Endocrinopatías por inmunoterapia oncológica / Endocrinopathies by oncological immunotherapy

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)

The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)

Type 1 diabetes induced by immune checkpoint inhibitors / 中华医学杂志(英文版)

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

Ethnopharmacological activity of Hedera nepalensis K. Koch extracts and lupeol against alloxan-induced type I diabetes

In this study, we investigated the protective effects of Hedera nepalensis crude extract, its fractions and lupeol in alloxan-induced diabetic rats. Lupeol and n-hexane (HNN) fraction significantly reduced the blood glucose level by increasing insulin level in time dependent manner, and also significantly increased amylase and lipase activity in diabetic rats. Elevated levels of alanine transaminases (ALT), aspartate transaminases (AST), thiobarbituric acid reactive substances (TBARS), nitrite, hydrogen peroxide (H2O2), total bilirubin and total protein in blood serum were efficiently restored to normal levels. Suppressed enzymatic activity of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH) and peroxidase (POD) were also restored to their normal levels. Kidney functions were also restored to normal level after treatment with HNN and lupeol. HNN fraction and lupeol of H. nepalensis prevented oxidative stress in alloxan-induced diabetic rats. This study signifies the importance of H. nepalensis and lupeol in ameliorating diabetes by inducing insulin secretion in diabetic model rats.

Diabetes mellitus tipo 1 en una paciente con hepatitis c durante el tratamiento con interferón alfa. Primer caso comunicado en Cuba / Type 1 diabetes mellitus in patient with hepatitis c treated with interferon á. First case in Cuba

El Interferón alfa (IFN-alfa), se utiliza junto a otros antivirales en el tratamiento de la hepatitis C crónica. Se han descrito alteraciones autoinmunes durante su uso, destacándose las enfermedades del tiroides y la diabetes mellitus tipo 1 (DM 1), entre otras. Se presenta el caso de una paciente con hepatitis C crónica que a los 6 meses de tratamiento con IFN-alfa y Ribavirina, manifestó síntomas graves de coma, cetoácidosis metabólica, hiperglucemía y deshidratación. Se diagnosticó el inicio de una DM 1 secundaria a la administración del IFN-alfa. No tenía antecedentes personales o familiares de factores genéticos predisponentes para el desarrollo de ésta enfermedad. Fue tratada en una Unidad de Urgencias Medicas, donde recibió medicamentos para el control de sus manifestaciones. Se suspendió la administración de IFN-alfa y se mantiene con tratamiento ambulatorio, aplicándose la insulina en dosis fraccionada, ajustada a los valores de glucemia

Interferon a (IFN-a), is used together with other antivirals in the treatment of chronic hepatitis C. Autoimmune disorders have been described during its use, particularly thyroid diseases and type 1 diabetes mellitus (DM1), among others. We report the case of a patient with chronic hepatitis C, showing severe symptoms of coma, metabolic ketoacidosis, hyperglycemia and dehydration after 6 months of treatment with IFN-aand ribavirin. The beginning of a secondary DM 1 at the administration of IFN-a was diagnosed. There was no personal or family history of genetic factors predisposing to the development of this disease. The patient was treated in an Emergency Medical Unit (MEU) where medication to control its manifestations was received. Administration of IFN-a was suspended and the ambulatory treatment is maintained, applying insulin in fractional doses adjusted to blood glucose values

Time-dependent changes of calbindin D-28K and parvalbumin immunoreactivity in the hippocampus of rats with streptozotocin-induced type 1 diabetes

The hippocampus is affected by various stimuli that include hyperglycemia, depression, and ischemia. Calcium-binding proteins (CaBPs) have protective roles in the response to such stimuli. However, little is known about the expression of CaBPs under diabetic conditions. This study was conducted to examine alterations in the physiological parameters with type 1 diabetes induced with streptozotocin (STZ) as well as time-dependent changes in the expression of two CaBPs changes of were being evaluated. Rats treated with STZ (70 mg/kg) had high blood glucose levels (>21.4 mmol/L) along with increased food intake and water consumption volumes compared to the sham controls. In contrast, body weight of the animals treated with STZ was significantly reduced compared to the sham group. CB-specific immunoreactivity was generally increased in the hippocampal CA1 region and granule cell layer of the dentate gyrus (DG) 2 weeks after STZ treatment, but decreased thereafter in these regions. In contrast, the number of PV-immunoreactive neurons and fibers was unchanged in the hippocampus and DG 2 weeks after STZ treatment. However, this number subsequently decreased over time. These results suggest that CB and PV expression is lowest 3 weeks after STZ administration, and these deficits lead to disturbances in calcium homeostasis.

