RESUMO
The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.
Assuntos
Hipoglicemia , Síndrome de Laron , Fatores Etários , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Modelos Animais de Doenças , Equador/epidemiologia , Humanos , Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Israel/epidemiologia , Síndrome de Laron/complicações , Síndrome de Laron/epidemiologia , Síndrome de Laron/metabolismo , Síndrome de Laron/patologia , Camundongos , Camundongos Knockout , Receptores da Somatotropina/genética , Transdução de Sinais/fisiologia , SuínosRESUMO
The accelerated growth of solid tumors leads to episodes of both hypoxia and hypoglycemia (HH) affecting their intermediary metabolism, signal transduction, and transcriptional activity. A previous study showed that normoxia (20% O2 ) plus 24 h hypoglycemia (2.5 mM glucose) increased glycolytic flux whereas oxidative phosphorylation (OxPhos) was unchanged versus normoglycemia in HeLa cells. However, the simultaneous effect of HH on energy metabolism has not been yet examined. Therefore, the effect of hypoxia (0.1-1% O2 ) plus hypoglycemia on the energy metabolism of HeLa cells was analyzed by evaluating protein content and activity, along with fluxes of both glycolysis and OxPhos. Under hypoxia, in which cell growth ceased and OxPhos enzyme activities, ΔΨm and flux were depressed, hypoglycemia did not stimulate glycolytic flux despite increasing H-RAS, p-AMPK, GLUT1, GLUT3, and HKI levels, and further decreasing mitochondrial enzyme content. The impaired mitochondrial function in HH cells correlated with mitophagy activation. The depressed OxPhos and unchanged glycolysis pattern was also observed in quiescent cells from mature multicellular tumor spheroids, suggesting that these inner cell layers are similarly subjected to HH. The principal ATP supplier was glycolysis for HH 2D monolayer and 3D quiescent spheroid cells. Accordingly, the glycolytic inhibitors iodoacetate and gossypol were more effective than mitochondrial inhibitors in decreasing HH-cancer cell viability. Under HH, stem cell-, angiogenic-, and EMT-biomarkers, as well as glycoprotein-P content and invasiveness, were also enhanced. These observations indicate that HH cancer cells develop an attenuated Warburg and pronounced EMT- and invasive-phenotype. J. Cell. Physiol. 232: 1346-1359, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Transição Epitelial-Mesenquimal , Glicólise , Hipoglicemia/patologia , Esferoides Celulares/patologia , Trifosfato de Adenosina/farmacologia , Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Invasividade Neoplásica , Oxigênio/farmacologia , Fenótipo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismoAssuntos
Hipoglicemia/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Tumores Fibrosos Solitários/diagnóstico por imagem , Tumores Fibrosos Solitários/patologia , Idoso , Feminino , Humanos , Síndromes Paraneoplásicas/diagnóstico por imagem , Síndromes Paraneoplásicas/patologia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/patologia , Síndrome , Tomografia Computadorizada por Raios XAssuntos
Humanos , Feminino , Idoso , Tumores Fibrosos Solitários/patologia , Tumores Fibrosos Solitários/diagnóstico por imagem , Hipoglicemia/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Síndromes Paraneoplásicas/patologia , Síndromes Paraneoplásicas/diagnóstico por imagem , Neoplasias Pleurais/patologia , Neoplasias Pleurais/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios XRESUMO
The purpose was to determine the possible effects of exercise and/or caffeine on hypoglycemia and liver gluconeogenesis in diabetic rats. These were divided into four subgroups: (a) intraperitoneal insulin only, (b) exercise bout before insulin, (c) caffeine after insulin, and (d) exercise bout before and caffeine after insulin. The marked glycemic drop 45 min after insulin (0 min = 229.00, 45 min = 75.75) was considerably reduced (p < 0.05) by caffeine or exercise (45 min: exercise = 127.00, caffeine = 104.78). However, this systemic effect was lost (p > 0.05) when they were combined (45 min: exercise + caffeine = 65.44) (Mean, in mg·dL-1). Caffeine alone strongly inhibited liver glucose production from 2 mM lactate 45 min after insulin (without caffeine = 3.05, with caffeine = 0.27; p < 0.05), while exercise + caffeine partially re-established the liver gluconeogenic capacity (exercise + caffeine = 1.61; p < 0.05 relative to the other groups) (Mean, in µmol·g-1). The improved hypoglycemia with caffeine or exercise cannot be explained by their actions on liver gluconeogenesis. As their beneficial effect disappeared when they were combined, such association in diabetic patients should be avoided during the period of hyperinsulinemia due to the risk of severe hypoglycemia.
