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Article in Chinese | WPRIM | ID: wpr-921681


The present study investigated the therapeutic efficacy and potential mechanism of Jinqi Jiangtang Tablets(JQJT) on pancreatic β cell dysfunction based on network pharmacology and molecular docking technology. TCMSP platform was used to retrieve the chemical components and targets of the three Chinese herbal medicines of JQJT. The genes were converted to gene symbol by the UniProt, and its intersection with targets related to pancreatic β cell function in GeneCards and CTD databases was obtained. The drugs, active components and common targets were imported into Cytoscape 3.8.2 to plot the drug-component-target network. The main effective components and targets were obtained by software analysis. The drug targets and targets related to pancreatic β cell function were imported separately into the STRING platform for the construction of protein-protein interaction(PPI) networks. The two PPI networks were merged by Cytoscape 3.8.2 and the key targets were obtained by plug-in CytoNCA. The targets obtained from drug-component-target network and PPI networks were imported into DAVID for GO analysis and KEGG enrichment analysis. AutoDock was used to carry out molecular docking of main active components and core targets and Pymol was used to plot the molecular docking diagram. The results showed that there were 371 active components and 203 targets related to JQJT and 2 523 targets related to pancreatic β cell damage, covering 136 common targets. The results revealed core targets(such as PTGS2, PTGS1, NOS2, ESR1 and RXRA) and effective key components(such as quercetin, kaempferol, luteolin, β-carotene and β-sitosterol). KEGG enrichment analysis indicated that apoptosis, inflammation, and other signaling pathways were mainly involved. Molecular docking results showed that the main active components could spontaneously bind to the targets. This study preliminarily revealed the mechanism of JQJT in improving pancreatic β cell damage through multi-component, multi-target and multi-pathway, and provided a theoretical basis for JQJT in the treatment of pancreatic β cell dysfunction.

Drugs, Chinese Herbal/pharmacology , Insulin-Secreting Cells , Medicine, Chinese Traditional , Molecular Docking Simulation , Tablets , Technology
Article in Chinese | WPRIM | ID: wpr-888017


Type 2 diabetes mellitus( T2 DM) is a common chronic metabolic disease characterized by persistent hyperglycemia and insulin resistance. In pancreatic β-cells,glucose-stimulated insulin secretion( GSIS) plays a pivotal role in maintaining the balance of blood glucose level. Previous studies have shown that geniposide,one of the active components of Gardenia jasminoides,could quickly regulate the absorption and metabolism of glucose,and affect glucose-stimulated insulin secretion in pancreatic β cells,but the specific mechanism needs to be further explored. Emerging evidence indicated that glycosylation of glucose transporter( GLUT) has played a key role in sensing cell microenvironmental changes and regulating glucose homeostasis in eucaryotic cells. In this study,we studied the effects of geniposide on the key molecules of GLUT2 glycosylation in pancreatic β cells. The results showed that geniposide could significantly up-regulate the mRNA and protein levels of Glc NAc T-Ⅳa glycosyltransferase( Gn T-Ⅳa) and galectin-9 but had no signi-ficant effect on the expression of clathrin,and geniposide could distinctively regulate the protein level of Gn T-Ⅳa in a short time( 1 h) under the conditions of low and medium glucose concentrations,but had no significant effect on the protein level of galectin-9. In addition,geniposide could also remarkably affect the protein level of glycosylated GLUT2 in a short-time treatment. The above results suggested that geniposide could quickly regulate the protein level of Gn T-Ⅳa,a key molecule of protein glycosylation in INS-1 rat pancreatic βcells and affect the glycosylation of GLUT2. These findings suggested that the regulation of geniposide on glucose absorption,metabolism and glucose-stimulated insulin secretion might be associated with its efficacy in regulating GLUT2 glycosylation and affecting its distribution on the cell membrane and cytoplasm in pancreatic β cells.

Animals , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Glycosylation , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Iridoids , Rats
Article in English | WPRIM | ID: wpr-880609


Type 1 diabetes (T1D) is an autoimmune disease characterized by T-cell mediated destruction of pancreatic B cells, absolute deficiency in insulin, and hyperglycemia. The incidence of T1D is increased sharply after the middle of the 20th century, suggesting that the environmental factors affect the occurrence and development of T1D. The diversity of human intestinal flora forms early in life and tends to stabilize around age 3. Early intestinal flora is in a dynamic process of change and is closely related to the maturation of the immune system, suggesting that early environmental exposure may be involved in the development of T1D. A variety of factors such as antibiotics and cesarean section can affect the colonization of early intestinal flora. To clarify the influence of these factors on early intestinal flora and its association with T1D, it is necessary to understand the pathogenesis of T1D and to provide an effective means for the primary prevention of T1D.

