Hyperglycemic memory in diabetic cardiomyopathy / 医学前沿

Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic cardiovascular complication. Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy, fibrosis, apoptosis, and other pathophysiological changes. Although glycemic control has long been at the center of diabetes therapy, multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes. This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level. This process is now referred to as hyperglycemic memory (HGM) phenomenon. We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.

Teoria do risco de padrão glicêmico desequilibrado em adultos e idosos com diabetes mellitus em tratamento / Theory of the Risk of Imbalanced Glycemic Pattern in adults and elderly people with diabetes mellitus under treatment

Introdução: os padrões referentes à glicemia não foram descritos e explicados utilizando-se uma teoria de enfermagem como referencial, nem tão pouco articulados e modelados às estruturas preditoras de interesse para ação da enfermagem diante destas condições. Sendo assim, presume-se a relevância de construir uma teoria de médio alcance que aborde os fatores predisponentes e precipitantes para os padrões de variabilidade relativos à glicemia, explicando relações e predizendo associações que possam suportar o julgamento diagnóstico de enfermagem para a população com diabetes mellitus em tratamento. Objetivo: desenvolver uma teoria de médio alcance sobre variações glicêmicas em adultos e idosos com diabetes mellitus em tratamento tendo por base o Modelo Conceitual da Adaptação de Roy. Método: pesquisa teórica do tipo desenvolvimento de uma nova teoria. Para teorização utilizou-se a proposta de processo geral de pesquisa de Holton e Lowe (2007). Os procedimentos metodológicos desenvolvidos foram implementados em três partes: parte 1 ­ a) entendimento dos fenômenos; b) identificação e recuperação dos estudos na revisão sistemática de etiologia e risco e análise do modelo de adaptação de Roy; c) análise do construto; parte 2 ­ d) identificação de unidades da teoria; e) estipular as leis de interação com a produção de um modelo de interações guiado pelas dez etapas de construção de modelos de causalidade proposto por Jaccard e Jacoby (2010); f) determinação dos limites da teoria; g) especificação dos estados do sistema; h) desenvolvimento das afirmativas axiomáticas; parte 3 ­ i) especificação das proposições da teoria. Resultados: produziu-se a análise do modelo de adaptação de Roy e uma revisão sistemática da literatura sobre fatores de risco para hiperglicemia e hipoglicemia em adultos e idosos com diabetes mellitus em tratamento. Essas estratégias permitiram na análise do construto o desenvolvimento do diagnóstico "Risco de Padrão Glicêmico Desequilibrado no adulto/idoso com Diabetes Mellitus". O processo de teorização determinou as unidades e estados focais, contextuais e residuais da teoria do Risco de Padrão Glicêmico Desequilibrado em adultos e idosocom diabetes mellitus em tratamento. Produziu-se um modelo interativo das unidades focais, nove afirmativas axiomáticas, quatorze proposições teóricas e um modelo representativo da teoria. Conclusões: esta pesquisa elaborou uma teoria de médio alcance, que descreve e explica o Risco de Padrão Glicêmico Desequilibrado, examinando os fatores que influenciam no surgimento da hipoglicemia e hiperglicemia em adultos e idosos com Diabetes Mellitus em tratamento. A presente tese contribui de forma original ao estruturar riscos associados a hipoglicemia e hiperglicemia em um construto de interesse para a enfermagem que pode ter futuros impactos na organização e delimitações de ações do cuidado profissional.

Introduction: the patterns referring to glycemia were not described and explained using a nursing theory as a reference, nor were they articulated and modeled on the predictive structures of interest for nursing action under these conditions. Thus, the relevance of constructing a meddle-range theory that addresses the predisposing and precipitating factors for the variability patterns related to glycemia is presumed, explaining relationships and predicting associations that can support the nursing diagnostic judgment for the population with diabetes mellitus in treatment. Objective: to develop a meddle-range theory on glycemic variations in adults and the elderly with diabetes mellitus undergoing treatment based on Roy's Conceptual Adaptation Model. Method: theoretical research on the type of development of a new theory. For theorizing, Holton and Lowe's (2007) general research process proposal was used. The methodological procedures developed were implemented in three parts: part 1 - a) understanding of the phenomena; b) identification and recovery of studies in the systematic review of etiology and risk and analysis of Roy's adaptation model; c) constructo analysis; part 2 - d) identification of theory units; e) stipulate as laws of interaction with the production of an interaction model guided by the ten stages of construction of causality models addressed by Jaccard and Jacoby (2010); f) determining the limits of the theory; g) replacement of system states; h) development of axiomatic statements; part 3 - i) registration of theory proposals. Results: an analysis of the Roy adaptation model and a systematic review of the literature on risk factors for hyperglycemia and hypoglycemia in adults and the elderly with diabetes mellitus under treatment were carried out. These strategies allowed, in the construct analysis, the development of the diagnosis "Risk of Imbalanced Glycemic Pattern in the adult/ elderly with Diabetes Mellitus". The theorization process determined the focal, contextual and residual units and states of the Imbalanced Glycemic Pattern Risk theory in adults and the elderly with diabetes mellitus being treated. An interactive model of the focal units was produced, nine axiomatic statements, fourteen theoretical propositions and a representative model of the theory. Conclusions: this researcdeveloped a meddle-range theory, which describes and explains the Risk of Imbalanced Glycemic Pattern, examining the factors that influence the appearance of hypoglycemia and hyperglycemia in adults and elderly people with Diabetes Mellitus under treatment. The present thesis contributes in an original way by structuring risks associated with hypoglycemia and hyperglycemia in a construct of interest to nursing that may have future impacts on the organization and delimitations of professional care actions.