Assuntos
Cafeína/efeitos adversos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Gluconeogênese/efeitos dos fármacos , Hipoglicemia/metabolismo , Fígado/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Regulação para Baixo/efeitos dos fármacos , Hipoglicemia/complicações , Hipoglicemia/patologia , Fígado/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
A 62-year-old man admitted to our outpatient clinic with two months of recurrent life threatening hypoglycemia episodes. He was diagnosed as malignant insulinoma with multiple metastases of liver and peripancreatic lymph nodes. Liver biopsy specimen was demonstrated grade 2 neuroendocrine tumor compatible with clinical and radiological results. He was followed under the treatment of continuous intravenous glucose infusion during the diagnostic procedures. He had a pancreatic lesion history measured 20 x 12 mm in diameter via the abdominal tomography examination approximately two years before the diagnosis. Unusual course of this case suggests the transformation of nonfunctioning pancreatic neuroendocrine tumor into functional insulin secreting tumor with metastases. The patient was found inoperable and started on chemotherapy.
Assuntos
Insulinoma/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Biópsia , Humanos , Hipoglicemia/patologia , Insulinoma/secundário , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities. RESEARCH DESIGN AND METHODS: We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease. RESULTS: Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (-9.55 [95% CI -15.21, -3.90] vs. -15.38 [95% CI -16.64, -14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants' brain MRI scans. CONCLUSIONS: Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
Assuntos
Encéfalo/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemia/patologia , Hipoglicemiantes/efeitos adversos , Imageamento por Ressonância Magnética , Adulto , Idoso , Atrofia/induzido quimicamente , Atrofia/epidemiologia , Atrofia/patologia , Glicemia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Hipoglicemia/epidemiologia , Masculino , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The aim of the present review is to offer a current perspective about the consequences of hypoglycemia and its impact on the diabetic disorder due to the increasing incidence of diabetes around the world. The main consequence of insulin treatment in type 1 diabetic patients is the occurrence of repetitive periods of hypoglycemia and even episodes of severe hypoglycemia leading to coma. In the latter, selective neuronal death is observed in brain vulnerable regions both in humans and animal models, such as the cortex and the hippocampus. Cognitive damage subsequent to hypoglycemic coma has been associated with neuronal death in the hippocampus. The mechanisms implicated in selective damage are not completely understood but many factors have been identified including excitotoxicity, oxidative stress, zinc release, PARP-1 activation and mitochondrial dysfunction. Importantly, the diabetic condition aggravates neuronal damage and cognitive failure induced by hypoglycemia. In the absence of coma prolonged and severe hypoglycemia leads to increased oxidative stress and discrete neuronal death mainly in the cerebral cortex. The mechanisms responsible for cell damage in this condition are still unknown. Recurrent moderate hypoglycemia is far more common in diabetic patients than severe hypoglycemia and currently important efforts are being done in order to elucidate the relationship between cognitive deficits and recurrent hypoglycemia in diabetics. Human studies suggest impaired performance mainly in memory and attention tasks in healthy and diabetic individuals under the hypoglycemic condition. Only scarce neuronal death has been observed under moderate repetitive hypoglycemia but studies suggest that impaired hippocampal synaptic function might be one of the causes of cognitive failure. Recent studies have also implicated altered mitochondrial function and mitochondrial oxidative stress.
