Anti-diabetic effects of Inonotus obliquus extract in high fat diet combined streptozotocin-induced type 2 diabetic mice / Efectos antidiabéticos del extracto de Inonotus obliquus en ratones diabéticos tipo 2 inducidos por estreptozotocina combinada con una dieta rica en grasas

Introduction: type 2 diabetes (T2DM) is a complex disease affected by lifestyle and genetic factors. Although the drugs currently used to treat T2DM have certain curative effects, they still have some adverse side effects. Therefore, it is urgent to find new effective drugs with few side effects to cure T2DM. Objective: to study the role of Inonotus obliquus (IO) in diabetic model mice. Methods: we used high-fat diet (HFD) combined with streptozocin (STZ) to establish a diabetic mouse model. Mice were divided into non-high-fat diet group (ND), diabetes model group (HFD + STZ) and IO-treated diabetes model group (IO). The mice in the IO group were orally treated with IO (150 mg/kg) at 10 ml/kg for five weeks. Body weight, glucose level, food intake and water consumption, glucose tolerance and insulin tolerance were evaluated in all mice. The pathological sections of liver, kidney and pancreas were observed by hematoxylin-eosin staining. Results: after IO administration, the blood glucose level, water consumption, low-density lipoprotein (LDL) and triacylglycerol (TG) levels of mice decreased. Compared with the HFD + STZ group, the number of normal islet iiiiiiii cells increased and focal necrosis of the liver was significantly reduced in the IO administration group. Conclusions: IO reduced the levels of blood glucose, restored body weight, and enhanced insulin sensitivity along with insulin tolerance and glucose tolerance in diabetic mice. Additionally, IO also reversed HFD and STZ-induced organ injury. (AU)

Introducción: la diabetes mellitus tipo 2 (T2DM) es una enfermedad compleja influenciada por el estilo de vida y los factores genéticos. En la actualidad, aunque los medicamentos para la diabetes tipo 2 tienen cierto efecto curativo, todavía tienen algunos efectos secundarios. Por lo tanto, es urgente encontrar nuevos medicamentos para la diabetes tipo 2 que tengan un buen efecto curativo y menos efectos secundarios. Objetivo: estudiar el papel del Inonotus obliquus (IO) en ratones diabéticos. Métodos: se estableció un modelo de ratón diabético con dieta de alto contenido en grasas (HFD) y estreptozocina (STZ). Los ratones se dividieron en el grupo de dieta no alta en grasas (ND), el grupo modelo de diabetes mellitus (HFD + STZ) y el grupo modelo de diabetes mellitus tratado con IO. Los ratones del grupo IO recibieron 10 ml/kg de IO (150 mg/kg) durante cinco semanas. Se observaron el peso corporal, el nivel de azúcar en sangre, la ingesta de alimentos, la ingesta de agua potable, la tolerancia a la glucosa y la tolerancia a la insulina de los ratones de cada grupo, y se estudiaron muestras de biopsias hepáticas, renales y pancreáticas mediante tinción de hematoxilina eosina. Resultados: los niveles de glucosa en sangre, el consumo de agua, la lipoproteína de baja densidad (LDL) y los triglicéridos (TG) disminuyeron después de la administración de IO. En comparación con el grupo HFD+STZ, el número de células β pancreáticas normales y la necrosis focal hepática disminuyeron significativamente en el grupo IO. Conclusiones: el IO redujo el nivel de glucosa en sangre, ayudó a recuperar el peso corporal y mejorar la sensibilidad a la insulina, la tolerancia a la insulina y la tolerancia a la glucosa en ratones diabéticos. Además, el IO revirtió el daño orgánico inducido por HFD y STZ. (AU)

Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury

It has been shown that diabetes modifies the myocardial responses to ischemia/reperfusion (I/R) and to cardioprotective agents. In this study, we aimed to investigate the effects of combined treatment with ischemic postconditioning (IPostC) and cyclosporine A (CsA) on inflammation and apoptosis of the diabetic myocardium injured by I/R. Eight weeks after induction of diabetes in Wistar rats, hearts were mounted on a Langendorff apparatus and were subsequently subjected to a 30-min regional ischemia followed by 45-min reperfusion. IPostC was induced at the onset of reperfusion, by 3 cycles of 30-s reperfusion/ischemia (R/I). The concentration of creatine kinase (CK), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined; the levels of total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β) and B-cell lymphoma 2 (Bcl-2) were quantified by western blotting, and the rate of apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Administration of either IPostC or CsA alone in nondiabetic animals significantly reduced CK, TNF-α, IL-1β, and IL-6 concentrations, increased the p-GSK3β and Bcl-2, and decreased the level of apoptosis (P < 0.05) but had no effect on diabetic hearts. However, in diabetic animals, after administration of CsA, the cardioprotective effects of IPostC in increasing the p-GSK3β and Bcl-2 and decreasing apoptosis and inflammation were restored in comparison with nonpostconditioned diabetic hearts. IPostC or CsA failed to affect apoptosis and inflammation and failed to protect the diabetic myocardium against I/R injury. However, combined administration of IPostC and CsA at reperfusion can protect the diabetic myocardium by decreasing the inflammatory response and apoptosis (AU)

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Dietary flaxseed oil and fish oil ameliorates renal oxidative stress, protein glycation, and inflammation in streptozotocin-nicotinamide-induced diabetic rats

Protective and prophylactic effects of omega-3 fatty acids on oxidative stress and inflammation are well known. We assessed beneficial effects of flaxseed oil and fish oil on streptozotocin (65 mg/kg; i.p.)-nicotinamide (110 mg/kg; i.p.) induced diabetic rats by studying renal expression of antioxidant and inflammatory genes. Diabetic rats given 10 % flaxseed oil or 10 % fish oil diet for 35 days showed significant decrease in renal lipid peroxidation. Flaxseed oil diet resulted in up-regulation of renal superoxide dismutase-1 (SOD-1) (activity and expression) and glutathione peroxidase-1 (GPx-1) expression. Furthermore, both diets up-regulated catalase (CAT) (activity and expression) and down-regulated heme oxygenase-1 (HO-1) expression. Both diets were able to limit the renal advanced glycation end products (AGEs) formation and reduced receptor of AGE (RAGE) protein expression significantly. Expressions of interleukin-6 (IL-6) and NF-κB p65 subunit were down-regulated significantly by flaxseed oil or fish oil diet. The histological tubular injuries were also lowered by both diets. These results suggest that dietary ω-3 fatty acids may slow the progression of diabetic nephropathy (DN) associated with oxidative stress, glycation, and inflammation in the kidney (AU)

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Metabolic effects of B-glucans (Saccharomyces cerevisae) per os administration in rats with streptozotocin-induced diabetes / Efectos metabólicos de los β-glucanos (saccharomyces cerevisiae) a través de la administración oral en ratas con diabetes inducida por estreptozotocina

Introduction: beta-glucans (BG) derived from plant tissues are reported to show metabolic effects. In contrast, those fibers isolated from yeast seem to be more related to immune response modulation. Since diabetic individuals are more susceptible to exacerbation of inflammatory signs, the ingestion of fibers that could conjugate both metabolic and immune effects would be of great importance. Objective: we investigated the effect of BG - Saccharomyses cerevisae - ingestion on glycemic and lipoprotein profile of diabetic rats. Design: twenty-four adult Wistar rats were used, distributed into 4 groups in a design of entirely casualized delineation with a 2 x2 factorial model (with and without diabetes; with and without BG). Diabetes Mellitus was induced by an intraperitoneal injection of 80mg/kg of strepzotocin. Thus, animals with fasting glycemia of over 250mg/dl were considered diabetic. Forty-eight hours after induction, the rats received daily doses of 30 mg/kg of BG or saline solution by gavage during 28 days. Results and discussion: the Groups with DM presented a higher glycemic index and lower C peptide levels than the control groups, in addition to lower weight gain and higher ration consumption, water ingestion and urinary volume. Total cholesterol levels (CT), LDL-C + VLDL-C, plasma triacylglycerides (TAG) and alanine aminotransferase (ALT) were also higher in the diabetic animals (p<0.05). No histopathological hepatic alterations were observed in any of the groups. Furthermore, the diabetic animals present increase in villous:crypt ratio (V:C) in the duodenum, without interference of BG. No alterations in the carcass were observed between the groups. Conclusion: it was concluded that the use of BG significantly reduced the glycemic, TAG and ALT levels, showing its therapeutic potential (AU)