Introducción: los patrones que se refieren a la glucemia no se describieron ni explicaron utilizando una teoría de enfermería como referencia, ni se articularon y modelaron sobre las estructuras predictivas de interés para la acción de enfermería en estas condiciones. Por lo tanto, se presume la relevancia de construir una teoría de rango medio que aborde los factores predisponentes y precipitantes para los patrones de variabilidad relacionados con la glucemia, explicando las relaciones y prediciendo asociaciones que pueden apoyar el juicio diagnóstico de enfermería para la población con diabetes mellitus en tratamiento. Objetivo: desarrollar una teoría de rango medio sobre las variaciones glucémicas en adultos y ancianos con diabetes mellitus en tratamiento según el Modelo de Adaptación Conceptual de Roy. Método: investigación teórica como el desarrollo de una nueva teoría. Para la teorización, se utilizó la propuesta del proceso de investigación general de Holton y Lowe's (2007). Los procedimientos metodológicos desarrollados se implementaron en tres partes: parte 1 - a) comprensión de los fenómenos; b) identificación y recuperación de estudios en la revisión sistemática de etiología y riesgo y análisis del modelo de adaptación de Roy; c) análisis de la construcción; parte 2 - d) identificación de unidades teóricas; e) estipular las leyes de interacción con la producción de un modelo de interacción guiado por las diez etapas de construcción de modelos de causalidad propuestos por Jaccard y Jacoby (2010); f) determinar los límites de la teoría; g) especificación de los estados del sistema; h) desarrollo de enunciados axiomáticos; parte 3 - i) especificación de las proposiciones de la teoría. Resultados: se realizó un análisis del modelo de adaptación de Roy y una revisión sistemática de la literatura sobre los factores de riesgo de hiperglucemia e hipoglucemia en adultos y ancianos con diabetes mellitus en tratamiento. Estas estrategias permitieron, en el análisis de la construcción, el desarrollo del diagnóstico "Riesgo de patrón glucémico desequilibrado en adultos / ancianos con diabetes mellitus". El proceso de teorización determinó las unidades y estados focales, contextuales y residuales de la teoría del riesgo de patrón glucémico desequilibrado en adultos y ancianos con diabetes mellitus que se está tratando. Se produjo un modelo interactivo de las unidades focales, nueve declaraciones axiomáticas, catorce proposiciones teóricas y un modelo representativo de la teoría. Conclusiones: esta investigación desarrolló una teoría de rango medio, que describe y explica el riesgo de un patrón glucémico desequilibrado, examinando los factores que influyen en la aparición de hipoglucemia e hiperglucemia en adultos y ancianos con diabetes mellitus bajo tratamiento. La presente tesis contribuye de manera original al estructurar los riesgos asociados con la hipoglucemia y la hiperglucemia en un constructo de interés para la enfermería que puede tener impactos futuros en la organización y delimitaciones de las acciones de atención profesional.

Biochemical and Molecular Mechanisms of Glucose Uptake Stimulated by Physical Exercise in Insulin Resistance State: Role of Inflammation / Mecanismos Bioquímicos e Moleculares da Captação da Glicose Estimulada pelo Exercício Físico no Estado de Resistência à Insulina: Papel da Inflamação

Abstract Obesity associated with systemic inflammation induces insulin resistance (IR), with consequent chronic hyperglycemia. A series of reactions are involved in this process, including increased release of proinflammatory cytokines, and activation of c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-κB) and toll-like receptor 4 (TLR4) receptors. Among the therapeutic tools available nowadays, physical exercise (PE) has a known hypoglycemic effect explained by complex molecular mechanisms, including an increase in insulin receptor phosphorylation, in AMP-activated protein kinase (AMPK) activity, in the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) pathway, with subsequent activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Rac1, TBC1 domain family member 1 and 4 (TBC1D1 and TBC1D4), in addition to a variety of signaling molecules, such as GTPases, Rab and soluble N-ethylmaleimide-sensitive factor attached protein receptor (SNARE) proteins. These pathways promote greater translocation of GLUT4 and consequent glucose uptake by the skeletal muscle. Phosphoinositide-dependent kinase (PDK), atypical protein kinase C (aPKC) and some of its isoforms, such as PKC-iota/lambda also seem to play a fundamental role in the transport of glucose. In this sense, the association between autophagy and exercise has also demonstrated a relevant role in the uptake of muscle glucose. Insulin, in turn, uses a phosphoinositide 3-kinase (PI3K)-dependent mechanism, while exercise signal may be triggered by the release of calcium from the sarcoplasmic reticulum. The objective of this review is to describe the main molecular mechanisms of IR and the relationship between PE and glucose uptake.

