The anxiolytic drug opipramol inhibits insulin-induced lipogenesis in fat cells and insulin secretion in pancreatic islets

The antidepressant drug opipramol has been reported to exert antilipolytic effect in human adipocytes, suggesting that alongside its neuropharmacological properties, this agent might modulate lipid utilization by peripheral tissues. However, patients treated for depression or anxiety disorders by this tricyclic compound do not exhibit the body weight gain or the glucose tolerance alterations observed with various other antidepressant or antipsychotic agents such as amitriptyline and olanzapine, respectively. To examine whether opipramol reproduces or impairs other actions of insulin, its direct effects on glucose transport, lipogenesis and lipolysis were investigated in adipocytes while its influence on insulin secretion was studied in pancreatic islets. In mouse and rat adipocytes, opipramol did not activate triglyceride breakdown, but partially inhibited the lipolytic action of isoprenaline or forskolin, especially in the 10–100 μM range. At 100 μM, opipramol also inhibited the glucose incorporation into lipids without limiting the glucose transport in mouse adipocytes. In pancreatic islets, opipramol acutely impaired the stimulation of insulin secretion by various activators (high glucose, high potassium, forskolin...). Similar inhibitory effects were observed in mouse and rat pancreatic islets and were reproduced with 100 μM haloperidol, in a manner that was independent from alpha2-adrenoceptor activation but sensitive to Ca2+ release. All these results indicated that the anxiolytic drug opipramol is not only active in central nervous system but also in multiple peripheral tissues and endocrine organs. Due to its capacity to modulate the lipid and carbohydrate metabolisms, opipramol deserves further studies in order to explore its therapeutic potential for the treatment of obese and diabetic states. (AU)

Glycemia-reducing effects of Bolivian nutraceutical plants / Efectos reductores de la glucemia de las plantas nutracéuticas bolivianas

INTRODUCTION: The prevalence of diabetes type 2 is increasing worldwide, thus the search of novel alternative ther¬apies is needed. According to their traditional use, we selected five Bolivian plants Chenopodium quinoa (CQ) Ama¬ranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) and Smallanthus sonchifolius (SS) that are traditionally used to control glycemia. METHODS: The effect of a single oral administration of Ethanolic (EtOH), hydro-ethanolic (EtOH70) and aqueous (Aq) extracts from all plant species were tested for their effect on blood glucose in non-fasted mice and during the oral glucose tolerance test (OGTT). The effect on insulin secretion was evaluated in mice pancreatic islets. RESULTS: EtOH70 extracts of all the plants showed glucose-reducing effect at the highest dose evaluated (2000 mg/ kg b.w.). EtOH70 extracts improved the glucose tolerance evaluated by the OGTT in mice fasted for 12 hours. The extracts have different effects on glucose homeostasis since just extracts of AC, LM and CQ but not CP and SS in¬creased insulin secretion as shown on mice pancreatic islets. The phytochemical qualitative characterization of EtOH70 extracts detected phenolic acids and flavonoids in AC, CP and CQ; alkaloids in LM and anthocyanidins in SS. None of EtOH70 extracts tested showed in vitro or in vivo acute toxicity at concentrations where they exhibit glucose lowering effects. CONCLUSIONS: We report here that extracts from AC, CQ, CP, LM and SS exhibit glucose lowering effect while just AC, CQ and LM stimulate directly the insulin secretion