Introdución: los beta-glucanos (BG) derivados de tejidos vegetales se ha informado que muestran efectos metabólicos. Por el contrario, esas fibras aisladas de levadura parecen estar más relacionadas con la modulación de la respuesta inmune. Dado que los individuos con diabetes son más susceptibles a la exacerbación de los signos inflamatorios, la ingestión de fibras sí podría conjugar ambos efectos metabólicos e inmunológicos, lo cual sería de gran importancia. Objetivo: el objetivo de este estudio fue investigar los efectos de la ingestión de los BG —Saccharomyses cerevisiae— en el perfil glucémico y la lipoproteína de ratas diabéticas. Metodos: en el diseño de delineación, totalmente precario, fueron utilizadas 24 ratas Wistar macho adultas distribuidas en cuatro grupos, con un modelo factorial 2x2 (con y sin diabetes, con y sin BG). La diabetes mellitus fue inducida por la inyección intraperitoneal de un 80 mg/kg de estrepzotocina. Por lo tanto, los animales con glucemia en ayunas de más de 250 mg/dl fueron considerados diabéticos. Cuarenta y ocho horas después de la inducción, las ratas recibieron dosis diarias de 30 mg/kg de BG o solución salina mediante alimentación forzada durante 28 días. Resultados y discusión: los grupos con DM presentó el mayor índice glucémico y menores niveles de péptido C que los grupos de control, además de reducir el aumento de peso y un mayor consumo de la ración, la ingestión de agua y el volumen urinario. Los niveles de colesterol total (CT), LDL-C + VLDL-C, triacilglicéridos plasmáticos (TAG) y alanina aminotransferasa (ALT) también fueron más altos en los animales diabéticos (p<0,05), y había alteraciones en los niveles de HDL-C. La ingestión de BG redujo las concentraciones de glucosa en sangre (30%), TAG (32%) y ALT (41%) (p<0.05). No se observaron alteraciones hepáticas en ninguno de los grupos. Además, los animales diabéticos presentaron un aumento de la relación cripta:vellosidades (V:C) en el duodeno, sin interferencia de BG. No se observaron alteraciones en la carcasa entre los grupos. Conclusión: se concluyó que el uso de BG redujo significativamente la glucemia, los niveles de TAG Y ALT, mostrando su potencial terapéutico (AU)

Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal

This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and beta cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and beta cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent (AU)

Secoisolariciresinol diglucoside in high-fat diet and streptozotocin-induced diabetic nephropathy in rats: a possible renoprotective effect

Due to substantial morbidity and high complication rate of diabetes mellitus, which is considered as the third killer in the world, a search for the effective blockade of the progression of diabetic nephropathy (DN) remains a therapeutic challenge. Alternative antidiabetic drugs from natural plants are highly demanded nowadays. The aim of this study was to investigate the renoprotective effect of secoisolariciresinol diglucoside (SDG) on DN induced in rats. Diabetes was induced in male Sprague-Dawley rats by a high-fat diet (HFD) and an intraperitoneal 35 mg/kg streptozotocin (STZ) injection. Rats were divided into four groups: normal control rats, diabetic control rats, diabetic rats treated with SDG at 10 mg/kg/day for 4 weeks, and diabetic rats treated with SDG at 20 mg/kg/day for 4 weeks. At the end of the treatment, blood and renal tissue samples were collected for biochemical examination. The results revealed that SDG treatment significantly increased insulin level and decreased blood glucose, fructosamine, creatinine, and blood urea nitrogen levels in diabetic rats. Also, SDG significantly increased renal reduced glutathione, superoxide dismutase and decreased malondialdehyde and nitric oxide levels. In addition, SDG downregulated the renal nuclear factor kappa-B (NF-κB), tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) and upregulated renal survivin and B-cell lymphoma-2 (Bcl-2) expressions when compared with untreated diabetic control rats. This study demonstrated, for the first time, the renoprotective effects of SDG in HFD/STZ-induced DN in rats through correction of hyperglycemia; attenuation of oxidative/nitrosative stress markers; downregulation of renal expressions of inflammatory markers NF-κB, TNF-α, and iNOS; along with upregulation of renal expressions of antiapoptotic markers survivin and Bcl-2

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Modulation of neuropathic pain in experimental diabetes mellitus

