Zarzio Ameliorates Non-alcoholic Fatty Liver Induced By a High Fat Diet in a Rat Experimental Model: A Histological and Immunohistochemical Study

SUMMARY: The therapeutic effect of a granulocyte-colony stimulating factor (G-CSF) biosimilar drug, zarzio, on non-alcoholic fatty liver disease (NAFLD) in a rat model was investigated in this study. Thirty-two rats were randomly divided into four groups. Groups I and II were fed a standard laboratory diet, whereas groups III and IV were fed a high fat diet (HFD) for 14 weeks. After 12 weeks of feeding, groups I and III were administered normal saline, and groups II and IV were intraperitoneally administered zarzio (200 mg/kg/day) for two consecutive weeks. Hematoxylin-eosin (H&E) staining was used to assess hepatic and pancreatic morphology in all groups, oil red O (ORO) staining for lipid accumulation, Masson's staining for fibrosis, and immunohistochemistry assay for hepatic protein expression of insulin receptor substrate 1 (IRS1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumour necrosis factor alpha (TNF-α) and pancreatic caspase-3. The NAFLD rats (group III) developed hepatic steatosis with increased lipid accumulation, perisinusoidal fibrosis, upregulated IRS1, TNF-α (all P<0.05) without a significant increase in Nrf2 protein expression compared with normal control. In comparison, model rats treated with zarzio (group IV) showed significant rejuvenation of the hepatic architecture, reduction of fat accumulation, and fibrosis. This was accompanied by the upregulation of Nrf2, downregulation of IRS1 and TNF-α protein expression (all P<0.05). No correlation was detected between NAFLD and non-alcoholic fatty pancreas disease (NAFPD). However, the pancreatic β-cells in group III showed increased caspase-3 expression, which was decreased (P<0.05) in group IV. In conclusion, zarzio ameliorates NAFLD by improving the antioxidant capacity of liver cells, reducing hepatic IRS1, TNF-α protein expression and pancreatic β-cells apoptosis, suggesting that zarzio could be used as a potential therapy for NAFLD.

En este estudio se investigó el efecto terapéutico de un fármaco biosimilar del factor estimulante de colonias de granulocitos (G-CSF), zarzio, sobre la enfermedaddel hígado graso no alcohólico (NAFLD) en un modelo de rata. Treinta y dos ratas se dividieron aleatoriamente en cuatro grupos. Los grupos I y II fueron alimentados con una dieta estándar de laboratorio, mientras que los grupos III y IV fueron alimentados con una dieta alta en grasas (HFD) durante 14 semanas. Después de 12 semanas de alimentación, a los grupos I y III se les administró solución salina normal, y a los grupos II y IV se les administró zarzio por vía intraperitoneal (200 mg/kg/ día) durante dos semanas consecutivas. Se utilizó tinción de hematoxilina-eosina (H&E) para evaluar la morfología hepática y pancreática en todos los grupos, tinción con rojo aceite O (ORO) para la acumulación de lípidos, tinción de Masson para la fibrosis y ensayo de inmunohistoquímica para la expresión de la proteína hepática del sustrato 1 del receptor de insulina (IRS1), factor nuclear eritroide 2 relacionado con el factor 2 (Nrf2), factor de necrosis tumoral alfa (TNF-α) y caspasa-3 pancreática. Las ratas NAFLD (grupo III) desarrollaron esteatosis hepática con aumento de la acumulación de lípidos, fibrosis perisinusoidal, IRS1 y TNF-α regulados positivamente (todos P <0,05) sin un aumento significativo en la expresión de la proteína Nrf2 en comparación con el control normal. En comparación, las ratas modelo tratadas con zarzio (grupo IV) mostraron un rejuvenecimiento significativo de la arquitectura hepática, una reducción de la acumulación de grasa y fibrosis. Esto estuvo acompañado por la regulación positiva de Nrf2, la regulación negativa de la expresión de la proteína IRS1 y TNF-α (todas P <0,05). No se detectó correlación entre NAFLD y la enfermedad del páncreas graso no alcohólico (NAFPD). Sin embargo, las células β pancreáticas en el grupo III mostraron una mayor expresión de caspasa-3, que disminuyó (P <0,05) en el grupo IV. En conclusión, zarzio mejora la NAFLD al mejorar la capacidad antioxidante de las células hepáticas, reduciendo el IRS1 hepático, la expresión de la proteína TNF-α y la apoptosis de las células β pancreáticas, lo que sugiere que zarzio podría usarse como una terapia potencial para la NAFLD.