INTRODUCCIÓN: La prevalencia de diabetes tipo 2 está aumentando en todo el mundo, por lo que se necesita la búsqueda de nuevas terapias alternativas. Según su uso tradicional, seleccionamos cinco plantas bolivianas Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) y Smallanthus sonchifolius (SS) que se usan tradicionalmente para controlar la glucemia. MÉTODOS: Se evaluó el efecto de la administración oral única de extractos etanólicos (EtOH), hidroetanólicos (EtOH70) y acuosos (Aq) de las plantas mencionadas para determinar su efecto sobre la glucosa en sangre en ratones en o sin ayunas y durante la prueba de tolerancia a la glucosa oral (PTGO). El efecto sobre la secreción de insulina se evaluó en islotes pancreáticos de ratones. RESULTADOS: Los extractos de EtOH70 de todas las plantas disminuyeron la glucemia a la dosis más alta evaluada (2000 mg / kg b.w.). Los extractos de EtOH70 mejoraron la tolerancia a la glucosa evaluada mediante la PTGO en ratones con ayuno de 12 horas. Los extractos tienen diferentes efectos sobre la homeostasis de la glucosa, ya que solo los extractos de AC, LM y CQ pero no CP y SS aumentaron la secreción de insulina como se muestra en los islotes pancreáticos de los ratones. La caracterización cualitativa fitoquímica de extractos de EtOH70 detectó ácidos fenólicos y flavonoides en AC, CP y CQ, alcaloides en LM y antocianidinas en SS. Ninguno de los extractos de EtOH70 probados mostró toxicidad aguda in vitro o in vivo a concentraciones en las que exhiben efectos reductores de glucosa. CONCLUSIÓN: Los extractos de AC, CQ, CP, LM y SS exhiben un efecto reductor de la glucosa, mientras que solo AC, CQ y LM estimulan directamente la secreción de insulina

Microscopic study of the rat pancreas after denervation

The aim of this study is to demonstrate that the denervation of the pancreas may affect the enteric neuronal plexus, which controls both the endocrine and exocrine parts of the pancreas. By using the light microscope, the histological changes of the islets of Langerhans and the pancreatic acini in the rat pancreas were studied two and three weeks after sympathectomy and truncal vagotomy. More-over, measurements of the changes infasting blood glucose levels and glucose tolerance tests in the control and experimental animals were recorded. Atrophic changes and degeneration of the pancreatic acinar cells and islets of Langerhans cells were observed after both sympathectomy and vagotomy. Biochemical measurements of fasting blood, and the glucose tolerance tests after sympathectomy and vagotomy were increased significantly, which is consistent with the histological results. The results of this study explain that the exocrine and endocrine parts of the pancreas are dependent on both sympathetic and parasympathetic innervation via the enteric plexuses of the rat pancreas. These results establish a firm correlation between the autonomic innervation and the enteric plexus, which controls the function of the endocrine and exocrine parts of the pancreas

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Invasive ductal adenocarcinoma arising from heterotopic pancreas in the jejunum: case report and literature review / Adenocarcinoma ductal invasivo sobre páncreas heterotópico en yeyuno: caso clínico y revisión de la literatura

Although the presence of pancreatic tissue outside of the usual anatomical location of the pancreas is not an uncommon incidental finding, the risk of malignancy is extremely low. We report a case of ductal adenocarcinoma arising within a focus of heterotopic pancreas, occurring in the jejunum of an 81 year old woman. The patient presented with a history of progressive gastrointestinal occlusive symptoms. Computerized tomography showed a mass in the jejunum, which was surgically removed. Histopathology revealed an invasive pancreatic ductal adenocarcinoma from pancreatic tissue with no connection with the original gland (Heinrich type II). At the 12-month follow-up, there were no signs of recurrence. Despite the low risk of malignancy in heterotopic pancreas, adenocarcinoma is the most frequent histological type, and the prognosis is still not clear. Lesions incidentally detected during surgery and in symptomatic patients need to be removed by conservative procedures in order to exclude malignant disease

Aunque la presencia de tejido pancreático fuera del páncreas es un hallazgo incidental no infrecuente, el riesgo de malignidad es extremadamente bajo. Presentamos el caso de una mujer de 81 años de edad con historia progresiva de síntomas oclusivos gastrointestinales, que presentó en el estudio por tomografía computarizada una lesión oclusiva localizada en yeyuno. El estudio histológico reveló la presencia de un adenocarcinoma ductal invasivo de tipo pancreático sobre tejido pancreático sin conexión con la glándula original (Heinrich tipo II). En el seguimiento posterior de la paciente a 12 meses, no se observaron signos de recurrencia. A pesar de que el riesgo de malignización del páncreas heterotópico es raro, el tipo histológico más frecuente es el adenocarcinoma. El pronóstico es aún incierto. Es necesaria la resección quirúrgica de estas lesiones en el momento del diagnóstico con el fin de descartar la presencia de enfermedad maligna