The main objective of the current article is to investigate the diabetic polyneuropathy which represents a major preoccupation within the context of high incidence of diabetes mellitus (DM) and its complications. Moreover, neuropathy may develop despite intensive hyperglycaemic control. The effect of Zn and black grape seed polyphenols (BGSP) in streptozotocin diabetic rats was studied. Zn and BGSP were administered by gavage, daily, for 16 weeks to Wistar rats that have been rendered diabetic by a single i.v. injection of streptozotocin (55 mg/kg body weight). Dysalgesia was investigated under the conditions of nociceptive stimulation through the following tests: the thermoalgesic mechanism through the tail-flick test, the hot plate test and the plantar test, and the mechanoalgesic mechanism through the algesimetric test. Thermal hyperalgesia detected in the diabetic group is significantly reduced (p < 0.001) through the administration of polyphenols, or even better, of Zn. Diabetes-associated mechanical hyperalgesia decreased significantly (p < 0.001) probably through the inhibition of the NMDA receptors. Administration of Zn or BGSP to the diabetic group improves glycosylated haemoglobin (HbA1c) values but does not bring them to normal. The present data suggest a favourable effect of Zn and BGSP in inhibiting diabetic complications by several mechanisms

Hepatoprotective effects of melatonin against pronecrotic cellular events in streptozotocin-induced diabetic rats

Oxidative stress-mediated damage to liver tissue underlies the pathological alterations in liver morphology and function that are observed in diabetes. We examined the effects of the antioxidant action of melatonin against necrosis-inducing DNA damage in hepatocytes of streptozotocin (STZ)-induced diabetic rats. Daily administration of melatonin (0.2 mg/kg) was initiated 3 days before diabetes induction and maintained for 4 weeks. Melatonin-treated diabetic rats exhibited improved markers of liver injury (P < 0.05), alkaline phosphatase, and alanine and aspartate aminotransferases. Melatonin prevented the diabetes-related morphological deterioration of hepatocytes, DNA damage (P < 0.05), and hepatocellular necrosis. The improvement was due to containment of the pronecrotic oxygen radical load, observed as inhibition (P < 0.05) of the diabetes-induced rise in lipid peroxidation and hydrogen peroxide increase in the liver. This was accompanied by improved necrotic markers of cellular damage: a significant reduction in cleavage of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) into necrotic 55- and 62-kDa fragments, and inhibition of nucleus-to-cytoplasm translocation and accumulation in the serum of the high-mobility group box 1 (HMGB1) protein. We conclude that melatonin is hepatoprotective in diabetes. It reduces extensive DNA damage and resulting necrotic processes. Melatonin application could thus present a viable therapeutic option in the management of diabetes-induced liver injury

Evaluation of antioxidant potential of methanolic leaf extract of Anacardium Occidentale (Linn) on the testes of streptozotocin-induced diabetic wistar rats

Anacardium occidentale is a plant with reported anti-diabetic and antioxidant properties. The objective of this work was to determine the effects of Anacardium occidentale leaf extract (AOLE) on the activities of glucose-6-phosphate dehydrogenase (G-6-PDH), thiobarbituric acid reactive substances (TBARS) and anti-oxidant enzymes (Glutathione peroxidase, GPx and superoxide dismutase, SOD) in the testicular homogenate of streptozotocin-induced diabetic rats. Forty (40) wistar rats (Rattus norvegicus) were randomly divided into four experimental groups. Diabetes was induced by a single intraperitoneal injection of Streptozotocin (70 mg/kg b.w.). Five days after the confirmation of hyperglycemia, Groups A and B were treated with 300 mg/kg b.w of the extract and 1 I.U/kg b.w. insulin respectively. Groups C and D served as hyperglycemic and normal controls respectively. Animals were sacrificed 16 days after treatment. Our study showed that AOLE ameliorated the level of TBARS and improved the activities of G-6-PDH, SOD and GPx in the testes of extract-treated rats (AU)

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Cytoprotective activities of Anacardium occidentale (Linn) on the testis of streptozotocin-induced diabetic rats