Resumo A obesidade associada à inflamação sistêmica induz resistência à insulina (RI), com consequente hiperglicemia crônica. Este processo envolve o aumento na liberação de citocinas pró-inflamatórias, ativação da enzima c-Jun N-terminal cinase (JNK), do fator nuclear kappa-B (NF-κB) e dos receptores do tipo Toll 4 (TLR4). Dentre as ferramentas terapêuticas disponíveis, o exercício físico (EF) tem efeito hipoglicemiante conhecido, explicado por mecanismos moleculares complexos. Dentre eles, ocorre aumento na fosforilação do receptor da insulina, na atividade da proteína quinase ativada por AMP (AMPK), na via da proteína cinase cinase dependente de Ca+2/calmodulina (CaMKK), com posterior ativação do coativador-1α do receptor ativado por proliferador do peroxissoma (PGC-1α), proteínas Rac1, TBC1 membro das famílias de domínio 1 e 4 (TBC1D1 e TBC1D4), além de uma variedade de moléculas de sinalização, como as proteínas GTPases, Rab e proteína solúvel de fusão sensível a N-etil-maleimida (SNARE); estas vias promovem maior translocação de transportador de glicose do tipo 4 (GLUT4) e consequente captação de glicose pelo músculo esquelético. A cinase fosfatidilinositol-dependente (PDK), proteína quinase C atípica (aPKC) e algumas das suas isoformas, como a PKC-iota/lambda também parecem desempenhar papel fundamental no transporte de glicose. Nesse sentido, a associação entre autofagia e EF também tem demonstrado papel relevante na captação de glicose muscular. A insulina, por sua vez, utiliza um mecanismo dependente da fosfatidilinositol-3-quinase (PI3K), enquanto que o sinal do EF pode ter início mediante liberação de cálcio pelo retículo sarcoplasmático e concomitante ativação da AMPK. O objetivo desta revisão é descrever os principais mecanismos moleculares da RI e da relação entre o EF e a captação de glicose.

Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simple carbohydrates / 亚洲男科学杂志(英文版)

High-fat diets affect male reproduction and sexual function. Therefore, we evaluated the effects of prolonged resveratrol administration on the metabolic, sperm, and testicular parameters of rats fed a cafeteria diet. Male Wistar rats were divided at weaning into control (C, n = 20) and cafeteria (CAF, n = 16) groups. At 3 months, half of them were given daily supplementations of resveratrol (C-R, n = 10; CAF-R, n = 8) at a dosage of 30 mg kg-1 body mass for 2 months. Animals were killed at 5 months of age, and blood, spermatozoa, and testes were collected for further analysis. Data were analyzed by one-way ANOVA, and P < 0.05 was considered statistically significant. The CAF diet promoted hyperglycemia (P < 0.0001), and treatment with resveratrol reversed this condition (P < 0.0001). The CAF diet reduced sperm viability and motility, while resveratrol improved these parameters (P < 0.05). Regarding testicular morphology, the height of the seminiferous epithelium was reduced in the CAF group compared with that of the C group (P = 0.0007). Spermatogenic cell proliferation was also reduced in the CAF group compared with that of the C group. However, the CAF-R showed an increase in cell proliferation rate compared with that of the untreated CAF group (P = 0.0024). Although it did not modify body mass, the consumption of a CAF diet promoted hyperglycemia, adverse testicular morphology remodeling, and abnormal sperm, which were attenuated by treatment with resveratrol, thus suggesting a protective effect of this antioxidant on spermatogenesis.

Hiperglicemia por sepsis: del mecanismo a la clínica / Sepsis hyperglycemia in the ICU: from the mechanism to the clinic

Stress hyperglycemia is frequently diagnosed in septic patients in critical care units (ICU) and it is associated with greater illness severity and higher morbimortality rates. In response to an acute injury, high levels of counterregulatory hormones such as glucocorticoids and catecholamines are released causing increased hepatic gluconeogenesis and insulin resistance. Furthermore, during sepsis, proinflammatory cytokines also participate in the pathogenesis of this phenomenon. Septic patients represent a subtype of the critical ill patients in the ICU: this metabolic disarrangement management strategies and insulin therapy recommendations had been inconsistent. In this article, we describe the pathophysiological mechanisms of stress hyperglycemia in critical patients including the action of hormones, inflammatory cytokines and tissue resistance to insulin. In addition, we analyzed the main published studies for the treatment of acute hyperglycemia in critical patients.