Variations in adrenal gland medulla and dopamine effects induced by the lack of Irs2

The adrenomedullary chromaffin cells' hormonal pathway has been related to the pathophysiology of diabetes mellitus. In mice, the deletion of insulin receptor substrate type 2 (Irs2) causes peripheral insulin resistance and reduction in Beta-cell mass, leading to overt diabetes, with gender differences on adrenergic signaling. To further unravel the relevance of Irs2 on glycemic control, we analyzed in adult Irs2 deficient (Irs2-/-) mice, of both sexes but still normoglycemic, dopamine effects on insulin secretion and glycerol release, as well as their adrenal medulla by an immunohistochemical and morphologic approach. In isolated islets, 10 μM dopamine significantly inhibited insulin release in wild-type (WT) and female Irs2−/− mice; however, male Irs2−/− islets were insensitive to that catecholamine. Similarly, on isolated adipocytes, gender differences were observed between WT and Irs2-/- mice in basal and evoked glycerol release with crescent concentrations of dopamine. By immunohistochemistry, reactivity to tyrosine hydroxylase (TH) in female mice was significantly higher in the adrenal medulla of Irs2-/- compared to WT; although no differences for TH-immunopositivity were observed between the male groups of mice. However, compared to their corresponding WT animals, adrenomedullary chromaffin cells of Irs2-/- mice showed a significant decrease in the cellular and nuclear areas, and even in their percentage of apoptosis. Therefore, our observations suggest that, together with gender differences on dopamine responses in Irs2-/- mice, disturbances in adrenomedullary chromaffin cells could be related to deficiency of Irs2. Accordingly, Irs2 could be necessary for adequate glucose homeostasis and maintenance of the population of the adrenomedullary chromaffin cells

Páncreas heterotópico. Obstrucción intestinal por invaginación del yeyuno / Heterotopic Pancreas. Intestinal Obstruction Caused by a Yeyunal Intussuception

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Páncreas ectópico: una masa intestinal muy infrecuente / Ectopic pancreas: a very unusual intestinal mass

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Tumores quísticos neuroendocrinos de páncreas (cPNET): revisión sistemática y metaanálisis de series de casos / Cystic pancreatic neuroendocrine tumors (cPNETs): a systematic review and meta-analysis of case series

Los tumores quísticos neuroendocrinos representan entre el 13% de los tumores neuroendocrinos de páncreas. El objetivo del trabajo es realizar una revisión sistemática y un metaanálisis de las series de casos descritas. Se realizó una revisión sistemática hasta septiembre de 2016 mediante una búsqueda en Medline, Scopus y EMBASE con los términos: "cystic pancreatic endocrine neoplasm", "cystic islets tumors" y "cystic islets neoplasms". De 795 citas se seleccionaron 80 estudios que describían 431 pacientes, incluyendo 5 casos propios. El 87,1% (n = 387) eran tumores esporádicos y el 10,3% (n = 40) correspondían a neoplasia endocrina múltiple tipo 1. El 44,6% (n = 135) fueron diagnosticados de forma incidental. La citología mostró una sensibilidad del 78,5%. El 85% (n = 338) eran tumores no funcionantes; y el insulinoma fue el más frecuente entre los funcionantes. Según la estadificación European Neuroendocrine Tumor Society, el 87,8% estaban limitados al páncreas (I-IIb) y el 12,2% eran avanzados (III-IV). La supervivencia libre de enfermedad a los 5 años en estadios (I-IIIa) y en los estadios (IIIb-IV) fue del 91,5% y 54,2% respectivamente; y fue significativamente menor (p = 0,0001) en los tumores funcionantes. En los pacientes con MEN-1 hubo mayor incidencia de funcionantes (62,5%) y multicéntricos (28,1%). Los tumores quísticos neuroendocrinos de páncreas expresan un fenotipo diferente a los tumores endocrinos sólidos, pero tienen un pronóstico similar, tras la resección a excepción de los tumores hereditarios (AU)