This study presents the protective effects of methanolic Anacardium occidentale leaf extract (AOLE) on the testes of streptozotocin (STZ)-induced diabetic rats. Forty male wistar rats (Rattus norvegicus) were randomly divided into four experimental groups A,B,C and D. Hyperglycaemia was induced by a single intraperitoneal injection of 0.1 M STZ (70 mg/kg b.w). Five days after the confirmation of hyperglycaemia by using a glucometer (Roche(R)) and compatible glucose test strips, groups A and B were treated with 300 mg/kg b.w of the extract and 1 I.U/kg b.w insulin respectively. Groups C and D served as hyperglycaemic and normal controls and received 1 ml/kg b.w citrate buffer respectively.After 16 days of treatment, blood was collected through retro-orbital puncture for insulin and reproductive hormone (FSH, LH and testosterone) analysis; the animals were then sacrificed and the testes were processed for histological staining. Data obtained were expressed as means of ten (10) replicates ± SEM and subjected to one-way analysis of variance (ANOVA) and the Scheffe’s post hoc test for multiple comparisons.Results showed that the levels of testosterone, FSH and LH in the AOLE- and insulin-treated rats increased significantly compared to the hyperglycaemic controls (P<0.05).Histological sections revealed improved cellularity, germinal epithelium, tubular diameter, cross-sectional area and luminal spermatids in the AOLE- and insulin-treated rats when compared with the hyperglycaemic control.AOLE improved the structural integrity of the testes, promoted spermatogenesis, and improved the profile of reproductive hormones (AU)

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Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats

In the present study, the putative antihyperglycemic and antioxidant effects of a flavanone, naringenin, were evaluated in comparison with those of glyclazide, a standard drug for therapy of diabetes mellitus. Diabetes was induced experimentally in 12-h-fasted rats by intraperitoneal injections of first streptozotocin (50 mg/kg b.w.) and then of nicotinamide (110 mg/kg b.w.) after a 15-min interval. Untreated diabetic rats revealed the following in comparison with normal rats: significantly higher mean levels of blood glucose and glycosylated hemoglobin, significantly lower mean levels of serum insulin, significantly lower mean activities of pancreatic antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), significantly lower mean levels of plasma non-enzymatic antioxidants (reduced glutathione, vitamin C , vitamin E), significantly elevated mean levels of pancreatic malondialdehyde (MDA) and significantly elevated mean activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Following oral administration of naringenin (50 mg/kg b.w./day) to diabetic rats for 21 days, the following observations were made in comparison with (..) (AU)

Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

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Valproic acid (VLP) is a widely used anticonvulsant and mood-stabilizing drug that relieves the endoplasmic reticulum (ER) stress response, a pathogenetic process related to diabetes. The aim of the present study was to evaluate whether acute valproic acid is able to interfere with glucose intolerance in two different diabetes models: The first model was a Wfs1 mutant mouse with an elevated ER stress response and the second model a streptozocin-induced diabetic mouse. VLP (300 mg/kg, i.p.) was administered to Wfs1 knockout (KO) mice and glucose tolerance test was performed 15 min later. VLP did not have an effect on the course of the glucose tolerance test in wild-type mice, while it did normalize the glucose intolerance in Wfs1 knockout mice. Acute valproic acid also lowered the blood glucose levels in streptozocin-treated mice and potentiated the effect of insulin in these mice. Thus, acute valproic acid is effective in lowering blood glucose levels possibly by potentiating insulin action in both Wfs1 KO mice and in streptozocin-induced type 1 diabetic mice (AU)

Beneficial effects of banana (Musa sp. var. elakki bale) flower and pseudostem on hyperglycemia and advanced glycation end-products (AGEs) in streptozotocin-induced diabetic rats

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Diabetes is a chronic health problem and major cause of death in most of the countries. Diet management plays an important role in controlling diabetes and its complications along with insulin and drugs. We have examined the effect of banana (Musa sp. var. elakki bale) flower and pseudostem on hyperglycemia and advanced glycation end-products (AGEs) in streptozotocin-induced diabetic rats. Our results indicated that banana flower and pseudostem have low glycemic index and have a high content of dietary fiber and antioxidants. Diabetic symptoms like hyperglycemia, polyuria, polyphagia, polydipsia, urine sugar, and body weight were ameliorated in banana flower- and pseudostem-treated rats. Increased glomerular filtration rate in the diabetic group (5.1 ± 0.22 ml/min) was decreased in banana flower-fed (2.5 ± 0.37 ml/min) and pseudostem-fed (3.0 ± 0.45 ml/min) groups and were significant at P < 0.001 and P < 0.01, respectively. Fructosamine and AGEs formed during diabetes were inhibited in treated groups when compared with the diabetic group. The diabetic group showed 11.5 ± 0.64 ìg of AGEs/mg protein in kidney, whereas, in banana flower- and pseudostem-fed groups, it was reduced to 9.21 ± 0.32 and 9.29 ± 0.24 ìg/mg protein, respectively, and were significant at P < 0.01. These findings suggest that banana flower and pseudostem have anti-diabetic and anti-AGEs properties and are beneficial as food supplements for diabetics (AU)