A memória hiperglicêmica no rim diabético: marcas metabólicas, moleculares e epigenéticas / The hyperglycemic memory in diabetic kidney: metabolic, molecular, and epigenetic marks

A nefropatia diabética (ND) é uma das complicações microvasculares do diabetes e consiste no dano ao parênquima renal por consequência de uma série de fatores hemodinâmicos e moleculares. A ocorrência de ND e de outras complicações mesmo em indivíduos sob adequado controle glicêmico tem sido associada a um fenômeno conhecido como memória metabólica. Neste trabalho foram investigadas vias bioquímicas e moleculares persistentemente alteradas no rim de animais diabéticos tratados após um período inicial de hiperglicemia, com o propósito de entender os mecanismos envolvidos na memória metabólica. Para tanto, ratos com diabetes induzida por estreptozotocina foram mantidos hiperglicêmicos durante 4 semanas (período curto) ou 12 semanas (período longo) e posteriormente tratados com insulina isoladamente ou combinada com metformina (100mg/kg/dia) durante as 4 (período curto) ou 12 (período longo) semanas seguintes. Todos os animais tratados tiveram os seus níveis glicêmicos e função renal normalizados. Os tratamentos também foram capazes de normalizar os níveis elevados de malonaldeído no rim, bem como a excreção aumentada dos adutos de DNA 8-oxo-2'-desoxiguanosina (8-oxodG) e N2-carboxietil-2'- desoxiguanosina (CEdG) na urina observados nos animais diabéticos. Níveis aumentados de 8-oxodG foram detectados em DNA mitocondrial (mtDNA), mas não em DNA nuclear, de animais diabéticos apenas no período curto de estudo e também foram normalizados após o controle glicêmico. Nós identificamos uma via gradualmente alterada durante o curso do diabetes que permanece persistentemente alterada após o controle glicêmico tardio. Essa via compreende um declínio precoce do clearance de ácido úrico e expressão da pAMPK, seguida pelo acúmulo de fumarato, expressão aumentada de TGF-ß, expressão reduzida de PGC-1α e redução da metilação e hidroximetilação do mtDNA. A redução persistente do clearance de ácido úrico em animais diabéticos tratados pode sustentar as alterações bioquímicas renais prolongadas observadas após o controle glicêmico, e essa regulação é provavelmente mediada pela redução sustentada da expressão de pAMPK e pela indução de inflamação. Este trabalho propõe a primeira consideração do possível papel da hiperuricemia e das alterações bioquímicas subjacentes como parte da memória metabólica na nefropatia diabética

Diabetic nephropathy is one of the diabetes microvascular complications, and it consists on the damage to the renal parenchyma due to several hemodynamic and molecular factors. The occurrence of diabetic nephropathy and other complications even in those individuals under tight glycemic control has been associated to a phenomenon known as metabolic memory. Here we investigated biochemical and molecular pathways persistently altered in the kidney of diabetic animals treated after a previous period of hyperglycemia, aiming to understand underlying mechanisms in metabolic memory. Streptozotocin-induced diabetic rats were maintained hyperglycemic during 4 (short period) or 12 weeks (long period), and then they were treated with insulin alone or combined with metformin (100 mg/kg/day) for the following 4 or 12 weeks, respectively. All the treated animals had them glycemic levels and renal function normalized. The treatments were also able to control enhanced kidney malondialdehyde levels, as well as the increased urine excretion of the DNA adducts 8-oxo-2'- deoxyguanosine (8-oxodG) and N2-carboxyethyl-2'-deoxyguanosine seen in diabetic animals. Increased levels of 8-oxodG were detected in mitochondrial DNA, but not in nuclear DNA of diabetic animals in the short period, and were also recovered after glycemic control. We have identified a kidney pathway that is gradually altered during the course of diabetes and remains persistently changed after late glycemic control. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-ß expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This work proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy

Glutamine treatment attenuates hyperglycemia-induced mitochondrial stress and apoptosis in umbilical vein endothelial cells

OBJECTIVE: The aim of this study was to determine the in vitro effect of glutamine and insulin on apoptosis, mitochondrial membrane potential, cell permeability, and inflammatory cytokines in hyperglycemic umbilical vein endothelial cells. MATERIALS AND METHODS: Human umbilical vein endothelial cells were grown and subjected to glutamine and insulin to examine the effects of these agents on the hyperglycemic state. Mitochondrial function and the production of inflammatory cytokines were assessed using fluorescence analysis and multiple cytotoxicity assays. Apoptosis was analyzed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. RESULTS: Glutamine maintains the integrity of the mitochondria by reducing the cell permeability and cytochrome c levels and increasing the mitochondrial membrane potential. The cytochrome c level was significantly (p<0.005) reduced when the cells were treated with glutamine. An apoptosis assay revealed significantly reduced apoptosis (p<0.005) in the glutamine-treated cells. Moreover, glutamine alone or in combination with insulin modulated inflammatory cytokine levels. Interleukin-10, interleukin-6, and vascular endothelial growth factor were up-regulated while tumor necrosis factor-α was down-regulated after treatment with glutamine. CONCLUSION: Glutamine, either alone or in combination with insulin, can positively modulate the mitochondrial stress and cell permeability in umbilical vein endothelial cells. Glutamine regulates the expression of inflammatory cytokines and maintains the balance of the mitochondria in a cytoprotective manner. .

Anti-hyperglycemic activity of Rutin in streptozotocin-induced diabetic rats: An effect mediated through cytokines, antioxidants and lipid biomarkers.