Cystic pancreatic neuroendocrine tumors represent 13% of all neuroendocrine tumors. The aim of this study is to analyze the phenotype and biologic behavior of resected cystic neuroendocrine tumors. A systematic review and meta-analysis were conducted until September 2016 using a search in Medline, Scopus, and EMBASE with the terms "cystic pancreatic endocrine neoplasm", "cystic islets tumors" and "cystic islets neoplasms". From the 795 citations recovered 80 studies reporting on 431 patients were selected. 87.1% (n = 387) were sporadic tumors and 10.3% (n = 40) corresponded to multiple endocrine neoplasia endocrine type 1. Were diagnosed incidentally 44.6% (n = 135). Cytology was found to have a sensitivity of 78.5%. Were non-functional tumors 85% (n = 338), and among the functional tumors, insulinoma was the most frequent. According to the European Neuroendocrine Tumor Society staging, 87.8% were limited to the pancreas (I-IIb), and 12.2% were advanced (III-IV). Disease-free survival at 5 years in stages (I-IIIa) and (IIIb-IV) was 91.5% and 54.2%, respectively; and was significantly lower (p = 0.0001) in functional tumors. In patients with multiple endocrine neoplasia there was a higher incidence of functional (62.5%) and multifocal (28.1%) tumors. Disease-free survival at 5 and 10 years was 60%. Cystic pancreatic neuroendocrine tumors exhibit phenotypical characteristics which are different to those of solid neuroendocrine tumors (AU)

A study on the effect of nicotine on the pancreas of albino rat

Nicotine forms the major addictive component of the tobacco smoke. The pancreas is one of the organs where the metabolic processes of tobacco take place. This work was designed to study the effect of nicotine administration and the effect of its withdrawal on the pancreas of albino rat. Twenty-five male albino rats were separated into two groups. Group I acted as control. Rats in group II received 1.5 mg/kg body weight of nicotine by subcutaneous injection day after day divided into two subgroups, each one containing ten rats. The first one received treatment for 4 months, and then the rats were sacrificed, while the second group received treatment for 4 months, and the rats were sacrificed after one month from treatment stoppage. The pancreases were removed and processed for histological examination and electron microscopy. Histopathological and electron microscopic examination of the pancreas of nicotinetreated rats showed degenerated and distorted pancreatic acini and β cells. These changes included pyknotic nucleus, cytoplasmic swelling, vacuolization and interstitial edema in pancreatic acinar cells. Some of the islets of Langerhans showed vaculation inside their cell and others did not show apparent changes. There was also a significant decrease in lipase and glucose levels. However, after withdrawal of nicotine, the pancreas showed more degenerated pancreatic acini and β cells. There was significant increase in blood glucose level and significant decrease in lipase of treated rats. Nicotine treatment for four months induced histopathological changes in both exocrine and endocrine pancreatic tissue that resemble the picture of chronic pancreatitis. These changes persisted long after cessation of nicotine exposure

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Light and electron microscopy of the pancreas of the Egyptian one-humped camel(Camelus dromedarius)

The exocrine portion of the pancreas consists of the pancreatic acini and their ducts. Hormones are synthesized by the cells of islets of Langerhans; they include insulin- (β- cells), glucagon- (α-cells), somatostatin- (∆-cells), and pancreatic polypeptide- (F- or PP-cells) immunoreactive cells. This study discusses the light and electron microscopic architecture of both the exocrine and endocrine pancreas of the dromedary camel. The cells of the pancreatic acini were pyramidal in shape with large spherical and centrally located heterochromatic nuclei. The basophilic basal and eosinophilic apical regions seen under the light microscope showed concentrated rough endoplasmic reticulum and homogenous electron-dense zymogen granules, respectively, on ultramicroscopy. Abundant elongated numerous mitochondria and Golgi complexes were found in the cytoplasm. The islets were scattered randomly among the acini and appeared as irregular spherical or oval masses of cells in light microscopy. The islet cells could be identified based on their location, cytological features, density of granules, and the degree to which the granule matrix was separated from its limiting membrane by an electron-dense area. The peripherally located α-cells had an irregular outline and possessed numerous relatively small membrane-bound granules with a moderate to high density core. Beta cells were larger in size and had fewer granules than of α-cells. Halo areas surrounded the moderate electron-dense granules. The polygonal ∆-cells were found in clumps throughout the islet and in between β-cells. Their granules were of moderate electron density and were tightly enclosed by a limiting membrane. Pancreatic polypeptide cells were seen associated with α and β cells. They were irregular small cells with small granules and dark cytoplasm. The juxtaposition of the endocrine and exocrine elements of the pancreas can be traced back to their embryological origin and can be also of functional significance. It facilitates the mutual functional interaction of both portions of the pancreas