Cesarean Section , Child, Preschool , Diabetes Mellitus, Type 1 , Female , Gastrointestinal Microbiome , Humans , Insulin , Insulin-Secreting Cells , Pregnancy
Acta Physiologica Sinica ; (6): 133-138, 2020.
Article in English | WPRIM | ID: wpr-827075


Lycopene is an antioxidant which has potential anti-diabetic activity, but the cellular mechanisms have not been clarified. In this study, different concentrations of lycopene were used to treat pancreatic alpha and beta cell lines, and the changes of cell growth, cell apoptosis, cell cycle, reactive oxygen species (ROS), ATP levels and expression of related cytokines were determined. The results exhibited that lycopene did not affect cell growth, cell apoptosis, cell cycle, ROS and ATP levels of alpha cells, while it promoted the growth of beta cells, increased the ratio of S phase, reduced the ROS levels and increased the ATP levels of beta cells. At the same time, lycopene treatment elevated the mRNA expression levels of tnfα, tgfβ and hif1α in beta cells. These findings suggest that lycopene plays cell-specific role and activates pancreatic beta cells, supporting its application in diabetes therapy.

Adenosine Triphosphate , Metabolism , Apoptosis , Carotenoids , Pharmacology , Cell Cycle , Cells, Cultured , Cytokines , Metabolism , Glucagon-Secreting Cells , Humans , Insulin-Secreting Cells , Lycopene , Pharmacology , Reactive Oxygen Species , Metabolism
Article in English | WPRIM | ID: wpr-876091


@#Objectives. To describe the characteristics of long-standing T1DM in Thai patients and assess residual beta-cell function with status of pancreatic autoantibodies. Methodology. This is a cross-sectional study of Thai subjects with T1DM and disease duration ≥ 25 years seen at the Theptarin Hospital. Random plasma C-peptide and pancreatic auto-antibodies (Anti-GAD, Anti-IA2, and Anti-ZnT8) were measured. Patients who developed complications were compared with those who remained free of complications. Results. A total of 20 patients (males 65%, mean age 49.4±12.0 years, BMI 22.5±3.1 kg/m2, A1C 7.9±1.6%) with diabetes duration of 31.9±5.1 years were studied. Half of the participants remained free from any diabetic complications while the proportions reporting retinopathy, nephropathy, and neuropathy were 40%, 30%, and 15%, respectively. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy but not in those who were free from other complications. The prevalence rates of anti-GAD, anti- IA2, and anti-ZnT8 were 65%, 20%, and 10%, respectively. None of the patients who tested negative for both anti-GAD and anti-IA2 was positive for anti-ZnT8. Residual beta-cell function based on detectable random plasma C-peptide (≥ 0.1 ng/mL) and MMTT was found in only 3 patients (15%). There was no relationship between residual beta-cell function and protective effects of diabetic complications. Conclusion. Endogenous insulin secretion persists in some patients with long-standing T1DM and half of longstanding T1DM in Thai patients showed no diabetic complications. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy

Diabetes Mellitus, Type 1 , Autoantibodies , Thailand , Pancreas , Insulin-Secreting Cells , Disease Progression
Clinics ; 75: e1656, 2020. graf
Article in English | LILACS | ID: biblio-1133444


OBJECTIVES: Mesenchymal stem cells (MSCs) are potentially ideal for type 2 diabetes treatment, owing to their multidirectional differentiation ability and immunomodulatory properties. Here we investigated whether the stem cells from human exfoliated deciduous teeth (SHED) in combination with hyperbaric oxygen (HBO) could treat type 2 diabetic rats, and explored the underlying mechanism. METHODS: SD rats were used to generate a type 2 diabetes model, which received stem cell therapy, HBO therapy, or both together. Before and after treatment, body weight, blood glucose, and serum insulin, blood lipid, pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), and urinary proteins were measured and compared. After 6 weeks, rats were sacrificed and their organs were subjected to hematoxylin and eosin staining and immunofluorescence staining for insulin and glucagon; apoptosis and proliferation were analyzed in islet cells. Structural changes in islets were observed under an electron microscope. Expression levels of Pdx1, Ngn3, and Pax4 mRNAs in the pancreas were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: In comparison with diabetic mice, those treated with the combination or SHE therapy showed decreased blood glucose, insulin resistance, serum lipids, and pro-inflammatory cytokines and increased body weight and serum insulin. The morphology and structure of pancreatic islets improved, as evident from an increase in insulin-positive cells and a decrease in glucagon-positive cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining of islet cells revealed the decreased apoptosis index, while Ki67 and proliferating cell nuclear antigen staining showed increased proliferation index. Pancreatic expression of Pdx1, Ngn3, and Pax4 was upregulated. CONCLUSION: SHED combined with HBO therapy was effective for treating type 2 diabetic rats. The underlying mechanism may involve SHED-mediated increase in the proliferation and trans-differentiation of islet β-cells and decrease in pro-inflammatory cytokines and apoptosis of islets.