Assuntos
Transtornos Cognitivos/complicações , Hipoglicemia/complicações , Neurônios/patologia , Animais , Transtornos Cognitivos/patologia , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controleRESUMO
Introducción: La hipoglicemia es un síndrome clínico ocasionado por múltiples causas y definido por una glicemia < 60 mg/dl. Se dice que la hipoglicemia es severa cuando necesita la asistencia de terceros u hospitalización. En el paciente diabético, la hipoglicemia es la complicación aguda más frecuente y representa el factor limitante del control glicémico en estos enfermos. Objetivo: determinar la incidencia de ingresos hospitalarios por hipoglicemia, y determinar las variables biodemográficas y las causas de las hipoglicemias. Pacientes y método: Se realizó un estudio descriptivo retrospectivo de la población de pacientes ingresados con el diagnóstico de hipoglicemia al Servicio de Urgencia del Hospital Dr. Gustavo Fricke entre Agosto 2001 y Agosto 2006. Resultados: Se analizaron 93 casos. La edad promedio del grupo fue de 72,3 años y la distribución por sexo fue de 60,2 por ciento de mujeres. De ellos, 85 pacientes (91.4 por ciento) eran DM tipo 2, un paciente DM tipo 1 (1.1 por ciento) y 7 pacientes no diabéticos (7,5 por ciento). Con respecto a la causa de la hipoglicemia, 79 casos (85 por ciento) fueron secundarios a hipoglicemiantes orales, 7 casos (8 por ciento) de causa no precisada, 4 casos (4 por ciento) de intento de suicidio (3 casos con insulina y un caso con glibenclamida), 2 casos (2 por ciento) de hipoglicemia reactiva y 1 caso (1 por ciento) secundario a uso de insulina. Discusión: Es interesante destacar que dentro de los pacientes diabéticos tipo 2 usuarios de sulfonilureas que ingresaron por hipoglicemia, la mayor parte se encontraba con dosis iguales o menores a 10 mg/día (dosis bajas).
Introduction; Hypoglycemia (HG) (glycemia < 60 mg/dl) is a clinical syndrome that may be due to different causes. Severe hypoglycemia is defined by the need of help of another person or the need of hospitalization. Being a limitation of optimal therapy, is the most frequent complication in the diabetic patient. Main: determine the etiology, biodemographic features and incidence of hospital admissions due to HG. Patients and method: descriptive retrospective study of all the patients that were hospitalized due to HG in the Emergency Ward of the Gustavo Fricke Hospital between August 2001 and 2006. Results: 93 cases were included in the study. Mean age: 72,3 years, 60,2 per cent were women. One patient was diabetic type 1 and 91,4 per cent (n=85) were type 2 diabetics; 7 patients were not diabetics. Causes of HG: 79 due to oral hypoglycemiants, 7 unknown, 4 suicidal attempts, 2 reactive hypoglycemia and 1 due to insullim therapy. Discussion: the patients admitted due to hypoglycemia secundary to sulfonylurea were using a small dose of it and 23.5 per cent had impaired renal fuction. We think education about hypoclycemic events es very important to prevent and treat this frequent complication.
Assuntos
Humanos , Masculino , Feminino , Idoso , Diabetes Mellitus , Hipoglicemia/patologia , Hospitalização , Educação de Pacientes como AssuntoRESUMO
La hipoglucemia facticia es un atentado deliberado para provocar niveles séricos bajos de glucosa con el uso de insulina o de agentes hipoglucemiantes orales. Paciente JCB, masculino, 12 años, blanco, diabético tipo 1 de 2 años de evolución. Motivo de consulta: episodios de hipoglucemia severa con convulsiones y coma. Se tomaron muestras para anticuerpos antiislotes pancreáticos (ICA) y péptido C en condiciones basales y durante la hipoglucemia, así como determinaciones de hemoglobina glucosilada (HBA1) durante la evolución de la enfermedad, ultrasonografía, tomografía axial computadorizada (TAC) y resonancia magnética nuclear (RMN) de páncreas. Se obtuvieron insulinemias elevadas, valores extremadamente disminuidos de peptinemia C, incremento del índice de masa corporal y función renal y hepática dentro de parámetros normales. Los estudios imagenológicos fueron normales. Se concluye que a pesar de la relativa baja frecuencia de la hipoglucemia facticia en el diabético, es imprescindible tenerla en cuenta. La detección precoz facilita la atención psicológica temprana del paciente y previene la exposición a acciones que impliquen riesgo para la vida o daño permanente(AU)