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Tumores neuroendocrinos pancreáticos. ¿Qué conocemos de su historia? / Pancreatic neuroendocrine tumours. What do we know of their history?

Tomando como punto de partida la descripción de los islotes pancreáticos realizada por Paul Langerhans en 1869 se efectúa una revisión histórica de los diferentes protagonistas que, aproximadamente, a lo largo de este último siglo y medio han contribuido a la identificación de las principales hormonas que tienen su origen en el páncreas, de los métodos analíticos que permiten cuantificarlas, de las técnicas de imagen que informan sobre la localización de los tumores y de los diferentes tipos de neoplasias que se originan en esta glándula

Starting with Paul Langerhans, who first described pancreatic islets in 1869, this article reviews the various protagonists who, in the last century and a half, have contributed to the discovery of the main hormones originating in the pancreas, the analytical methods for their measurement, the imaging techniques for identifying tumoural location, and the various pancreatic neoplasms

Over-nutrient environment during both prenatal and postnatal development increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring

Prenatal and postnatal over-nutrition has emerged as a new health issue contributing to metabolic disorders in early development of the offspring. Accumulating evidence has suggested that adverse prenatal and postnatal environments gave rise to the predisposition to metabolic syndromes including hyperglycemia, obesity, and diabetes. However, little research has concentrated on the effects of exposures to both adverse conditions before and after birth of the offspring. In this study, we aimed to investigate whether prenatal and postnatal over-nutrition is able to cause metabolic disorders to female mice feed on high-fat/fructose diet (HFFD) as well as their offspring. Female mice were fed on either HFFD or a normal chow diet (NC), while their offspring were divided into four experimental groups as NC/NC, HFFD/NC, NC/HFFD, and HFFD/HFFD (prenatal/postnatal diet order), respectively. Both NC/HFFD and HFFD/HFFD offspring exhibited obvious body weight and fat content gain, hyperglycemia, and severe insulin resistance. Interestingly, when compared to NC/HFFD offspring, the HFFD/HFFD offspring exhibited more severe alterations in their metabolism and dysfunctions on pancreatic β-cells, suggesting a potential impact of prenatal HFFD on the programming of pancreatic β-cell deficiency in the fetus. Meanwhile, the results from HFFD/NC mice indicated that a balance diet after birth partially compensated the adverse prenatal HFFD impact. In conclusion, this study demonstrated that prenatal and postnatal over-nutrition increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring

Reunión anual del grupo de trabajo «islotes pancreáticos» de la Sociedad Española de Diabetes / Annual meeting of the working group "pancreatic islet" of the Spanish Society of Diabetes

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Secretory leukocyte protease inhibitor is a proliferation and survival factor for pancreatic cancer cells