Administration of rutin (50 and 100 mg/kg) and pioglitazone (10 mg/kg) orally for 3 weeks treatment significantly improved body weight, reduced plasma glucose and glycosylated hemoglobin, pro-inflammatory cytokines (IL-6 and TNF-α), restored the depleted liver antioxidant status and serum lipid profile in high fat diet + streptozotocin induced type 2 diabetic rats. Rutin treatment also improved histo-architecture of ß islets and reversed hypertrophy of hepatocytes. Rutin exhibited significant antidiabetic activity, presumably by inhibiting inflammatory cytokines, improving antioxidant and plasma lipid profiles in High fat diet + streptozotocin induced type 2 diabetic model and may be useful as a diabetic modulator along with standard antidiabetic drugs. However, such effects need to be confirmed on human subjects in clinical condition.

Respuestas metabólicas inducidas por ejercicio físico de alta intensidad en mujeres sedentarias con glicemia basal alterada e hipercolesterolemia / Metabolic response to high intensity exercise training in sedentary hyperglycemic and hypercholesterolemic women

Background: High intensity training could be an effective way of improving health on individuals at high metabolic risk. Aim: To investigate the effects of a high intensity training intervention on metabolic-related markers in sedentary women at high metabolic risk. Material and Methods: Forty six sedentary women with a body mass index (BMI) over 25 kg/m² were assigned to four groups, according to their metabolic profile; hyperglycemia (H, n = 12), hyperglycemia/hypercholesterolemia (HH, n = 13), normoglycemia (N, n = 10) and normoglycemia/hypercholesterolemia (NH, n = 11). For 12 weeks and five days per week, subjects performed seven intervals of high intensity training (20 to 30 seconds) during a training session of 20 minutes. Anthropometric (body weight, body mass index (BMI), waist circumference) and metabolic variables (glucose, total cholesterol, LDL, HDL and TG) were measured at baseline, at 6 and 12 weeks of intervention. Results: BMI and waist circumference decreased significantly after 12 weeks of intervention. Similarly, glucose decreased significantly after 12 weeks of intervention in all groups. The reduction was of higher magnitude in those groups with hyperglycemia (H = -16%, HH = -22%, N = -7,5%, NH = -9,6%). However, lipid profile (TG, total cholesterol, LDL and HDL) improved significantly only in the hypercholesterolemic groups. Conclusions: Physical activity programs incorporating high intensity training can improve glucose and lipid profile in women with metabolic disorders. Moreover, this benefit is greatest in those individuals with highest metabolic burden.

Role of insulin resistance and diet in acne.

There is increasing evidence in support of the interplay of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signaling during puberty, which have a causal role in pathogenesis of acne by influencing adrenal and gonadal androgen metabolism. Milk consumption and hyperglycemic diets can induce insulin and IGF-1-mediated PI3K ⁄ Akt-activation inducing sebaceous lipogenesis, sebocyte, and keratinocyte proliferation, which can aggravate acne. Occurence of acne as part of various syndromes also provides evidence in favor of correlation between IGF-1 and acne.

Alleviation of metabolic abnormalities induced by excessive fructose administration in Wistar rats by Spirulina maxima.

Background & objectives: Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia. Several natural products have been isolated and identified to restore the complications of diabetes. Spirulina maxima is naturally occurring fresh water cyanobacterium, enriched with proteins and essential nutrients. The aim of the study was to determine whether S. maxima could serve as a therapeutic agent to correct metabolic abnormalities induced by excessive fructose administration in Wistar rats. Methods: Oral administration of 10 per cent fructose solution to Wistar rats (n=5 in each group) for 30 days resulted in hyperglycaemia and hyperlipidaemia. Aqueous suspension of S. maxima (5 or 10%) was also administered orally once daily for 30 days. The therapeutic potential of the preparation with reference to metformin (500 mg/kg) was assessed by monitoring various biochemical parameters at 10 day intervals during the course of therapy and at the end of 30 days S. maxima administration. Results: Significant (P<0.001) reductions in blood glucose, lipid profile (triglycerides, cholesterol and LDL, VLDL) and liver function markers (SGPT and SGOT) were recorded along with elevated level of HDL-C at the end of 30 days therapy of 5 or 10 per cent S. maxima aquous extract. Co-administration of S. maxima extract (5 or 10% aqueous) with 10 per cent fructose solution offered a significant protection against fructose induced metabolic abnormalities in Wistar rats. Interpretation & Conclusions: The present findings showed that S. maxima exhibited anti-hyperglycaemic, anti-hyperlipidaemic and hepatoprotective activity in rats fed with fructose. Further studies are needed to understand the mechanisms.