A microcirculação da bolsa da bochecha do hamster sob a influência do diabetes mellitus experimental induzido por estreptozotocina: aspectos morfofuncionais / Microcirculation of hamster cheek pouch under the influence of experimental Diabetes Mellitus induced by streptozotocin: morpho-functional aspects

O Diabetes Mellitus é uma doença metabólica crônica com múltiplos fatores etiológicos (genético, viral e imunológico) que condiciona deficiência absoluta ou relativa de insulina, causando persistência de níveis elevados de glicose no sangue. Atualmente, o Diabetes Mellitus é considerado um importante problema de saúde devido a sua prevalência e alta morbimortalidade. Sua importância clínica resulta essencialmente de suas graves complicações, especialmente as microvasculares. A hiperglicemia crônica ou intermitente tem sido identificada como o fator indutor de lesão endotelial, sendo este, o agente desencadeante das complicações microvasculares. As células endoteliais, por serem influenciadas pela força hemodinâmica local, respondem com a transdução de sinais (mecanotrans dução), as quais podem ser responsáveis pelo início de processos patológicos na parede dos vasos. Desta forma, o objetivo deste estudo foi analisar a microcirculação da bolsa da bochecha do hamster sob a influência do Diabetes Mellitus tipo 1 experimental induzido por estreptozotocina, avaliando seus aspectos morfofuncionais aos 6 e 15 dias de evolução da doença. As características morfológicas de arteríolas e vênulas foram estimadas por medidas do diâmetro do lúmen e da espessura da parede; pela densidade de volume e de área destes vasos na bolsa da bochecha; pela análise imunohistoquímica da expressão de actina, talina, alfa-actina de músculo liso, vimentina, laminina e colágeno IV através da microscopia de luz com a utilização de um sistema semiquantitativo baseado em uma escala de intensidade de imunomarcação; e por microscopia eletrônica de transmissão. Também foi avaliado o relaxamento dependente do endotélio, medido pela variação do diâmetro do lúmen antes e após a aplicação de acetilcolina e a permeabilidade de vênulas pós-capilares à histamina, determinada pelo número de pontos de extravasamento plasmático. Nossos resultados mostraram que arteríolas e vênulas...

Diabetes Mellitus is a chronic metabolic disease with multiple etiologic factors (genetic, viral and immunological) that results in absolute or relative insulin deficiency, causing persistent elevated blood glucose levels. Nowadays, Diabetes Mellitus is considered as an important health concern due to its increasing prevalence and high morbimortality. Its clinical importance comes from the complications, especially harm inductor factor, being this the first outcome of microvascular complications. Endothelial cells, under local hemodynamic strength, produce signal transduction (mechanotransduction), which can be responsible for the beginning of patholgical events in vessels wall. In this regard, the objective of this study was to analyze hamster cheek pouch microcirculation under the influence of type 1 diabetes mellitus induced by streptozotocin, evaluationg its morpho-functional aspects at 6 and 15 days of diseases evolution. Morphological characteristics of arterioles and venules were estimated by the measurement of lumen diameter and wall thickness; the volume density and area of these vessels from cheek pouch; immunohistochemistry of the expression of actin, talin, smooth muscle alpha-actin, vimentin, laminin and type IV collagen through light microscopy with the utilization of a semi-quantitative score system based on the intensity of the immunostaining; and transmission electron microscopy. It was also evaluated the endothelium dependent relaxation, measured by the variation of lumen diameter before and after acetylcholine administration and post-capillary venules permeability to histamine, determined by number of points of plasma extravasation. Our results reveal that arterioles and venules do not show differences between the groups concerning wall thickness, luminal diameter, density per area and volume density. Vascular permeability, after 2 minutes of histamine administration, was reduced significantly in diabetic groups...

Diabetes melito transitório relacionado à terapia com L-asparaginase / Transient diabetes mellitus related to L-asparaginase therapy

O tratamento de neoplasias hematológicas malignas com L-asparaginase tem sido associado com o desenvolvimento de diabetes melito (DM) em cerca de 1-2 por cento dos casos. A associação com corticosteróides tem efeito sinérgico na ocorrência dessa complicação. Este artigo relata o desenvolvimento de DM transitório em uma adolescente de 13 anos, tratada com L-asparaginase e dexametasona devido a leucemia linfoblástica aguda. O DM foi diagnosticado 120 dias após o início da terapia com L-asparaginase, requerendo o uso de insulina por 12 meses. Investigação para auto-imunidade contra células beta pancreáticas foi negativa. Também não foram encontradas alterações laboratoriais sugestivas de pancreatite. O DM associado à L-asparaginase é insulinopênico e de caráter transitório, desaparecendo após a suspensão do medicamento. O diagnóstico do DM associado à L-asparaginase é baseado na associação temporal com o uso da droga e na exclusão de outras causas. Não existe um teste laboratorial capaz de diagnosticá-lo. Portanto, a investigação para DM tipo 1A, DM tipo 1B, DM induzido por corticoterapia e DM secundário a pancreatite tóxica é fundamental. O tratamento com insulinoterapia deve ser acompanhado de perto, uma vez que este tipo de diabetes tem um curso transitório.