Objectives: A variety of inflammatory cytokines have been demonstrated to participate in tumorigenesis and progression. Secretory leukocyte protease inhibitor (SLPI) has been demonstrated to show a broad-spectrum of anti-inflammatory effects. This study investigates the expression of SLPI in human pancreatic cancer tissues and cells as well as its biological effects in human pancreatic cancer cells. Methods: Reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot were used to detect SLPI mRNA and protein levels in human pancreatic cancer tissues, adjacent tissues, and pancreatic cancer Bxpc-3 and Panc-1 cells. Knockout of SLPI expression was established by recombinant viral vector expressing short hairpin RNA (shRNA) targeting SLPI. Cell viability was analyzed by MTT assay. Cell apoptosis was detected by Hochest33258 staining and flow cytometry assay. Results: Higher SLPI expression was observed in pancreatic tissues, Bxpc-3 cells, and Panc-1 cells compared to the peritumoral tissues (p < 0.01). SLPI expression in Bxpc-3 and Panc-1 cells was effectively silenced by shRNA (p < 0.001). Silencing of SLPI expression significantly reduced cell viability, inhibited cell proliferation, and induced cell apoptosis (p < 0.001). Conclusions: Abnormal over-expression of SLPI in pancreatic cancer cells may be associated with the development of disease through its roles in promoting cancer cell survival and proliferation as well as anti-apoptosis. SLPI can be used as a target for developing targeted therapy of pancreatic cancer (AU)

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Immunohistochemical identification of the endocrine cells in the pancreatic islets of the camel, horse and cattle

This study considers the distribution of various endocrine cells in islets of Langerhans in the pancreas of several species of domestic animal, including the dromedary camel (Camelus dromedarius) using immunohistochemistry, and relates our observations with reference to the well-documented general histology of the mammalian pancreas. The pancreatic islets were observed as compact areas of pale cells surrounded by darker presumably exocrine tissue. The most distinct delineation of the islets from the surrounding acini was in the horse and the least was in cattle. Insulin-immunoreactive cells (β-cells) were most abundant followed by glucagon- (α-), somatostatin- (∆-), and pancreatic polypeptide-immunoreactive (F- or PP-) cells in decreasing order, in all species except cattle where PP-cells were second to β-cells in their distribution. The most prominent special pattern was observed in the distribution of α- and β- cells in the pancreatic islet of the horse where α-cells were located in the center of the islet surrounded by β-cells. In the camel, β-cells were distributed throughout the islet in the center and the periphery. Alpha cells were mostly observed as clumps in the periphery area. Clumps of small number of ∆-cells and a few PP cells were found throughout the islet. In cattle, β-cells were distributed throughout the islets. Other cells occupied a more peripheral location. The physical differences in distribution of endocrine cells might result in differences in the need and interaction of hormones to each other in different species

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Regulatory role of adenosine in insulin secretion from pancreatic Beta-cells—Action via adenosine A1 receptor and beyond

Under physiological conditions, insulin secretion from pancreatic beta-cells is tightly regulated by different factors, including nutrients, nervous system, and other hormones. Pancreatic beta-cells are also influenced by paracrine and autocrine interactions. The results of rodent studies indicate that adenosine is present within pancreatic islets and is implicated in the regulation of insulin secretion; however, effects depend on adenosine and glucose concentrations. Moreover, species differences in adenosine action were found. In rat islets, low adenosine was demonstrated to decrease glucose-induced insulin secretion and this effect is mediated via adenosine A1 receptor. In the presence of high adenosine concentrations, other mechanisms are activated and glucose-induced insulin secretion is increased. It is also well established that suppression of adenosine action increases insulin-secretory response of beta-cells to glucose. In mouse islets, low adenosine concentrations do not significantly affect insulin secretion. However, in the presence of higher adenosine concentrations, potentiation of glucose-induced insulin secretion was demonstrated. It is also known that upon stimulation of insulin secretion, both rat and mouse islets release ATP. In rat islets, ATP undergoes extracellular conversion to adenosine. However, mouse islets are unable to convert extracellularly ATP to adenosine and adenosine arises from intracellular ATP degradation

Melatonin modulates Ca2+ mobilization and amylase release in response to cholecystokinin octapeptide in mouse pancreatic acinar cells

