Metformina, el fármaco paradigma del siglo XXI / Metformin, the paradigm medication of the XX1th century

Por muchos años, la metformina se ha consolidado como el principal pilar del tratamiento de la diabetes mellitus; sin embargo, los aspectos de su mecanismo de acción han permanecido mal definidos. Avances recientes han revelado que esta droga, además de su propiedad de reducir la glucemia, puede ser promisoria para identificar blancos metabólicos entre la señalización metabólica normal y anormal. El centro del mecanismo de acción de la metformina es la alteración del metabolismo energético de la célula, de tal forma que su efecto hipoglucemiante ocurre por inhibición de la gluconeogénesis hepática, opuesto a la acción del glucagón. La inhibición del complejo I mitocondrial resulta en defectos en AMPc y señalización de la protein cinasa A en respuesta al glucagón. La estimulación de la protein cinasa activada 5'AMP, aunque dispensable para el efecto hipoglucemiante de la metformina, confiere sensibilidad a la insulina, principalmente por modulación del metabolismo lipídico. Conjuntamente con su efecto hipoglucemiante se ha despertado interés en las potenciales acciones relevantes sobre las enfermedades cardiovasculares y cáncer. No obstante, tales mecanismos de acción permanecen esquivos. La data convincente coloca al metabolismo energético en el centro del mecanismo de acción de la metformina en la diabetes y también puede jugar un papel importante en las enfermedades cardiovasculares y cáncer. En esta revisión se discute el conocimiento actualizados de la acción antigluconeogénica de la metformina y sus implicaciones en el descubrimiento de nuevos objetivos(AU)

Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the aspects of its action remained ill defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signaling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us develop novel treatments. The center of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Here, we discuss the updated understanding of the antigliconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer(AU)

Diagnóstico y manejo de la hipoglicemia en adultos diabéticos hospitalizados: evaluación de competencias en un equipo profesional multidisciplinario de salud / Competences on hypoglycemia management among healthcare professionals in a clinical hospital

Background: A tight glycemic control of hospitalized patients increases the risk of hypoglycemia, whose management is not always optimal. Aim: To assess the hypoglycemia management competences of a multidisciplinary team in a clinical hospital. Material and Methods: An anonymous questionnaire about hypoglycemia management was answered by 11 staff physicians, 42 residents and 28 nurses of the department of medicine and critical care unit ofa university hospital. Results: Respondents had a mean of 60 percent of correct answers, without significant differences between groups. The capillary blood glucose level that defines hypoglycemia was known by most of the respondents, but the value that defines severe episodes was known only by 60 percent. The initial management and follow up was well known only for severe episodes. Less than 50 percento knew the blood glucose value that required continuing with treatment. Conclusions: Although most professionals are able to recognize hypoglycemia, the knowledge about is management if insufficient.

Hipoglicemia induzida por insulina como fator desencadeador de déficit cognitivo em crianças portadoras de diabetes mellitus tipo 1 / Insulin-induced hypoglycemia as a triggering factor of cognitive impairment in children with type 1 diabetes mellitus

O Diabetes mellitus tipo 1 (DM1) surge mais frequentemente em crianças e caracteriza-se pela deficiência total de insulina, o que torna a insulinoterapia necessária. Durante a insulinoterapia a hipoglicemia é uma reação adversa comum e poderia acarretar dano cerebral associado ao déficit cognitivo (DC). Porém, o assunto é controverso, já que existem estudos nos quais a associação DC e hipoglicemia induzida por insulina (HII) não foi comprovada. Desse modo, com o objetivo de esclarecer esta questão utilizou-se o PubMed (www.ncbi.nlm.nih.gov/pubmed), um banco de dados que possui mais de 20 milhões de trabalhos científicos disponíveis on line. Utilizou-se as palavras-chave: ?hypoglycemia and cognitive function and children? ou ?diabetes and cognitive deficit and children?. Selecionou-se publicações do período entre 1960 e 2010. Excluiu-se estudos em animais experimentais, investigações restrita a adultos e estudos nos quais a avaliação do DC ocorreu durante o episódio de HII. Assim, investigações que associaram DC com HII e dano cerebral (estrutural e funcional) foram analisados. Desta maneira, após uma cuidadosa avaliação dos estudos selecionados concluiu-se que existe uma forte correlação entre dano cerebral causado pela hipoglicemia e DC envolvendo múltiplos fatores: duração, intensidade e frequência dos episódios de HII, precocidade no surgimento do DM e duração da doença. Conclui-se que é relevante o contínuo e intensivo cuidado e educação da criança portadora de DM1 submetida à insulinoterapia, com vistas a reduzir a possibilidade do dano cerebral e DC.