Presencia de autoanticuerpos anti islotes pancreáticos en diabetes tipo 1 durante la edad pediátrica / Presence of anti-pancreatic islet autoantibodies in type 1 diabetes in children

En la Diabetes tipo 1 (DM1) la pérdida de células ß pancreáticas es consecuencia de un proceso de autoinmunidad que cursa con la presencia de autoanticuerpos anti-islotes pancreáticos (AAPs). Estos AAPs son marcadores útiles para la clasificación de la enfermedad. En un centro pediátrico de tercer nivel se analizó la frecuencia de presentación de GADA, IA-2A, ZnT8A e IAA en un grupo con reciente debut entre enero 2018 y agosto 2021 (n= 90). Además, se investigó la frecuencia de presentación y relación de los AAPs con la edad, sexo y tiempo de evolución en pacientes en seguimiento (n= 240). En el grupo de debut se obtuvo positividad de GADA, IA-2A, ZnT8A y IAA en 77,8; 60; 62 y 47,8% de los pacientes respectivamente, un 4% no presentó AAPs. El 95,6% de los pacientes presentaron al menos un AAPs positivo. La frecuencia de IAA en el grupo en debut fue mayor en menores de 5 años. En el grupo en seguimiento el 75,2% resultaron GADA positivo (85,7% en mujeres y 62,8% en varones) p<0,05. IA-2A y ZnT8A fueron positivos en 45 y 51.7% respectivamente. El 91% presentaron al menos un AAP positivo. En este grupo se evidenció una menor positividad en función del tiempo de evolución. Se pudo determinar la frecuencia de presentación de los AAPs en un grupo en debut y la relación con la edad, sexo y tiempo de evolución en pacientes en seguimiento. La determinación de APPs facilita la correcta clasificación y elección de la terapia adecuada (AU)

In type 1 diabetes (DM1) the loss of pancreatic ß-cells is a consequence of an autoimmune process that results in the presence of pancreatic anti-islet autoantibodies (PAAs). PAAs are useful markers for the classification of the disease. The frequency of presentation of GADA, IA-2A, ZnT8A, and IAA in a group with recent debut seen between January 2018 and August 2021 (n= 90) was analyzed in a tertiary pediatric center. In addition, we investigated the frequency of presentation and association of PAAs with age, sex, and time of evolution in patients in follow-up (n= 240). In the debut group, GADA, IA2A, ZnT8A, and IAA positivity was found in 77.8, 60, 62, and 47.8% of patients, respectively; no PAAs were observed in 4% of the patients. Overall, 95.6% presented at least one positive PAA. The frequency of IAA in the debut group was higher in children younger than 5 years. In the follow-up group, 75.2% were GADA positive (85.7% of females and 62.8% of males) p<0.05. IA-2A and ZnT8A were positive in 45 and 51.7% respectively. Ninety-one percent presented with at least one positive PAA. In this group, a lower positivity was evidenced as a function of the time of evolution. The frequency of presentation of PAAs in a debut group and the relationship with age, sex, and time of evolution in patients in follow-up was demonstrated. The assessment of PAAs facilitates the correct classification and choice of adequate therapy (AU)

Long-term resveratrol administration improves diabetes-induced pancreatic oxidative stress, inflammatory status, and ß cell function in male rats

Abstract Diabetes is a metabolic disorder caused by insulin resistance or a defect in the pancreatic beta cells in insulin secretion. The aim of this study was to evaluate the possible effectiveness of long-term administration of resveratrol on inflammatory and oxidative stress markers in the pancreatic tissue of diabetic rats. Male Wistar rats (n = 24) were randomly divided into four groups of six animals, namely a healthy group, a healthy group receiving resveratrol, a diabetic control group, and a diabetic group receiving resveratrol. Diabetes was induced by single dose injection of streptozotocin (50 mg/kg; ip), 15 min after injection of nicotinamide (110 mg/kg; ip). Resveratrol was also administered by gavage (5 mg/kg/day) for 4 months. Administration of resveratrol alleviated hyperglycemia, weight loss and pancreatic ß cell function measured by HOMA-ß. Resveratrol improved oxidative stress (nitrate/nitrite, 8-isoprostane and glutathione) and proinflammatory markers (tumor necrosis factor α, cyclooxygenase 2, interleukin 6 and nuclear factor kappa B) in the pancreatic tissue of diabetic rats. Resveratrol administration had no significant effect on the activity of superoxide dismutase and catalase enzyme. These observations indicate that resveratrol administration may be effective as a beneficial factor in improving pancreatic function and reducing the complications of diabetes