In the present work, we have evaluated the effect of an acute addition of melatonin on cholecystokinin octapeptide (CCK-8)-evoked Ca2+ signals and amylase secretion in mouse pancreatic acinar cells. For this purpose, freshly isolated mouse pancreatic acinar cells were loaded with fura-2 to study intracellular free Ca2+ concentration ([Ca2+]c). Amylase release and cell viability were studied employing colorimetric methods. Our results show that CCK-8 evoked a biphasic effect on amylase secretion, finding a maximum at a concentration of 0.1 nM and a reduction of secretion at higher concentrations. Pre-incubation of cells with melatonin (1 ìM–1 mM) significantly attenuated enzyme secretion in response to high concentrations of CCK-8. Stimulation of cells with 1 nM CCK-8 led to a transient increase in [Ca2+]c, followed by a decrease towards a constant level. In the presence of 1 mM melatonin, stimulation of cells with CCK-8 resulted in a smaller [Ca2+]c peak response, a faster rate of decay of [Ca2+]c and lower values for the steady state of [Ca2+]c, compared with the effect of CCK-8 alone. Melatonin also reduced the oscillatory pattern of Ca2+ mobilization evoked by a physiological concentration of CCK-8 (20 pM), and completely inhibited Ca2+mobilization induced by 10 pM CCK-8. On the other hand, Ca2+ entry from the extracellular space was not affected in the presence of melatonin. Finally, melatonin alone did not change cell viability. We conclude that melatonin, at concentrations higher than those found in blood, might regulate exocrine pancreatic function via modulation of Ca2+ signals (AU)

Protective effect of rat pancreatic progenitors cells expressing Pdx1 and nestin on islets survival and function in vitro and in vivo

To maintain islets survival and function is critical in successful pancreatic transplantation. Pancreatic progenitors cells (PPCs) with lineage potentials, giving rise to exocrine, endocrine, and duct cells, reside in developing and adult pancreas. As tissue-specific stem cells, they can produce pancreatic tissue-specific matrix factors to promote islets survival and function. The aim of our research was to investigate the protective effect of rat pancreatic-duodenal homeobox 1 (Pdx1)+/nestin+ PPCs on islets. In vitro, co-culturing islets with Pdx1+/nestin+ PPCs prolonged the former survival from 7 to 14 days. Furthermore, with high glucose (300.8 mg/dl) stimuli, the yield of insulin in co-cultures was significantly higher than that in control group (single islets group). In vivo, co-transplanting islets and Pdx1+/nestin+ PPCs for 3 days, the blood glucose of diabetic rat was significantly decreased to normal level and sustained for 2 weeks. Without Pdx1+/nestin+ PPCs in islets transplantation, hyperglycemia was reversed at day 7 and recovered at day 15. Pathology analysis showed that islets had remnants in co-transplantation at day 21, as complete graft rejection in alone islets transplantation. Our study showed that Pdx1+/nestin+ PPCs displayed the ability of preserving islets viability and function in vitro and prolonging their survival in vivo (AU)

Efecto citoprotector del tacrolimus a dosis bajas sobre islotes de Langeerhans en cultivo sometidos a estímulos por citocinas del rechazo agudo / Cytoprotective effect of low-dose tacrolimus on islets of Langerhans in cultures subjected to stimulation by acute rejection cytokines

Introducción La mejoría de los resultados en el trasplante de islotes pancreáticos se debe en gran parte a la introducción de nuevos protocolos de inmunosupresión que incluyen, entre otros, tacrolimus a bajas dosis. Este fármaco tiene efectos antioxidantes y antiapoptóticos que podrían ser de utilidad en la prevención del rechazo primario. Objetivos Evaluar la respuesta in vitro a tacrolimus a bajas dosis en islotes de rata estimulados con citocinas proinflamatorias implicadas en el rechazo primario de islotes. Material y método Se cultivaron islotes de rata en medio RPMI determinándose producción de lipoperóxido (LPO) y óxido nítrico (NO) y marcadores de apoptosis (nucleosomas y Bcl-2) en presencia de IL-1 (50UI/ml) e IF-γ (1000UI/ml) y adición de tacrolimus (FK-506; 5ng/ml).Resultados Tras la estimulación se apreció un aumento muy significativo (p<0,01) de los marcadores de estrés oxidativo (LPO 10,1±1,16pmol/islote x 24; NO 19,1±3,28pmol/islote x 24h) y apoptosis (nucleosomas 0,24±0,04; Bcl-2 0,69±0,212). Dichos efectos fueron contrarrestados de manera significativa tras añadir tacrolimus, siendo la reversión completa (p NS frente a controles) en el caso de la producción de lipoperóxidos (1,58pmol/islote x 24h) y óxido nítrico (9,81pmol/islote x 24h) así como en el descenso de Bcl-2 (1,37±0,23Ui/islote).Conclusiones El efecto citoprotector in vitro del tacrolimus a bajas dosis sobre islotes estimulados con citocinas proinflamatorias consigue aminorar la generación de estrés oxidativo y la activación de la apoptosis, habitualmente implicados en el rechazo en las primeras 48h postimplante (AU)