Treatment of hematological malignancies with L-asparaginase has been associated with diabetes mellitus in about 1-2 percent of patients. The concomitant use of steroids has an additional deleterious effect. In this article, we report the occurrence of diabetes in a 13 year-old girl treated with L-asparaginase and dexamethasone for acute lymphoblastic leukemia. The diabetes developed 120 days after the drug was started, requiring insulin therapy for 12 months. Anti-islet autoantibody was negative, and there were no laboratory findings suggestive of pancreatitis. The DM related do L-asparaginase therapy is insulinopenic and transient, resolving with suspension of the drug. The diagnosis of this type of diabetes is based on its temporal relationship with the L-asparaginase and in the exclusion of other known causes. There is no laboratory test capable of elucidating the diagnosis. Therefore, investigation to rule out type 1A DM, type 1B DM, insulin-resistant DM induced by corticotherapy and DM secondary to toxic pancreatitis is of utmost importance. The insulin therapy must be followed closely, since this is a transient form of diabetes.

Níveis glicêmicos e de colesterol em ratos com Diabetes mellitus aloxano induzido, tratados com infusäo de Bauhinia candicans ou Syzygium jambolanum / Glucose and cholesterol plasma levels in rats with alloxan-induced Diabetes mellitus treated with infusion of Bauhinia candicans or Syzygium jambolanum

Este estudo verificou a eficiência de infusäo de duas plantas usadas na medicina popular, Syzygium jambolanum (Sj) e Bauhinia candicans (Bc). Sessenta (60) ratos adultos, machos, da linhagem Wistar, pesando entre 220 e 240g, foram submetidos à induçäo de Diabetes mellitus insulino dependente (DMID) com Aloxano. O estudo foi dividido em dois experimentos. No primeiro, 15 ratos receberam a administraçäo de Aloxano na dosagem de 40mg/kg em dose única e no segundo, 60mg/kg uma vez ao dia, durante três dias, ambos por via intraperitonal. A hiperglicemia foi confirmada no terceiro dia de cada experimento. Após esta confirmaçäo, os animais foram divididos aleatoriamente em três grupos de cinco e quinze animais para o primeiro e segundo experimento, respectivamente. O grupo 1 (C) serviu como controle, o grupo 2 (TI) recebeu infusäo de Sj "ad libitum" como fonte líquida e o grupo 3 (TII) recebeu infusäo de Bc, por um período de 21 e 40 dias, para o primeiro e segundo experimento, respectivamente. A colheita de sangue foi realizada por punçäo do plexo venoso retro-orbitário com os animais anestesiados, nos dias 3, 9, 16 e 23 do primeiro experimento e nos dias 3, 16, 24 e 40 do segundo. Após vinte e um dias da fase de tratamento, o grupo TI do primeiro experimento apresentou marcante reduçäo de hiperglicemia (P < 0,001). Esta mesma observaçäo foi verificada no grupo TI do segundo experimento aos dezesseis dias da fase de tratamento (P < 0,004), estendendo-se até os quarenta dias (P < 0,0001), quando comparado ao grupo controle. Simultaneamente, sinais clínicos de DMID, como polifagia e polidipsia foram reduzidos neste grupo. O colesterol plasmático demonstrou aumento moderado somente nos animais do segundo experimento, näo sendo observado o efeito do tratamento com infusäo Sj e Bc sobre a colesterolemia dos animais em estudo. No 40§ dia de ambos os experimentos, os animais foram eutanasiados e foram colhidas amostras de pâncreas e fígado para avaliaçäo histopatológica. A análise histopatológica das amostras de pâncreas e fígado do experimento I näo demonstrou diferença entre os grupos tratados e o grupo C. No entanto, no experimento II, nove em dez amostras do grupo C e cinco em nove amostras do grupo TII apresentaram necrose de células das ilhotas de Langerhans do pâncreas, enquanto que somente duas das nove amostras do grupo TI apresentaram necrose de células das ilhotas de Langerhans. Os resultados obtidos neste estudo permitem concluir que ...