Insulinoma / Insulinoma

Los insulinomas son tumores neuroendocrinos pancreáticos secretores de insulina, infrecuentes (1-4 casos/millón de habitantes), generalmente pequeños, únicos, benignos y esporádicos; los casos múltiples (hasta un 10%) a menudo se presentan en las formas familiares (neoplasia endocrina múltiple tipo 1 [MEN1]), debidas a mutaciones germinales inactivadoras del gen menina, un gen supresor tumoral localizado en el cromosoma 11 (11q13). Por mecanismos aún no aclarados, se produce una secreción excesiva de insulina, aun en presencia de hipoglucemia, que es el rasgo clínico más constante. El diagnóstico funcional del insulinoma consiste en demostrar hiperinsulinismo endógeno (insulina, proinsulina y péptido-C dosificables) en presencia de hipoglucemia, detectada espontáneamente (generalmente, en ayunas o tras el ejercicio) o bien en el curso de una prueba de ayuno de hasta 72 h. La localización morfológica puede ser difícil, dado que la mayoría de los tumores son < 2 cm; las exploraciones más demostrativas son la tomografía computarizada helicoidal y la ecoendoscopia; puede ser útil la gammagrafía con indio-111 pentateótrido, y en casos seleccionados (no localizados, recidivas) la arteriografía selectiva con estimulación con calcio. El tratamiento de elección es quirúrgico, por laparotomía o laparoscopia, con extensión (enucleación, resección parcial o pancreatectomía) que dependerá del tamaño, la localización y la naturaleza única o múltiple del tumor. El tratamiento farmacológico, reservado para insulinomas malignos no resecables o contraindicaciones absolutas de la cirugía, incluye diazóxido, verapamilo, análogos de la somatostatina (efectivos en el 50% de los casos), y diversas pautas de asociación de estreptozotocina, 5-fluorouracilo e interferón α (AU)

Insulinomas are highly infrequent (1-4 cases/million) pancreatic endocrine insulinsecreting tumors; they are usually small, solitary, benign, and sporadic. Multifocal tumors (up to 10%) are usually familial (MEN-1), due to inactivating germinal mutations of a tumor suppressor gene (menin gene) located on chromosome 11q13. Excessive insulin secretion due to unknown mechanisms occurs in the presence of hypoglycemia, which is the main clinical manifestation. Functional diagnosis is established by the finding of endogenous hyperinsulinism (detectable insulin, proinsulin, and C-peptide) in the presence of either spontaneous or fastinduced hypoglycemia. Morphological localization can be difficult, as most tumors are smaller than 2 cm. The procedures of choice are spiral computed tomography and endoscopic ultrasonography; In111-pentatreotide scanning may be useful, and selective calcium-stimulated arteriography is an alternative in selected situations (negative localization or relapse). The treatment of choice is surgery, either through laparotomy or laparoscopy; surgical extent (enucleation, partial or total pancreatectomy) is determined by tumor size, localization, and uni- or multifocality. Drug treatment is limited to malignant, irresectable insulinomas, or to patients with absolute surgical contraindications; diazoxide, verapamil and somatostatin analogs may be used (the latter is only effective in 50% of cases), as well as various associations of streptozotocin, 5-fluorouracyl and interferon-alpha (AU)

Influence of streptozotocin-induced diabetes on hexokinase activity of rat salivary glands

The influence of diabetes on the enzyme hexokinase (HK) was examined in thesalivary glands of rats. Diabetes was induced by an intraperitoneal injection of streptozotocin(60 mg/Kg body weight) in overnight fasted rats (180-200 g). The animalswere killed 48 hours and 30 days after the induction of diabetes and the submandibularand parotid salivary glands extracted for use. Hyperglycemia was evaluatedby determining the blood sugar. The area occupied by each intralobular component,acini, ducts, total parenchyma and stroma was measured, and no differenceswere observed compared with control. In the soluble fraction of the submandibulargland, no difference in the specific activity of HK was observed, between the diabeticand control animals, however, the activity per gland and per g of tissue showedlower values than control. The specific activity of the bound form was reduced in thediabetic gland. The results obtained for the parotid gland were different from thesubmandibular. The specific activity of both the soluble and bound forms wereincreased in the diabetic animals. The DEAE-cellulose column chromatography ofthe soluble and bound forms of the enzyme from both glands showed a first peakappearing during the washing of the column and two other peaks were eluted by thegradient. Thus, three isoenzymes in the submandibular and parotid salivary glandsfor the control and diabetic rats have been found (AU)