Humans , Animals , Male , Mice , Rats , Mesenchymal Stem Cell Transplantation , Diabetes Mellitus, Experimental/therapy , Diabetes Mellitus, Type 2/therapy , Insulin-Secreting Cells , Hyperbaric Oxygenation/methods , Stem Cells , Tooth, Deciduous , China , Rats, Sprague-Dawley , Diabetes Mellitus, Type 2/chemically induced , Mesenchymal Stem Cells , Insulin
Int. j. morphol ; 37(4): 1331-1334, Dec. 2019. graf
Article in English | LILACS | ID: biblio-1040133


Obesity and its comorbidities are becoming epidemic in the Western world. Beta cell mass estimation is an important indicator to track the progression of insulin resistance/type 2 diabetes, particularly in experimental studies, where it can be performed with stereological tools in an unbiased way. In this work, we present a simple protocol that can contribute to doing the practice of estimating the mass of beta cells more frequent and reproducible. As with any quantitative study, the necessary precautions regarding sampling and randomness must be respected.

La obesidad y sus comorbilidades se están convirtiendo en una epidemia en el mundo occidental. La estimación de la masa de células beta es un indicador importante para rastrear la progresión de la resistencia a la insulina/diabetes tipo 2, particularmente en estudios experimentales, donde se puede realizar con herramientas estereológicas de manera imparcial. En este trabajo presentamos un protocolo simple que puede contribuir a que la práctica de estimar la masa de células beta sea más frecuente y reproducible. Como en cualquier estudio cuantitativo, deben respetarse las precauciones necesarias con respecto al muestreo y la aleatoriedad.

Humans , Cytological Techniques/methods , Islets of Langerhans/cytology , Insulin-Secreting Cells
Actual. osteol ; 15(2): 78-93, mayo - ago. 2019. ilus.
Article in Spanish | LILACS | ID: biblio-1048450


Los hallazgos osteológicos se intensi!caron en los últimos años. Se demostró que el esqueleto se comporta, además de sus funciones clásicas, como un órgano de secreción endocrina que sintetiza al menos dos hormonas: el factor de crecimiento de !broblastos 23 (FGF-23) y la osteocalcina (Ocn). La Ocn es un péptido pequeño que contiene 3 residuos de ácido glutámico. Estos residuos se carboxilan postraduccionalmente, quedando retenida en la matriz ósea. La forma decarboxilada en el primer residuo de ácido glutámico (GluOcn) fue reportada por poseer efectos biológicos; la resorción ósea es el mecanismo clave para su bioactivación. La presente revisión se centra en los conocimientos actuales sobre la función hormonal de la Ocn. A la fecha se reporta que la Ocn regularía el metabolismo energético aumentando la proliferación de células ` pancreáticas, y la secreción de insulina y de adiponectina. Sobre el músculo esquelético actuaría favoreciendo la absorción y el catabolismo de nutrientes. La función reproductiva masculina estaría regulada mediante el estímulo a las células de Leydig para sintetizar testosterona; en el desarrollo cerebral y la cognición, la Ocn aumentaría la síntesis de neurotransmisores monoaminados y disminuiría el neurotransmisor inhibidor GABA. Si bien son indispensables mayores evidencias para dilucidar los mecanismos reguladores por medio de los cuales actuaría la Ocn, los resultados enumerados en los distintos estudios experimentales establecen la importancia de este novedoso integrante molecular. Dilucidar su rol dentro de estos procesos interrelacionados en seres humanos abriría la posibilidad de utilizar a la Ocn en el tratamiento de enfermedades endocrino-metabólicas. (AU)

Osteological !ndings have intensi!ed in recent years. The skeleton behaves as an endocrine secretion organ that synthesizes at least two hormones: osteocalcin (Ocn) and !broblast growth factor 23 (FGF-23). Ocn is a small peptide that contains 3 glutamic acid residues. After translation, these residues are carboxylated to make possible its retention into the bone matrix. Decarboxylation on the !rst glutamic acid residue (GluOcn) has been reported to have biological effects. Bone resorption is the key mechanism for its bioactivation. This review focuses on current knowledge on Ocn hormonal function. It has been reported that Ocn regulates energy metabolism by increasing the proliferation of pancreatic ` cells, and the secretion of insulin and adiponectin. On the skeletal muscle, it may act by favoring the absorption and catabolism of nutrients. Male reproductive function might be regulated by stimulating Leydig cells to synthesize testosterone. Regarding brain development and cognition, Ocn would increase monoamine neurotransmitters synthesis and decrease inhibitory neurotransmitter GABA. Although more evidence is needed to elucidate the regulatory mechanisms of Ocn, different experimental studies establish the importance of this novel molecular mediator. Clarifying its role within interrelated processes in humans, might open the possibility of using Ocn in different treatments of endocrine-metabolic diseases. (AU)