Glucose disturbances in non-diabetic patients receiving acute treatment with methylprednisolone pulses / Distúrbios de glicose em pacientes não diabéticos que recebem tratamento agudo com pulsos de metilprednisolona

OBJECTIVE: Methylprednisolone pulses are used in a variety of disease conditions, both for acute and chronic therapy. Although well tolerated, they increase glucose levels in both non-diabetic and diabetic patients. They may also be considered a significant risk for acute metabolic alterations. The purpose of this report is to determine the metabolic changes in blood glucose levels in non-diabetic patients receiving methylprednisolone pulses and identify the presence of predictive factors for its development. METHODS: Observational, prospective study in 50 non-diabetic patients receiving 1 g intravenous methylprednisolone pulses for three consecutive days as an indication for diverse autoimmune disorders. Demographic, anthropometric, and metabolic variables were analyzed, and glucose, insulin and C-peptide levels after each steroid pulse were identified. Different variables and the magnitude of hyperglycemia were analyzed using Pearson's correlation. RESULTS: 50 patients were included, predominantly women (66 percent, n = 33). The average age was 41 ± 14 years with a BMI of 26 ± 3 kg/m². Baseline glucose was 83 ± 10 mg/dL. After each steroid pulse, glucose increased to 140 ± 28, 160 ± 38 and 183 ± 44, respectively (p < 0.001). C-peptide and insulin concentrations increased significantly (p < 0.001). The prevalence of fasting hyperglycemia after each pulse was 68 percent, 94 percent and 98 percent, respectively. We found no correlation between the magnitude of hyperglycemia and the studied variables. CONCLUSION: Methylprednisolone pulses produced significant increases in fasting glucose in most patients without diabetes. Further studies are needed to define its role in long-term consequences.

OBJETIVO: Pulsos de metilprednisolona são usados em diversas doenças, tanto para tratamento agudo quanto crônico. Embora bem tolerados, eles aumentam os níveis de glicose em ambos os pacientes, não diabéticos e diabéticos. Eles também podem ser considerados um risco significativo para alterações metabólicas agudas. O propósito deste estudo é determinar as alterações metabólicas nos níveis de glicose no sangue de pacientes não diabéticos que recebem pulsos de metilprednisolona e identificar a presença de fatores preditivos para seu desenvolvimento. MÉTODOS: Estudo observacional prospectivo em 50 pacientes não diabéticos que recebem pulsoterapia com 1 g de metilprednisolona intravenosa por três dias consecutivos como tratamento para diversas doenças autoimunes. Variáveis demográficas, antropométricas e metabólicas foram analisadas, e glicose, insulina e níveis de peptídeo C foram identificados após cada pulso de esteroide. Diferentes variáveis e a magnitude da hiperglicemia foram analisadas utilizando a correlação de Pearson. RESULTADOS: 50 pacientes foram incluídos, predominantemente mulheres (66 por cento, n = 33). A idade média foi de 41 ± 14 anos com um IMC de 26 ± 3 kg/m². A glicose de base foi de 83 ± 10 mg/dL. Após cada pulso de esteroide, a glicose aumentou para 140 ± 28, 160 ± 38 e 183 ± 44, respectivamente (p < 0,001). Peptídeo C e concentrações de insulina aumentaram significativamente (p < 0,001). A prevalência de hiperglicemia em jejum após cada pulso foi de 68 por cento, 94 por cento e 98 por cento, respectivamente. Não encontramos nenhuma correlação entre a magnitude da hiperglicemia e as variáveis estudadas. CONCLUSÃO: Os pulsos de metilprednisolona produziram aumentos significativos na glicemia de jejum na maioria dos pacientes sem diabetes. Mais estudos são necessários para definir o seu papel nas consequências em longo prazo.

Electroacupuncture stimulation using different frequencies (10 and 100 Hz) changes the energy metabolism in induced hyperglycemic rats / Eletroacupuntura usando diferentes freqüências (10 e 100 Hz) altera o metabolismo energético em ratos hiperglicêmicos induzidos

PURPOSE: To investigate the effect of 10 and 100 Hz peripheral electro-estimulation (electroacupuncture, EAc) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints on blood glucose and lactate levels and tissue (liver and kidney) concentrations of lactate in hyperglycemic induced anesthetized rats. METHODS: Thirty-six rats were randomly assigned to 3 groups (n=12): G1: basal (anesthesia: ketamine (90mg kg-1 body weight)+ xylazine (10mg/kg-1 body weight, i.p.); G2: anesthesia+EA10Hz EAc and G3: anesthesia+EA100Hz EAc). EAc stimulation was delivered for 30 min at 10 mA at selected acupoints. Blood and tissue (kidney, liver) samples were collected at the end of the EAc application (n=6, T30) and 30 minutes later (n=6, T60) for biochemical analysis. G1 samples were collected at the same timepoints. ANOVA followed by Tukey's Multiple Comparison Test was used for statistical analyses. RESULTS: Glycemia decreased significantly (p<0.001) in G2/G3 rats in all timepoints. Kidney and liver lactate concentrations decreased significantly (p>0.001) in G2/G3 rats at T-60 and at T30 timepoints in G2 compared with G1 rats. Lactacedemia decreased significantly at T30 timepoint in G2 compared with G1 rats. G1/G3 tissue lactate levels were not different. CONCLUSIONS: Electroacupuncture (10 Hz) applied to St-36 and CV-12 acupoints decreases glycemia and lactacedemia and liver and kidney lactate concentrations. We hypothesize that the decrease in lactate levels may be related to greater energy production due to enhanced lactate to pyruvate conversion. Higher frequency (100 Hz) failed to promote the same effect.