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Influencia del cocultivo de islotes pancreáticos con células hepáticas sobre la liberación de insulina y sobre la implantación de los islotes en hígado sin inmunosupresión / Influence of co-culture of pancreatic islets with hepatic cells on insulin release and on implantation of islets in liver without immunosuppression

El objetivo de este trabajo es estudiar la influencia de las células hepáticas sobre la liberación de insulina cuando se co-cultivan con islotes, así como la influencia que puedan tener sobre la implantación de los islotes en el hígado en ratas Wistar, sin el empleo de drogas inmunosupresoras. In vitro tenemos 2 grupos: A) Cultivo de islotes solos y B) Co-cultivo de islotes y células hepáticas, ambos durante 7 días. Se realiza un estudio morfológico, numérico y de liberación de insulina. In vivo tenemos 7 grupos de Tx: A) Tx ficticio con suero fisiológico (4), B) Tx-ch solas (4), C) Tx-1 solos (6), D) Tx-I solos tras cultivo 7 días (5), E) Tx-1 co-cultivados con ch 24 h (5), F) Tx-I co-cultivados con ch 7 días (7) y G) Tx-I co-cultivados con ch 48 h, en placas transwell (5). La proporción de ch/I ha sido de 150:1. ENI ha sido de 1678 ñ 343 con pureza del 90 por ciento. Análisis de datos mediante el test de ANOVA del SPSS 8.0.In vitro: observamos una gran diversidad celular hepática, un descenso en el ENI durante el co-cultivo, sin embargo la insulino-liberación es mayor en los islotes co-cultivados con ch (p < 0.005). In vivo: Los días de euglucemia tras el Tx han sido: grupo A (0 ñ 0), B (0 ñ 0), C( 2.0 ñ 3.098), D 1.8 ñ 2.17), E (8.6 ñ 12.33), F (9.14 ñ 11.02) y G (0 ñ 0). Los resultados de E y F, confirman un efecto favorable de las ch sobre la implantación de los islotes alogénicos en hígado, consiguiéndose un 20 por ciento y un 14.3 por ciento de reversión de la diabetes. El resultado de G parece indicar la posibilidad de que más que una interacción celular entre las ch e islotes, se trate más bien de la secreción constante de algún producto, y este sea el responsable de la supervivencia de los islotes implantados en hígado. (AU)

Inducción de tolerancia al trasplante de islotes, en ratas Wistar, mediante células hepáticas / Induction of tolerance to islet transplantation, in Wistar rats, by hepatic cells

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Modificación de los mediadores inflamatorios en isquemia-reperfusión intestinal en un modelo de diabetes tipo 2 / Modification of inflammatory mediators in intestinal ischemia-reperfusion in a model of type II diabetes