Streptozotocin induced hyperglycemia is decreased by nitric oxide inhibition

1. Diabetes mellitus type 1 was induced in 3-month old maleC57 BL/KS-mdb mice (N = 24)) by ip injection of streptozotocin (STZ, 45 mg/Kg body weight) for 5 days. 2. To determine the possible protective effects of nitric oxide inhibition against hyperglycemia, the STZ-diabetic rats received two doses of Ng-nitro-l-arginine-methyl ester (L-NAME) (10 mg/Kg body weight and 10 mg/mouse) dissolved in PBS for 45 consecutive days. Another group of STZ-treated rats was similarly treated with L-arginine (5 mg/mouse). 3. Blood glucose levels were 118 ñ 37 mg/dl after 8 days of L-NAME administration (10 mg/Kg body weight, N = 12) and 186 ñ 22 mg/dl (N = 12) after 5 days of L-NAME administration at the 5 mg/mouse dose. Treatment with L-arginine (5-mg/mouse, N = 12) caused a significant increase in blood glucose level to 151 ñ 17,5 mg/dl, showing the relevance of nitric oxide formation in this type of diabetes. 4. In STZ-diabetic mice treated with L-NAME (N = 12), diuresis was reduced by approximately 58 per cents compared to STZ animals, whereas in L-arginine-treated animals (N = 12) diuresis returned to STZ levels. Urinary protein excretion, which, was significantly affected by STZ (123 per cents compared to control) was significanty reduced by 66 per cents after treatment with L-NAME for 45 days, whereas treatment with-L-arginine caused a return to STZ values. 5. Urinary kallikrein excretion, which was reduced by 80 per cents in STZ mice compared to control, returned to control levels after L-NAME treatment. 6. The present results suggest a relationship between nitric oxide levels and the reduction of diabetic state improved renal function by L-name

Pancreatic lipid peroxidation in alloxan-induced diabetes mellitus

The time-course of pancreatic lipid peroxidation and reduced glutathione, and blood glucose were studied in adult male CD-1 mice after each of three sequential injection of alloxan, administered at intervals of 48 h. Twenty four hours after alloxan administration an increment of blood glucose and pancreatic lipoperoxidation was observed. Lipoperoxication partially recovered, while blood glucose was increased after the third administration to a value of 150 mg/100 ml. Pancreas reduced glutathione content remained without any significant change throughout the experiment. These results suggest that the stablishment of alloxan-induced diabetes is proceded by an increment in pancreatic lipid peroxidation that could be associated with permanent damage to pancreatic tissue

Relación entre las lesiones electrolíticas del núcleo hipotalámico ventromedial y la diabetes mellitus insulino dependiente inducida por streptozotocina

Dada la función reguladora del sistema nervioso sobre el endocrino se busca analizar la correlación entre la lesión del núcleo hipotalámico ventromedial (HVM) y la severidad de la diabetes inducida por estreptozotocina (STZ). Se utilizan 29 ratas divididas en cuatro grupos: Grupo I: lesión del HVM e inyección de SS (murieron por complicaciones respiratorias); Grupo III: lesión del HVM e inyección de STZ; Grupo IV: lesión ficticia del HVM e inyección de STZ. Se observan por un período de 6 a 8 semanas. Se exploran semanalmente valores de química sanguínea como glicemia, colesterol y triglicéridos y se mide el peso corporal; cada dos días se determina el consumo de agua y en el momento del sacrificio se pesa la grasa perirrenal y se fijan los cerebros para determinar tamaño y sitio de la lesión. Los resultados muestran que el grupo III es el más afectado en cuanto a severidad de la diabetes y velocidad de deterioro de los animales; mientras que el grupo I sólo muestra aumento de peso corporal pero sin evidencia de diabetes. Todo parece indicar que el aumento de la ingesta inducido por la lesión del "núcleo de la sacidad" y por la misma diabetes produce efectos aditivos sobre el cuadro patológico

The Effect of Pertussis Vaccine and Cyclosporin on Streptozotocin Induced Diabetic Rats

The injection of streptozotocin(stz) at a high dose (60 mg/kg) into young male rats produces direct beta cell destruction and leads to insulin dependent diabetes (IDD). In contrast the injection of multiple smal doses of stz (40 mg/Kg/d for 5 days) produce IDD, which resembles type l diabetes in man. The provocative effects of the pertussis vaccine (PV) and cyclosporin(CA) against the development of IDD induced by stz were studied. When PV in a dose of 3.75 X 10(10) microorganism was administered to single or multiple stz treated rats, hyperglycemia still developed and persisted during the experiment. No difference was noted in blood glucose levels, but plasma insulin levels were higher in PV treated rats. When CA (10 mg/kg) was administered daily to single or multiple stz treated rats, hyperglycemia seemed to be lower, but this was not statistically significant, however, plasma insulin levels were higher in CA treated rats. The results of this experiment suggest that PV and CA provide some protection to the beta cells of the pancreas.