Type 1 diabetes (T1D) starts frequently in children and and it is characterized by total insulin deficiency and for this reason insulin therapy is necessary. During insulin therapy, hypoglycemia is a very common side effect and could bring brain damage associated with cognitive deficit (CD). However, there are controversies considering that there are studies in which the association of insulin induced hypoglycemia (IIH) and CD were not comproved. Therefore, to clarify this question it was used PubMed (www.ncbi.nlm.nih.gov/pubmed), with more than 20 millions of on line available publications. The key words ?hypoglycemia and cognitive function and children? or ?diabetes and cognitive deficit and children? were employed. The publications between 1960 and 2010 were selected. Studies from experimental animals, investigations restrict to adult people and studies in which the evaluation of CD occurred during the episode of IIH were excluded. Therefore, investigations that associated CD with IIH and brain damage (structural and functional) were analyzed. Consequently, after a care full evaluation from selected studies it was concluded that there is a strong relationship between brain damage caused by hypoglycemia and CD involving several factors: duration, intensity and frequency of IIH episodes, precocity of T1D and duration of the disease. It was concluded that the intensive care and education of children with T1D submitted to insulinoterapy is very important to reduce the possibility of brain damage and CD.

Controle glicêmico em terapia intensiva 2009: sem sustos e sem surpresas / Glucose control in critically ill patients in 2009: no alarms and no surprises

Na última década o controle glicêmico em pacientes críticos foi alvo de grande polêmica. Apesar de ter sido amplamente implementado na prática médica, os grandes estudos randomizados controlados obtiveram resultados bastante conflitantes, pois além de controlar a hiperglicemia, foi identificada a necessidade de se evitar os riscos da hipoglicemia, evento potencialmente grave nessa população. Dessa forma, o presente artigo se propõe a rever e avaliar de forma crítica os estudos publicados sobre controle glicêmico em terapia intensiva, propondo um novo alvo glicêmico (150 mg / dl) que seja capaz de minimizar os malefícios da hiperglicemia e ao mesmo tempo minimizar os riscos potenciais do uso de insulina de forma intensiva.

Glucose control is a major issue in critical care since landmark publications from the last decade leading to widespread use of strict glucose control in the clinical practice. Subsequent trials showed discordant results that lead to several questions and concerns about benefits and risks of implementing an intensive glucose control protocol. In the midst of all recent controversy, we propose that a new glycemic target -150mg/dl) should be aimed. This target glucose level could offer protection against the deleterious effects of hyperglycemia and at the same time keep patient's safety avoiding hypoglicemia. The article presents a critical review of the current literature on intensive insulin therapy in critically ill patients.