Introducción. Se ha demostrado que los polimorfonucleares aislados de pacientes diabéticos presentan un mayor grado de activación que los de los pacientes no diabéticos. Además, la diabetes, tanto de tipo 1 como de tipo 2, se asocia con un incremento de la peroxidación lipídica y valores elevados de moléculas de adhesión circulantes. La administración de estreptozotocina (STZ) en ratas neonatales conduce en las ratas adultas a una ligera deficiencia de insulina, con valores de glucemia normales, y son aceptadas como modelo de diabetes tipo 2.Objetivo. En este estudio hemos investigado posibles diferencias en plasma y tejidos de algunos mediadores de la inflamación entre ratas normales y ratas con diabetes tipo 2, después de isquemiareperfusión (I-R) intestinal. Material y métodos. Se utilizaron ratas Wistar a las que se les administró STZ (0 o 30 mg/kg) el día de su nacimiento. Dos meses después, tanto las ratas control como las que tenían diabetes tipo 2 (normoglucémicas) fueron asignadas aleatoriamente a dos grupos. El grupo I fue sometido a un período de 60 min de isquemia intestinal por pinzamiento de la arteria mesentérica superior. Cinco minutos después de la reperfusión, las ratas fueron sacrificadas y se obtuvieron muestras de vena porta (VP), cava infrahepática (CIH), cava suprahepática (CSH), páncreas e intestino. En el grupo control los animales se manipularon de igual forma, pero sin ser sometidos a IR. El óxido nítrico (NO) se midió como NO-2 + NO-3, por la reacción de Griess. Los hidroperóxidos lipídicos (LPO) fueron determinados espectrofotométricamente usando un kit comercial. Los receptores para factor de necrosis tumoral (TNF) de 60 kDa (TNF-R1) y 75 kDa (TNF-R2), y el ICAM-1 se determinaron por el método Elisa. Resultados. Tras la I-R, las ratas diabéticas evidenciaron un aumento de las concentraciones plasmáticas de LPO, NO, ICAM-1 (0,514 + 0,083 frente a 0,046 + 0,011 CIH; 0,574 + 0,075 frente a 0,037 + 0,009 CSH, y 0,528 + 0,067 frente a 0,033 + 0,009 VP; ng/ml; n = 10; p < 0,01), TNF (42,4 + 5,7 CIH, 248,4 + 28,2 CSH y 33,6 + 4,0 VP, pg/ml, en ratas diabéticas frente a no detectable en ratas control; n = 10), TNF-R1 (0,179 + 0,024 frente a 0,023 + 0,011 CIH; 0,233 + 0,032 frente a 0,033 + 0,005 CSH; 0,206 + 0,034 frente a 0,039 + 0,023 VP; ng/ml; n = 10; p < 0,001; p < 0,05 todas) mientras que no se encontraron diferencias en los valores de TNF-R2 entre ambos grupos. Tras I-R, los valores plasmáticos de TNF y NO fueron más elevados en CSH que en CIH y VP, lo que sugiere que el hígado es una importante fuente de ambos mediadores. Hemos observado que tras I-R en ratas diabéticas en el tejido intestinal se produce un aumento en los valores de TNF, interleucina (IL) 1, IL-6 (no significativo) e IL-10, mientras que en el tejido pancreático hay una disminución de TNF- e IL-10 y un aumento de IL-1 e IL-6.Conclusión. La diabetes tipo 2 intensifica la respuesta inflamatoria a la I-R intestinal (AU)

Co-trasplante alogénico de células hepáticas e islotes en ratas diabéticas / Allogen co-transplant of liver cells and islets in diabetic rats

Buscando una mayor tolerancia de los islotes sin necesidad de inmunosupresión, hemos realizado el co-trasplante (co-Tx) de islotes cultivados 3-5 días, mezclados una hora antes del trasplante con hepatocitos (y otras células hepáticas) recién aisladas, en una proporción aproximadamente de 100 y 200 hepatocitos por islote. La diabetes se ha inducido con estreptozotocina 60 mg/kg vía ip en ratas Wistar. Se han estudiado tres grupos de coTx: C) co-Tx islotes y células hepáticas frescas en proporción 1:100; D) co-Tx islotes y células hepáticas frescas en proporción 1:200, y E) co-Tx de islotes co-cultivados con células hepáticas 24 horas en proporción 1:100. Estos tres grupos se han comparado con dos grupos control: A) Tx con sólo células hepáticas y B) Tx con sólo islotes. El número de islotes trasplantados fue respectivamente de: B) 1.808 ñ 413; C) 1.515 ñ 198; D) 1.830 ñ 435, y E) 1.600 ñ 134.En los grupos A y B hubo una falta total de reversión de la diabetes. El grupo C (co-Tx con 1:100) mostró los mejores resultados con euglucemia global durante cuatro días, que en una de las ratas persistió un mes con valores menores de 200 mgldl. La reversión de la diabetes también se observó menos días en el grupo D sin que persistiera más de ocho días en ninguna rata. En el grupo E, co-Tx después del co-cultivo, los resultados fueron intermedios entre los grupos E y D. Estos resultados sugieren un efecto beneficioso de los hepatocitos (o de otras células hepáticas) sobre los islotes pancreáticos, facilitando su tolerancia o aumentando su viabilidad, sin necesidad de inmunosupresión medicamentosa. Considerando la novedad de estos resultados se hace necesario ampliar los estudios para aumentar la eficacia de la tolerancia y explicar el mecanismo de acción (AU)