Introduction The improvement in pancreatic islet transplantation results is due to immunosuppression protocols that include, among others, low-dose tacrolimus. Both anti-inflammatory and anti-oxidant effects of tacrolimus could be useful in preventing primary rejection. Aim To evaluate in vitro islet low-dose tacrolimus response after pro-inflammatory stimulation. Material and methodsIsolated rat islets were cultured in RPMI medium in the presence of IL-1 (50UI/mL) plus IF-γ (1000UI/mL) and tacrolimus (5ng/mL). The 24h production of lipoperoxide (LPO) and nitric oxide (NO) were measured as oxidative stress markers. Determination of apoptosis markers (nucleo some content and Bcl-2) was also performed. Results Oxidative stress (LPO 10.1±1.16pmol/islet x 24; NO 19.1±3.28pmol/islet x 24h) and apoptosis (nucleosome 0.24±0.04UI/islet; Bcl-2 0.69±0.212UI/islet) markers showed a very significant increase after cytokine stimulation (p<0.01). Both effects improved by adding tacrolimus to the medium. Protective effect was complete when lipoperoxide (1.58pmol/islet x 24h), nitric oxide (9.81pmol/islet x 24h) and Bcl-2 (1.37±0.23UI/islet) were determined. Conclusion In vitro cytoprotective effect of low-dose tacrolimus on isolated rat islets decreases both oxidative stress and apoptosis markers after stimulation of pro-inflammatory mediators (AU)

Aproximaciones de terapia génica para la diabetes tipo 1 / Gene therapy for type 1 diabetes

La diabetes mellitus tipo 1 es una enfermedad crónica que resulta de la destrucciónautoinmune de las células beta pancreáticas. Aunque la terapia sustitutivacon insulina permite a los pacientes llevar una vida activa, no impide laaparición de complicaciones secundarias graves cuando el control de la glucemiaes insufi ciente, y está asociada al riesgo de padecer episodios de hipoglucemia.Por tanto, es necesario disponer de terapias más efectivas y seguras. Laterapia génica se puede considerar una nueva aproximación o herramienta prometedoraen la búsqueda de una curación para la diabetes. Los avances en elcampo de la terapia génica nos permiten disponer de vectores más seguros yefi caces para transferir los genes de interés a las diferentes células/tejidos delorganismo. En esta revisión se presentan, por un lado, los elementos que espreciso tener en cuenta a la hora de diseñar una estrategia de terapia génicapara la diabetes y, por otro, las diferentes aproximaciones actuales para la diabetestipo 1. Por último, se discuten los resultados más relevantes descritos eneste campo(AU)

Type 1 diabetes mellitus is a chronic disease characterized by autoimmunedestruction of insulin-producing beta-cells. Current insulin replacement therapiesoffer many patient benefits, but do not prevent secondary complicationswhen glycemic control is insufficient and are associated with the risk of hypoglycemia.Therefore, more efficient and safer therapies are still required.Gene therapy is considered a new approach/tool to treat diabetes. Importantadvances in the field of gene therapy have made vectors both more efficientand safer in delivering genes to most tissues and cell types. In this review, wefirst analyze the key issues that should be considered for designing a newgene therapy approach for diabetes and second, we discuss main approachescurrently under investigation for this disease. Finally, most relevant results inthe field are presented(AU)