Animals , Osteocalcin/metabolism , Osteocalcin/therapeutic use , Skeleton/physiology , Skeleton/metabolism , Skeleton/pathology , Warfarin/therapeutic use , Cardiovascular Diseases/prevention & control , Osteocalcin/biosynthesis , Osteocalcin/chemistry , Diabetes Mellitus, Type 2/prevention & control , Endocrine System Diseases/therapy , Energy Metabolism/physiology , Insulin-Secreting Cells/physiology , Fertility , Fibroblast Growth Factors/metabolism , Genitalia, Male/metabolism , Infertility/prevention & control , Metabolic Diseases/therapy , Neoplasms/prevention & control
Arch. endocrinol. metab. (Online) ; 63(3): 222-227, May-June 2019. tab, graf
Article in English | LILACS | ID: biblio-1011165


ABSTRACT Objective Type 2 diabetes (T2DM) is characterized by the progressive deterioration of pancreatic islet β-cell function over time and insulin resistance. Knowing more about the differences in pancreatic islet function in T2DM patients who have had diabetes for different lengths of time can help improve therapy for T2DM. Subjects and methods We conducted a cross-sectional study to compare islet β-cell function and insulin resistance in T2DM patients (n = 3,254) who had had diabetes for different lengths of time and those in normal controls (n = 794) using ANOVA and LSD analysis. Results We found that compared with that in normal controls, HOMA-β in T2DM patients with a history of diabetes of less than 1 year was lower (approximately 52% of that of normal controls, p = 0.003), while HOMA-IR in these patients was higher (approximately 50% of that of normal controls, p = 0.007). Compared with that in other diabetic patients, HOMA-β in patients with a history of diabetes of more than 30 years was the lowest. HOMA-IR in patients with a history of diabetes of between 20 and 30 years was lower than that in other diabetic patients (p < 0.05). Conclusions There were obvious decreases in HOMA-β and increases in HOMA-IR in T2DM patients with a history of diabetes of less than 1 year compared with those in normal controls. Therefore, early screening and intervention for T2DM might help improve islet function and delay the progression of diabetes.

Humans , Adult , Middle Aged , Aged , Insulin Resistance , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , Homeostasis/physiology , Time Factors , Blood Glucose/analysis , Body Mass Index , Case-Control Studies , Cross-Sectional Studies , Islets of Langerhans/metabolism , Diabetes Mellitus, Type 2/physiopathology , Glucose Tolerance Test , Models, Biological
Rev. cuba. reumatol ; 21(1): e47, ene.-abr. 2019. tab
Article in Spanish | LILACS, CUMED | ID: biblio-1093801


Introducción: La diabetes se concibe como una enfermedad endocrina y metabólica determinada genéticamente y distinguida por un déficit parcial o total en la secreción de insulina, hormona segregada por las células beta del páncreas. Poco se ha escrito sobre las complicaciones musculoesqueléticas provocadas por esta enfermedad. Objetivo: reflexionar sobre las principales complicaciones musculoesqueléticas provocadas por la diabetes mellitus. Desarrollo: los síndromes periarticulares, los síndromes articulares y esqueléticos, los síndromes periarticulares y los síndromes musculares destacan entre las principales complicaciones musculoesqueléticas provocadas por la diabetes mellitus. Conclusiones: Resultan habituales los desórdenes reumáticos en la diabetes mellitus y sus tipologías se consideran amplias. Muchas de estas características están vinculadas con la duración de la enfermedad, al escaso control de la condición y a otras manifestaciones crónicas de la diabetes. Se establece como posible en la mayoría de casos que un control apropiado de la diabetes puede prevenir la mayoría de estas condiciones. Generalmente, el médico general se orienta a las complicaciones cardiovasculares, renales y oculares del paciente diabético por representar estas una gran afectación en la morbilidad y mortalidad. No obstante, las complicaciones reumáticas en los diabéticos pueden producir una discapacidad considerable. Por esta razón, se les debe incluir en el diseño de estrategias para perfeccionar el manejo clínico y la calidad de vida de los pacientes diabéticos(AU)