Nuclear factor-Y mediates pancreatic β-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress / 中华医学杂志(英文版)

BACKGROUND@#Pancreatic β-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in β-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of β-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in β-cell compensatory response to insulin resistance in obesity is unclear.@*METHODS@#In this study, using obese ( ob/ob ) mice with an absence of NF-Y subunit A (NF-YA) in β-cells ( ob , Nf-ya βKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to β-cell compensation upon metabolic stress.@*RESULTS@#Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of β-cell Nf-ya in obese mice worsened glucose intolerance and resulted in β-cell dysfunction, which was attributable to augmented β-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya βKO mice were sensitive to palmitate-induced β-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 β-cell line could rescue palmitate-induced β-cell apoptosis, dysfunction, and mitochondrial impairment.@*CONCLUSION@#Pancreatic NF-Y might be an essential regulator of β-cell compensation under metabolic stress.

Ferulic acid enhances insulin secretion by potentiating L-type Ca2+ channel activation / 中西医结合学报

OBJECTIVE@#To investigate the effect of ferulic acid, a natural compound, on pancreatic beta cell viability, Ca2+ channels, and insulin secretion.@*METHODS@#We studied the effects of ferulic acid on rat insulinoma cell line viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. The whole-cell patch-clamp technique and enzyme-linked immunosorbent assay were also used to examine the action of ferulic acid on Ca2+ channels and insulin secretion, respectively.@*RESULTS@#Ferulic acid did not affect cell viability during exposures up to 72 h. The electrophysiological study demonstrated that ferulic acid rapidly and concentration-dependently increased L-type Ca2+ channel current, shifting its activation curve in the hyperpolarizing direction with a decreased slope factor, while the voltage dependence of inactivation was not affected. On the other hand, ferulic acid have no effect on T-type Ca2+ channels. Furthermore, ferulic acid significantly increased insulin secretion, an effect inhibited by nifedipine and Ca2+-free extracellular fluid, confirming that ferulic acid-induced insulin secretion in these cells was mediated by augmenting Ca2+ influx through L-type Ca2+ channel. Our data also suggest that this may be a direct, nongenomic action.@*CONCLUSION@#This is the first electrophysiological demonstration that acute ferulic acid treatment could increase L-type Ca2+ channel current in pancreatic β cells by enhancing its voltage dependence of activation, leading to insulin secretion.

Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet β cells / 中国针灸

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Molecular mechanism of geniposide in regulating GLUT2 glycosylation in pancreatic β cells / 中国中药杂志

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.

Mechanism of Jinqi Jiangtang Tablets in treatment of pancreatic β cell dysfunction based on network pharmacology and molecular docking technology / 中国中药杂志

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.

Effects and mechanism of stem cells from human exfoliated deciduous teeth combined with hyperbaric oxygen therapy in type 2 diabetic rats

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.

Divergent effects of lycopene on pancreatic alpha and beta cells / 生理学报

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.

Clinical characteristics, residual beta-cell function and pancreatic auto-antibodies in Thai people with long-standing type 1 diabetes mellitus / Journal of the ASEAN Federation of Endocrine Societies

@#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

Changes in early intestinal flora and Type 1 diabetes / 中南大学学报(医学版)

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.

Pancreatic islet stereology: estimation of beta cells mass / Estereología de los islotes pancreáticos: estimación de la masa de células beta

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.

Rol de la osteocalcina más allá del hueso / Role of osteocalcin beyond bone

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)

The differences in homeostasis model assessment values in type 2 diabetic patients with different lengths of history of diabetes

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.

Complicaciones musculoesqueléticas de la diabetes mellitus / Musculoskeletal complications of diabetes mellitus

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)

Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5

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.

Pancreatic ß-cell function is inhibited by miR-3666 in type 2 diabetes mellitus by targeting adiponectin

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.

Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic ß-cells

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.