying mechanisms, we further analyzed the gut microbiota using 16S rRNA amplicon sequencing, as well as metabolites by non-targeted metabolomics. Here, SF-Alg significantly increased some benign bacteria (Lactobacillus, Bacteroides, Akkermansia Alloprevotella, Weissella and Enterorhabdus), and significantly decreased harmful bacteria (Turicibacter and Helicobacter). Meanwhile, SF-Alg dramatically decreased branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the colon of T2D mice, suggesting a positive benefit of SF-Alg as an adjvant agent for T2D.
Assuntos
Alginatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sargassum/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Camundongos , Estreptozocina , Triglicerídeos/sangueRESUMO
Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.
Assuntos
Processamento Alternativo/fisiologia , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Processamento Alternativo/genética , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Suscetibilidade a Doenças , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima/genéticaRESUMO
In both humans and rodent models, circulating glycine levels are significantly reduced in obesity, glucose intolerance, type II diabetes, and non-alcoholic fatty liver disease. The glycine cleavage system and its rate-limiting enzyme, glycine decarboxylase (GLDC), is a major determinant of plasma glycine levels. The goals of this study were to determine if the increased expression of GLDC contributes to the reduced plasma glycine levels seen in disease states, to characterize the hormonal regulation of GLDC gene expression, and to determine if altered GLDC expression has physiological effects that might affect the development of diabetes. The findings presented here show that hepatic GLDC gene expression is elevated in mouse models of obesity and diabetes, as well as by fasting. We demonstrated that GLDC gene expression is strongly regulated by the metabolic hormones glucagon and insulin, and we identified the signaling pathways involved in this regulation. Finally, we found that GLDC expression is linked to glutathione levels, with increased expression associated with elevated levels of glutathione and reduced expression associated with a suppression of glutathione and increased cellular ROS levels. These findings suggest that the hormonal regulation of GLDC contributes not only to the changes in circulating glycine levels seen in metabolic disease, but also affects glutathione production, possibly as a defense against metabolic disease-associated oxidative stress.
Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucagon/farmacologia , Glicina Desidrogenase (Descarboxilante)/metabolismo , Glicina/metabolismo , Estresse Oxidativo , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Fármacos Gastrointestinais/farmacologia , Glutationa/metabolismo , Glicina Desidrogenase (Descarboxilante)/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-DawleyRESUMO
Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In the present study, fragment peptides of neurotensin and xenin, acetyl-neurotensin and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro ß-cell function were studied. Subchronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high-fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (P<0.05 to P<0.01) in BRIN-BD11 ß-cells and isolated mouse islets. Ac-NT/XN-8-Gln augmented (P<0.001) the insulinotropic actions of GIP, while possessing independent ß-cell proliferative (P<0.001) and anti-apoptotic (P<0.01) actions. Twice daily treatment of HFF mice with Ac-NT/XN-8-Gln for 32 days improved glycaemic control and circulating insulin, with benefits significantly enhanced by combined exendin-4 treatment. This was reflected by reduced body fat mass (P<0.001), improved circulating lipid profile (P<0.01) and reduced HbA1c concentrations (P<0.01) in the combined treatment group. Following an oral glucose challenge, glucose levels were markedly decreased (P<0.05) only in combination treatment group and superior to exendin-4 alone, with similar observations made in response to glucose plus GIP injection. The combined treatment group also presented with improved insulin sensitivity, decreased pancreatic insulin content as well as increased islet and ß-cell areas. These data reveal that Ac-NT/XN-8-Gln is a biologically active neurotensin/xenin fusion peptide that displays prominent antidiabetic efficacy when administered together with exendin-4.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Estabilidade de Medicamentos , Quimioterapia Combinada , Hemoglobinas Glicadas/metabolismo , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos Endogâmicos C57BL , RatosRESUMO
Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice. The homeostatic model assessment of insulin resistance scores of NAG-1 Tg mice were lower than those of WT mice. Hematoxylin and eosin staining revealed a smaller lipid droplet size in the adipose tissues, lower lipid accumulation in the hepatocytes, and larger beta cell area in the pancreas of NAG-1 Tg mice than in those of WT mice. Immunohistochemical analysis revealed downregulated expression of cleaved caspase-3, an apoptosis marker, in the beta cells of NAG-1 Tg mice. Adiponectin and leptin mRNA levels were upregulated and downregulated in NAG-1 Tg mice, respectively. Additionally, the expression of IRS1/PI3K/AKT signaling pathway components, especially Foxo1, which regulates gluconeogenesis in the muscle and white adipose tissue, was downregulated in NAG-1 Tg mice. Furthermore, NAG-1 overexpression promoted the expression of As160 in both muscles and adipocytes, and the mRNA levels of the NLRP3 pathway members were downregulated in NAG-1 Tg mice. Our findings suggest that NAG-1 expression alleviates diabetes in mice.