Introduction: Diabetes is conceived as a genetically determined endocrine and metabolic disease and distinguished by a partial or total deficit in the secretion of insulin, a hormone secreted by the beta cells of the pancreas. Little has been written about the musculoskeletal complications caused by this disease. Objective: to reflect on the main musculoskeletal complications caused by diabetes mellitus. Development: periarticular, joint and skeletal, periarticular and muscular syndromes stand out among the main musculoskeletal complications caused by diabetes mellitus. Conclusions: Rheumatic disorders are common in diabetes mellitus and their typologies are considered broad. Many of these characteristics are linked to the duration of the disease, the poor control of the condition and other chronic manifestations of diabetes. It is established as possible in most cases that an appropriate control of diabetes can prevent most of these conditions. Generally, the general practitioner is oriented to the cardiovascular, renal and ocular complications of the diabetic patient because they represent a great affectation in morbidity and mortality. However, rheumatic complications in diabetics can produce considerable disability. For this reason, they should be included in the design of strategies to improve the clinical management and quality of life of diabetic patients(AU)

Humans , Quality of Life , Diabetes Mellitus , Insulin Secretion , Metabolic Diseases , Insulin-Secreting Cells
Article in English | WPRIM | ID: wpr-739802


BACKGROUND: Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5. METHODS: To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis. RESULTS: Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss. CONCLUSION: Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

Animals , Apoptosis , Blotting, Western , Calcium-Transporting ATPases , Cyclin-Dependent Kinase 5 , Diabetes Mellitus, Type 2 , Down-Regulation , Endoplasmic Reticulum Stress , Endoplasmic Reticulum , Gene Expression , Genes, Homeobox , Glucose , Hyperglycemia , Insulin-Secreting Cells , Membrane Potential, Mitochondrial , Polymerase Chain Reaction , Rats , Reactive Oxygen Species , Reticulum , Reverse Transcription , Up-Regulation
Neuroscience Bulletin ; (6): 25-33, 2019.
Article in English | WPRIM | ID: wpr-775451


The influence of β-cell function on cardiovascular autonomic neuropathy (CAN), an important diabetes-related complication, is still unclear. In this study, we aimed to investigate the association between residual β-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN+ group (diabetic patients with CAN, n = 20) and a CAN- group (diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured. Homeostasis model assessment-beta cells (HOMA-B) and HOMA-insulin resistance (IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN- group, the CAN+ group had significantly lower fasting plasma insulin (6.60 ± 4.39 vs 10.45 ± 7.82 μ/L, P = 0.029), fasting C-peptide (0.51 ± 0.20 vs 0.82 ± 0.51 nmol/L, P = 0.004), and HOMA-B (21.44 ± 17.06 vs 44.17 ± 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio (r = 0.24, P = 0.043) and the 30:15 test (r = 0.26, P = 0.023). Further analysis showed that fasting C-peptide (OR: 0.041, 95% CI 0.003-0.501, P = 0.012) and HOMA-B (OR: 0.965, 95% CI 0.934-0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values < 0.67 nmol/L were more likely to have CAN than those with C-peptide levels ≥0.67 nmol/L (OR: 6.00, 95% CI 1.815-19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased β-cell function was closely associated with CAN in this population.

Adult , Asian Continental Ancestry Group , Blood Glucose , Diabetes Mellitus, Type 2 , Metabolism , Diabetic Neuropathies , Fasting , Physiology , Female , Glucose , Metabolism , Humans , Insulin , Metabolism , Insulin Resistance , Physiology , Insulin-Secreting Cells , Metabolism , Male , Middle Aged
Article in English | WPRIM | ID: wpr-785705


BACKGROUND: Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress.METHODS: NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis.RESULTS: We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK.CONCLUSION: This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.

Adenosine Triphosphate , AMP-Activated Protein Kinases , Animals , Blotting, Western , Cell Survival , Electron Transport , Endoplasmic Reticulum , Endoplasmic Reticulum Stress , Fatty Acids, Nonesterified , Insulin , Insulin-Secreting Cells , Metformin , Mice , NADPH Oxidases , Oxidative Stress , Phosphorylation , Polymerase Chain Reaction , Reactive Oxygen Species , rho-Associated Kinases , RNA, Messenger
Braz. j. med. biol. res ; 52(6): e8344, 2019. graf
Article in English | LILACS | ID: biblio-1001533