OBJETIVO: Investigar o efeito da eletroacupuntura (10-100 Hz) aplicada nos acupontos Zusanli (ST-36) e Zhongwan (CV-12) sobre a glicemia, lactacedemia e concentrações de lactato no fígado/rim em ratos anestesiados. MÉTODOS: Trinta e seis ratos foram distribuídos aleatoriamente em três grupos (n= 12): G1: basal (anestesia: cetamina (90mg kg-1)+xilazina (10mg/kg-1, ip), G2: anestesia+10Hz EAc e G3: anestesia+100Hz EAc). EAc foi aplicada por 30 min (10 mA) em acupontos selecionados. Amostras de sangue e tecidos (rim, fígado) foram coletadas no final da aplicação da EAc (n=6, T30) e 30 minutos depois (n=6, T60) para análise bioquímica. Amostras de G1 foram coletadas nos mesmos tempos (T30 e T60). ANOVA seguido pelo teste de comparações múltiplas de Tukey foi utilizado para análises estatísticas. RESULTADOS: A glicemia diminuiu significativamente (p<0,001) nos grupos G2/G3 em todos os pontos temporais. As concentrações de lactato nos rins e no fígado diminuiu significativamente (p<0,001) nos ratos G2/G3 ratos no T-60 e no T30 no G2, comparados com ratos G1. Lactacedemia diminuiu significativamente no T30 no G2 comparado com G1. Os níveis de lactato tecidual não foram diferentes comparando os grupos G1/G3. CONCLUSÕES: Eletroacupuntura (10 Hz) aplicada aos acupontos ST-36 e CV-12 reduz a glicemia e lactacedemia bem como as concentrações de lactato no fígado e nos rins. Nossa hipótese é que a diminuição dos níveis de lactato possa estar relacionada à maior produção de energia devido ao aumento de conversão de lactato para piruvato. A utilização de uma freqüência mais alta (100 Hz) não produz o mesmo efeito.

Short-term diabetes attenuates left ventricular dysfunction and mortality rates after myocardial infarction in rodents

OBJECTIVES: To investigate the effects of hyperglycemia on left ventricular dysfunction, morphometry, myocardial infarction area, hemodynamic parameters, oxidative stress profile, and mortality rate in rats that had undergone seven days of myocardial infarction. INTRODUCTION: Previous research has demonstrated that hyperglycemia may protect the heart against ischemic injury. METHODS: Male Wistar rats were divided into four groups: control-sham, diabetes-sham, myocardial infarction, and diabetes + myocardial infarction. Myocardial infarction was induced 14 days after diabetes induction. Ventricular function and morphometry, as well as oxidative stress and hemodynamic parameters, were evaluated after seven days of myocardial infarction. RESULTS: The myocardial infarction area, which was similar in the infarcted groups at the initial evaluation, was reduced in the diabetes + myocardial infarction animals (23 ± 3 percent) when compared with the myocardial infarction (42 ± 7 percent, p<0.001) animals at the final evaluation. The ejection fraction (22 percent, p = 0.003), velocity of circumferential fiber shortening (30 percent, p = 0.001), and left ventricular isovolumetric relaxation time (26 percent, p = 0.002) were increased in the diabetes + myocardial infarction group compared with the myocardial infarction group. The diabetes-sham and diabetes + myocardial infarction groups displayed increased catalase concentrations compared to the control-sham and myocardial infarction groups (diabetes-sham: 32± 3; diabetes + myocardial infarction: 35± 0.7; control-sham: 12 ± 2; myocardial infarction: 16 ± 0.1 pmol min-1 mg-1 protein). The levels of thiobarbituric acid-reactive substances were reduced in the diabetes-sham rats compared to the control-sham rats. These positive adaptations were reflected in a reduced mortality rate in the diabetes + myocardial infarction animals (18.5 percent) compared with the myocardial infarction animals (40.7 percent, p = 0.001). CONCLUSIONS: These data suggest that short-term hyperglycemia initiates compensatory mechanisms, as demonstrated by increased catalase levels, which culminate in improvements in the ventricular response, infarcted area, and mortality rate in diabetic rats exposed to ischemic injury.

Los procesos de glucosilación no enzimática: [revisión] / The nonenzymatic glycosylation processes: [review]

Se realizó una revisión bibliográfica con el objetivo de actualizar los conocimientos sobre el proceso de glucosilación no enzimática. Su importancia fisiológica se puso de manifiesto a partir del hallazgo de que parte de la hemoglobina en la sangre de individuos sanos está glucosilada y que el nivel de glucosilación es mayor en pacientes diabéticos. La colágeno fue la primer proteína donde se demostró la existencia de enlaces intermoleculares covalentes producidos por este mecanismo en la base molecular de la glomerulopatía y retinopatía diabética. La disminución de la actividad biológica como consecuencia de la glucosilación aparece en un reducido número de pacientes, incluyendo varios sistemas enzimáticos donde grupos amino participaron en la catálisis enzimática. La activación de receptores por la unión de proteínas con los productos de glucosilación avanzada estimula la producción en macrófagos, células endoteliales y mesangiales de factores de crecimiento y mecanismos procoagulantes que favorecen la formación de trombos en los sitios de acumulación extracelular de estos compuestos, la oclusión de vasos, hipoxia y necrosis tisular. Las reacciones en las que intervienen radicales libres, participan en la formación de los productos de glucosilación avanzada provocando su unión de manera covalente e irreversible a las proteínas favoreciendo la ateroesclerosis. En la Diabetes la hemoglobina glucosilada y la fructosamina son las determinaciones de laboratorio más frecuentes utilizadas en el control metabólico y su estabilidad, que permite prevenir los efectos nocivos de la hiperglucemia.