Hipoglicemia hiperinsulinémica neonatal transitoria: A propósito de un caso

Objetivo: Presentar el caso de una recién nacida (RN) portadora de Hipoglicemia Hiperinsulinémica transitoria, patología de etiología variable, cuya incidencia es de 1/40.000 nacidos vivos. Se hace una revisión de la literatura. Caso Clínico: RN femenina a término, pequeña para la edad gestacional, de 2 días de vida, quien presenta movimientos tónico-clónicos generalizados, succión débil, e hipotonía, refractarios a tratamiento. Madre no diabética. Al examen físico: Peso: 2.100 gr, talla: 48 cms. Piel con leve tinte ictérico. Hipoactiva, con llanto agudo. Laboratorio: Glicemia central 7 mg/dL y capilar: 13 mg/dL, Insulina 30,8 mU/mL, Cortisol 5,68 μg/dL, Hormona de Crecimiento 25,8 ng/mL. Perfil tiroideo, gasometría y hemograma normal, bilirrubina elevada. Recibe aporte de dextrosa a razón de 8 mg/kg/min más un bolus de dexametasona (0,6 mg/stat). A las 12 horas de su ingreso y luego de iniciar la primera dosis de hidrocortisona (5 mg/kg/día) presentó: Glicemia basal 13 mg/dL, Insulina basal 16,8 mU/mL, Triglicéridos: 160 mg/dL, Colesterol 87 mg/dL, C-HDL 39 mg/dL. Estuvo hospitalizada durante 2 semanas con aporte continuo de dextrosa a razón de 9 mg/kg/min e hidrocortisona; evoluciona satisfactoriamente, con disminución progresiva de la necesidad de aporte de glucosa y de esteroides. Se egresa con glicemia de 50 mg/dL e insulina de 3 μU/mL. Conclusión: La hipoglicemia transitoria es frecuente en los primeros 5-7 días de vida. Se debe pensar en hipoglicemia hiperinsulinémica cuando los niveles de insulina son inapropiadamente elevados en estados de hipoglicemia, los requerimientos de glucosa son mayores de 6-8 mg/kg/min y el amonio está ligeramente elevado. Es prioritario tratar adecuadamente la hipoglicemia para prevenir secuelas neurológicas. Los casos transitorios en su mayoría son de resolución espontánea.

Objective: To report the case of a female newborn with transient hyperinsulinemic hypoglicemia which is a condition with several causes and an incidence of 1 in 40000 born alive babies. A review of the medical literature is done. Clinical Case: A female newborn from a complete pregnancy, with small size for her gestational age, presented at the age of two days with generalized tonic clonic movements, weak sucking and hypotonia that did not respond to medical treatment. Her mother was not diabetic. Physical Exam: Weight 2100 g, Height 48cm. There was a slight jaundiced color in the skin. She was hypoactive with an acute cry. Laboratory: Glycemia: 7 mg/dL. Capillary blood glucose: 13 mg/dL. Serum insulin levels: 30.8 mU/mL, Cortisol: 5.68ug/dL, Human growth Hormone: 25.8 ng/mL. Thyroid function tests, complete blood count and arterial blood gases were normal. Serum bilirrubin high. She received intravenous glucose at a rate of 8 mg/kg/min and Dexamethasone 0.6 mg in I.V. bolus. Twelve hours after her admission with a treatment with hydrocortisone, 5 mg/Kg/day, her blood glucose was 13 mg/dL, her serum insulin 16.8 mU/mL, triglycerides 160 mg/dL, Total cholesterol 87 mg/dL, C-HDL 39 mg/dL. She remained in the hospital for two weeks receiving an intravenous infusion of glucose (9 mg/kg/min) and hydrocortisone. The baby had a satisfactory evolution with a gradual lowering of her glucose needs as well as of glucocorticoids. She was discharged with a blood glucose level of 50 mg/dL and her insulin level was 3 mU/mL. Conclusion: Transient hypoglycemia is a frequent finding in babies at an age of 5-7 days. The diagnosis of hyperinsulinemic hypoglycemia should be thought when insulin levels are inappropriately elevated in states of hypoglycemia, the glucose requirements are higher than 6-8 mg/kg /min and the ammonia is slightly high. To prevent neurologic sequelae, the priority is to treat the hypoglycemia adequately. The majority of the transient cases are of spontaneous resolution.