Type 2 diabetes mellitus (T2D) is a common endocrine and metabolic disorder, and poses threats to human health worldwide. Recently, microRNAs (miRNAs) have been suggested to play important roles in the pathophysiology of T2D. In this study, we explored the role of miR-3666 in T2D. miR-3666 was significantly down-regulated in the serum of T2D patients when compared to that of healthy volunteers, and miR-3666 expression level was negatively correlated with blood glucose levels of T2D patients. Overexpression of miR-3666 inhibited cell proliferation, reduced insulin secretion, and promoted cell apoptosis of pancreatic β-cell line (INS-1 cells). On the other hand, knockdown of miR-3666 had the opposite effects in INS-1 cells. The bio-informatics analysis using TargetScan revealed that adiponectin (ADIPOQ) was a downstream target of miR-3666, and the interaction between miR-3666 and ADIPOQ was validated by luciferase reporter assay. In addition, miR-3666 negatively regulated the mRNA and protein expression of ADIPOQ. Overexpression of ADIPOQ promoted insulin secretion after glucose stimulation, promoted cell proliferation, inhibited cell apoptosis, and partially abolished the effects of miR-3666 overexpression on insulin secretion, cell proliferation, and cell apoptosis of INS-1 cells. In conclusion, our results revealed that miR-3666 inhibited pancreatic cell proliferation, reduced insulin sensitivity, and promoted apoptosis by targeting ADIPOQ.

Humans , Male , Female , Middle Aged , Insulin Resistance/physiology , MicroRNAs/metabolism , Diabetes Mellitus, Type 2/physiopathology , Insulin-Secreting Cells/physiology , Apoptosis , MicroRNAs/genetics , Cell Proliferation , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , Adiponectin/genetics , Adiponectin/metabolism , Real-Time Polymerase Chain Reaction , Flow Cytometry
Biol. Res ; 52: 44, 2019. graf
Article in English | LILACS | ID: biblio-1019508


BACKGROUND: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic ß-cells that is activated by a variety of free fatty acids (FFAs). Once activated, it promotes glucose-stimulated insulin secretion (GSIS). However, increased levels of FFAs lead to lipotoxicity, inducing loss of ß-cell function. FFAR1 plays a key role in the development of type 2 diabetes (T2D), and previous studies have indicated the importance of developing anti-diabetic therapies against FFAR1, although its role in the regulation of ß-cell function remains unclear. The present study investigated the role of FFAR1 under lipotoxic conditions using palmitic acid (PA). The rat insulinoma 1 clone 832/13 (INS-1 832/13) cell line was used as a model as it physiologically resembles native pancreatic ß-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1ß), were selected as candidates to be analyzed under lipotoxic conditions. RESULTS: We revealed that PA-induced lipotoxicity affected GSIS in INS-1 cells and negatively modulated the activity of both IRS-1 and Akt. Reduced phosphorylation of both IRS-1 S636/639 and Akt S473 was observed, in addition to decreased expression of both INSR1ß and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1ß; mRNA. Finally, PA affected localization of FFAR1 from the cytoplasm to the perinucleus. CONCLUSIONS: In conclusion, our study suggests a novel regulatory involvement of FFAR1 in crosstalk with mTOR-Akt and IRS-1 signaling in ß-cells under lipotoxic conditions.

Animals , Rats , Palmitic Acid/toxicity , Receptors, G-Protein-Coupled/metabolism , Insulin-Secreting Cells/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Lipid Metabolism/drug effects , TOR Serine-Threonine Kinases/metabolism , Signal Transduction , Cell Line , Apoptosis , Insulin-Secreting Cells/metabolism
Int. j. morphol ; 37(1): 76-81, 2019. graf
Article in Spanish | LILACS | ID: biblio-990008


RESUMEN: Numerosas hipótesis se invocan para explicar el efecto beneficioso sobre el metabolismo glucídico tras la cirugía bariátrica. Algunos autores abogan por la secreción y liberación de distintas sustancias con funciones endocrinas (enterohormonas). Una de las sustancias más señaladas como efector, con efectos contrastados pero datos controvertidos, es el GLP-1. Nuestro estudio se realizó en ratas Wistar macho sanas, para evitar la ausencia de factores de confusión como son la DMT2 y la obesidad. Para conocer el mapa de adaptación a la secreción de GLP-1 tras la cirugía, se designaron 5 grupos: dos grupos control (de ayuno y de estrés quirúrgico); y tres grupos quirúrgicos (gastrectomía vertical, resección del 50 % del intestino medio y el Bypass gástrico con montaje en Y de Roux). Después de tres meses se estudiaron mediante técnicas inmunohistoquímicas el patrón de síntesis de GLP-1 en las distintas porciones del intestino delgado. También se estudió la expresión de los receptores de membrana en las células de los islotes pancreáticos. Se observó la existencia de un significativo aumento del número de células secretoras en íleon, duodeno y yeyuno en los grupos quirúrgicos de técnicas mixtas (RYGB) y malabsortivas (RI50). Igualmente se observó una elevación de los receptores pancreáticos en las mismas técnicas frente a los controles. Nuestros datos indican que la secreción intestinal de GLP-1 y su sensibilidad a nivel pancreáticas están aumentada, como efecto adaptativo a la agresión mecánica del tubo y a la alteración del flujo de nutrientes tras la cirugía.