Assuntos
Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Suscetibilidade a Doenças , Fator 15 de Diferenciação de Crescimento/genética , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Fator 15 de Diferenciação de Crescimento/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Pâncreas/metabolismo , Pâncreas/patologia , Transdução de Sinais , Estreptozocina/efeitos adversosRESUMO
Probiotics are health beneficial bacterial populations colonizing the human gut and skin. Probiotics are believed to be involved in immune system regulation, gut microbiota stabilization, prevention of infectious diseases, and adjustments of host metabolic activities. Probiotics such as Lactobacillus and Bifidobacterium affect glycemic levels, blood lipids, and protein metabolism. However, the interactions between probiotics and metabolic diseases as well as the underlying mechanisms remain unclear. We used streptozotocin (STZ)-induced diabetic animal models to study the effect of ProbiogluTM, a multi-strain probiotic supplement including Lactobaccilus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, L. reuteri GL-104, and Bifidobacterium animalis subsp. lactis CP-9, on the regulation of physiochemical parameters related to type-2 diabetes. Experimental rats were randomly assigned into five groups, control group, streptozotocin (STZ)-treated rats (STZ group), STZ + 1× ProbiogluTM group, STZ + 5× ProbiogluTM group, and STZ + 10× ProbiogluTM group, and physiological data were measured at weeks 0, 2, 4, 6, and 8. Our results indicate that supplementation with ProbiogluTM significantly improved glucose tolerance, glycemic levels, insulin levels, and insulin resistance (HOMA-IR). Furthermore, we observed reduction in urea and blood lipid levels, including low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC). ProbiogluTM administration increased the ß-cell mass in STZ-induced diabetic animal models, whereas it reduced the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1ß. In addition, the enhancement of oxidative stress biomarkers and superoxide dismutase (SOD) activities was associated with a decrease in malondialdehyde (MDA) levels. We conclude that ProbiogluTM attenuates STZ-induced type-2 diabetes by protecting ß-cells, stabilizing glycemic levels, and reducing inflammation. Among all probiotic treating groups, the 10×ProbiogluTM treatment revealed the best results. However, these experimental results still need to be validated by different animal models of type-2 diabetes and human clinical trials in the future.
Assuntos
Biomarcadores/metabolismo , Morte Celular , Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Inflamação/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Probióticos/administração & dosagem , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Hipoglicemiantes/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-DawleyRESUMO
Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson's trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
Assuntos
Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Frutose/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , eIF-2 Quinase/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Metabolismo Energético/efeitos dos fármacos , Fibrose , Indóis/química , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Compostos Benzidrílicos/farmacologia , Glicemia/análise , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Ocidental , Modelos Animais de Doenças , Progressão da Doença , Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
Lipids are highly diverse in their composition, properties and distribution in different biological entities. We aim to establish the lipidomes of several insulin-sensitive tissues and to test their plasticity when divergent feeding regimens and lifestyles are imposed. Here, we report a proton nuclear magnetic resonance (1H-NMR) study of lipid abundance across 4 tissues of C57Bl6J male mice that includes the changes in the lipid profile after every lifestyle intervention. Every tissue analysed presented a specific lipid profile irrespective of interventions. Glycerolipids and fatty acids were most abundant in epididymal white adipose tissue (eWAT) followed by liver, whereas sterol lipids and phosphoglycerolipids were highly enriched in hypothalamus, and gastrocnemius had the lowest content in all lipid species compared to the other tissues. Both when subjected to a high-fat diet (HFD) and after a subsequent lifestyle intervention (INT), the lipidome of hypothalamus showed no changes. Gastrocnemius and liver revealed a pattern of increase in content in many lipid species after HFD followed by a regression to basal levels after INT, while eWAT lipidome was affected mainly by the fat composition of the administered diets and not their caloric density. Thus, the present study demonstrates a unique lipidome for each tissue modulated by caloric intake and dietary composition.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Lipidômica , Obesidade/dietoterapia , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Restrição Calórica , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Estilo de Vida Saudável , Hipotálamo/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/complicações , Condicionamento Físico AnimalRESUMO
Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.