SUMMARY: Numerous hypotheses are invoked to explain the beneficial effect on glucose metabolism after bariatric surgery. Some authors advocate for the secretion and release of various substances with endocrine functions (enterohormones). One of the substances most marked as effector, with contrasting effects but controversial data, is Glucagon-like peptide-1 GLP-1. Our study was performed in healthy male Wistar rats, to avoid the absence of confounding factors such as DMT2 and obesity. In order to know the map of adaptation to GLP-1 secretion after surgery, five groups were designated: Two control groups (fasting and surgical stress); and three surgical groups (vertical sleeve gastrectomy, 50 % midgut resection and Roux-en-Y gastric bypass). After three months, the GLP-1 synthesis pattern was studied by immunohistochemical techniques in the different portions of the small digestive tract. The expression of membrane receptors in pancreatic islet cells was also studied. There was a significant increase in the number of secretory cells in ileum, duodenum and jejunum in mixed surgical (RYGB) and malabsorptive (RI50) groups. An elevation of pancreatic receptors was also observed in the same techniques against controls. Our data indicated that intestinal secretion of GLP1 and its sensitivity to the pancreatic level were increased, both to an adaptive effect to the mechanical aggression of the digestive tube and to the alteration of nutrient flow after surgery.

Animals , Male , Rats , Glucagon-Like Peptide 1/metabolism , Bariatric Surgery , Pancreas/metabolism , Islets of Langerhans , Rats, Wistar , Insulin-Secreting Cells/metabolism , Intestine, Small/metabolism
Int. j. morphol ; 36(4): 1235-1240, Dec. 2018. tab, graf
Article in English | LILACS | ID: biblio-975689


This study was aimed to search the effect of wheatgrass on the Total Antioxidan (TAS)-Oxidan Status (TOS) and DNA damage in rat with diabetes. The rats used in the study were randomly divided into 4 groups that each of has 10 rats: Control group; 1 ml single dose phosphate-citrate buffer injected i.p (pH: 4.5), Diabetes group; 45 mg/kg single dose streptozotocin injected i.p., Wheatgrass group; was given oral wheatgrass (10 ml/kg/day) for 6 weeks, Diabetes +Wheatgrass group; 45 mg/kg single dose streptozotocin injected i.p. and wheatgrass (10 ml/kg/day) was given by oral during 6 weeks. After the process of experiment during 6 weeks, blood sample and pancreas tissue were taken. The analysis were done of blood glucose levels, TAS, TOS levels by colorimetric kits; DNA damage by ELISA kits in serum. The pancreas tissues were examined histopathologically. In the group of Diabetes+Wheatgrass was determined that the levels of glucose levels (p<0.001), TOS (p<0.05) and OSI (p<0.01) statistically decreased and heal histopatolojical compared to diabetes group. In the group of Wheatgrass was determined that the levels of TAS p<0.05 statistically increased from other groups. The statistical significance were not found in the level of serum 8OHdG differences between the groups. The beta cells were seen to increase in the group receiving wheatgrass for therapeutic purposes.As a conclusion, it was determined that wheatgrass strengthened the anti-oxidant defense system and reduced the glucose level in diabetic rats.

El objetivo de este estudio fue buscar el efecto del pasto de trigo sobre el estado total de antioxidantes (TAS) -Oxidan Status (TOS) y el daño del ADN en ratas con diabetes. Las ratas analizadas en el estudio se dividieron aleatoriamente en 4 grupos de 10 ejemplares cada uno: grupo control; 1 ml de tampón fosfato-citrato de dosis única inyectado i.p. (pH: 4,5)., Grupo diabetes; 45 mg / kg de estreptozotocina en dosis única inyectada i.p., grupo pasto de trigo; se administró pasto de trigo oral (10 ml / kg / día) durante 6 semanas, grupo diabetes + pasto de trigo; 45 mg / kg de estreptozotocina en dosis única inyectada i.p. y pasto de trigo (10 ml / kg / día) por vía oral durante 6 semanas. Después del proceso experimental durante 6 semanas, se tomaron muestras de sangre y tejido de páncreas. Se midieron los niveles de glucosa en sangre, TAS, y TOS mediante kits colorimétricos; El daño al ADN fue realizado por kits de ELISA en suero. Los tejidos del páncreas se examinaron histopatológicamente. En el grupo de diabetes + pasto de trigo se determinó que los niveles de glucosa (p <0,001), TOS (p <0,05) y OSI (p <0,01) disminuyeron estadísticamente y curaron histopatológicamente en comparación con el grupo de diabetes. En el grupo de pasto de trigo se determinó que los niveles de TAS p <0,05 se incrementaron estadísticamente con respecto a otros grupos. No fue estadísticamente significativo el nivel de las diferencias séricas de 8OHdG entre los grupos. Se observó que las células beta aumentaron en el grupo que recibió pasto de trigo con fines terapéuticos. Como conclusión, se determinó que el pasto de trigo fortaleció el sistema de defensa antioxidante y redujo el nivel de glucosa en las ratas diabéticas.

Animals , Rats , Triticum/chemistry , Plant Extracts/administration & dosage , Diabetes Mellitus, Experimental/drug therapy , Pancreas/drug effects , Blood Glucose/drug effects , DNA Damage/drug effects , Plant Extracts/pharmacology , Oxidants/blood , Rats, Wistar , Oxidative Stress/drug effects , Insulin-Secreting Cells/drug effects , Antioxidants/analysis
Rev. bras. ter. intensiva ; 30(3): 286-293, jul.-set. 2018. tab
Article in Portuguese | LILACS | ID: biblio-977969


RESUMO Objetivo: Verificar a incidência da hiperglicemia de estresse em crianças em condição grave e investigar a etiologia da hiperglicemia com base em um modelo de avaliação da homeostasia. Métodos: Estudo prospectivo de coorte, conduzido em uma unidade de terapia intensiva pediátrica da Cairo University, que incluiu 60 crianças com doença grave e 21 controles saudáveis. Utilizaram-se os níveis séricos de glicose, insulina e peptídeo C, avaliados em até 24 horas após a admissão. O modelo de avaliação da homeostasia foi utilizado para analisar a função das células beta e a sensibilidade à insulina. Resultados: A hiperglicemia foi estimada em 70% dos pacientes. Valores de glicemia ≥ 180mg/dL se associaram com desfechos piores. Os níveis de glicemia se correlacionaram de forma positiva com o Pediatric Risk for Mortality (PRISM III) e o número de órgãos com disfunção (p = 0,019 e p = 0,022, respectivamente), enquanto os níveis de insulina se correlacionaram de forma negativa com o número de órgãos com disfunção (r = -0,33; p = 0,01). O modelo de avaliação da homeostasia revelou que 26 (43,3%) das crianças em condições graves tinham baixa função de células beta e 18 (30%) baixa sensibilidade à insulina. Detectou-se patologia combinada em apenas dois (3,3%) pacientes. Baixa função de células beta se associou de forma significante com a presença de disfunção de múltiplos órgãos, disfunção respiratória, cardiovascular e hematológica, e presença de sepse. Conclusões: A disfunção de células beta pareceu ser prevalente em nossa coorte e se associou com disfunção de múltiplos órgãos.

ABSTRACT Objective: This study aimed to study the incidence of stress hyperglycemia in critically ill children and to investigate the etiological basis of the hyperglycemia based on homeostasis model assessment. Methods: This was a prospective cohort study in one of the pediatric intensive care units of Cairo University, including 60 critically ill children and 21 healthy controls. Serum blood glucose, insulin, and C-peptide levels were measured within 24 hours of admission. Homeostasis model assessment was used to assess β-cell function and insulin sensitivity. Results: Hyperglycemia was estimated in 70% of patients. Blood glucose values ≥ 180mg/dL were associated with a poor outcome. Blood glucose levels were positively correlated with Pediatric Risk for Mortality (PRISM III) score and number of organ dysfunctions (p = 0.019 and p = 0.022, respectively), while insulin levels were negatively correlated with number of organ dysfunctions (r = −0.33, p = 0.01). Homeostasis model assessment revealed that 26 (43.3%) of the critically ill patients had low β-cell function, and 18 (30%) had low insulin sensitivity. Combined pathology was detected in 2 (3.3%) patients only. Low β-cell function was significantly associated with the presence of multi-organ dysfunction; respiratory, cardiovascular, and hematological dysfunctions; and the presence of sepsis. Conclusions: β-Cell dysfunction appeared to be prevalent in our cohort and was associated with multi-organ dysfunction.

Humans , Male , Female , Infant , Child, Preschool , Child , Stress, Physiological/physiology , Sepsis/complications , Hyperglycemia/etiology , Multiple Organ Failure/physiopathology , Blood Glucose/metabolism , C-Peptide/blood , Intensive Care Units, Pediatric , Case-Control Studies , Incidence , Prospective Studies , Cohort Studies , Critical Illness , Sepsis/epidemiology , Egypt , Insulin-Secreting Cells/pathology , Homeostasis , Hyperglycemia/epidemiology , Insulin/blood , Multiple Organ Failure/epidemiology
Article in English | WPRIM | ID: wpr-719117


Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

Adult , Autoantibodies , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Diagnosis , Diagnostic Errors , Humans , Hypoglycemic Agents , Insulin , Insulin Resistance , Insulin-Secreting Cells , Mass Screening , Phenotype