A bibliographical revision with the objective to bring-up-to date the knowledge on the nonenzymatic glycosylation process was carried out. Its physiologic importance was shown, starting from the discovery that a part of the hemoglobin in blood of healthy individuals is glycosylated and the glycosylation level is bigger in diabetic patients. The collagen was the first protein where the existence of covalent intermolecular bonds was demonstrated produced by this mechanism in the molecular basis of the glomerulopathy and diabetic retinopathy. The decrease of the biological activity as consequence of glycosylation appears in a reduced number of patients, including several enzymatic systems where amino groups participated in the enzymatic catalysis. The receptors´activation for proteins union with products of advanced glycosylation stimulates the production in macrophages, endothelial and mesangial cells of growth factors and procoagulant mechanisms that favor the thrombus formation in the places of extracellular accumulation of these compounds, the occlusion of vessels, hypoxia and tissular necrosis. Reactions in which intervene free radicals, participate in the formation of the advanced glycosylation products causing its union in covalent and irreversible way to the proteins favoring atherosclerosis. In diabetes the glycosylated hemoglobin and the fructosemia are the most frequent laboratory determinations used in the metabolic control and its stability allow us to prevent the noxious effects of hyperglycemia.

Protective role of Cassia auriculata leaf extract on hyperglycemia-induced oxidative stress and its safety evaluation.

Cassia auriculata L. (Caesalpiniaceae) is widely used from the ancient period to treat diabetes mellitus. In the present study, the antioxidant activity of C. auriculata aqueous leaf extract (CLEt) was evaluated in streptozotocin-induced mild diabetic (MD) and severe diabetic (SD) rats. A short-term toxicity assessment was also conducted in healthy rats to examine toxic effects of the extract. Oral administration of CLEt to MD and SD rats (100, 200 and 400 mg/kg body weight per day for a period of 21 days) produced significant fall in fasting blood glucose (FBG) in a dose-dependent manner. Treatment with the extract (400 mg/kg) showed significant reduction in serum levels of thiobarbituric acid reactive substances (TBARS) and oxidized low-density lipoprotein (OxLDL) in both MD and SD rats. The antioxidant defense system was also found to be improved in CLEt-treated (400 mg/kg) MD and SD rats, as revealed by significant increase in activities of erythrocyte’s antioxidant enzymes i.e. superoxide dismutase (SOD) and catalase (CAT) with a concomitant elevation in erythrocyte’s reduced glutathione (GSH) content. Moreover, there were no toxic signs in rats treated with high doses of the extract (1000 and 2000 mg/kg body weight per day for 21 days). Blood glucose, hepatic and renal function parameters in these rats were found within normal limits. Phytochemical screening of CLEt revealed the presence of alkaloids, flavonoids, saponins, tannins and cardiac glycosides with antihyperglycemic and antioxidant properties. This study suggests that CLEt possesses potent antioxidant activity along with antihyperglycemic potential, hence protective against diabetic complications.

Tear film and ocular surface changes in diabetes mellitus: [review] / Alterações do filme lacrimal e da superfície ocular no diabetes mellitus: [revisão]

Diabetes mellitus and its clinical association with dry eye and ocular surface are becoming a frequent and sometimes complicate problem in Ophthalmology. Epidemiological data show that an increase in the number of patients with this association is expected following the trend to rise of the disease. The present work reviews the clinical and functional aspects of this problem. The observations indicate that metabolic, neuropathic and vascular tissue damages lead to an inflammatory process and functional degeneration. The physiopathological mechanism include hyperglycemia, advanced glycated end product accumulation, oxidative stress and inflammation mediated by NF-κB signaling pathways. Potential treatments enlightened by those findings would include antioxidant, anti-inflammatory, secretagogues and/or anabolic agents that would mimic insulin effects.

O diabetes mellitus e sua associação clínica com olho seco e doença da superfície ocular estão se tornando um problema freqüente e muitas vezes complicado em oftalmologia. Os dados epidemiológicos mostram que o número de casos deve crescer acompanhando a tendência de aumento da incidência da doença. Esse trabalho revê seus aspectos clínicos e funcionais. As observações indicam que as lesões metabólicas, neuropáticas e vasculares levam a um processo inflamatório e degeneração funcional. Os mecanismos fisiopatológicos incluem hiperglicemia, acúmulo de produtos finais de glicosilação avançada, estresse oxidativo e inflamação mediada pelas vias de sinalização do NF-kB. Os tratamentos potenciais sugeridos por essas observações incluiriam antioxidantes, antiinflamatórios, secretagogos e/ou agentes anabólicos com efeitos miméticos ao da insulina.

Avaliação da prevalência do diabetes e da hiperglicemia de estresse no infarto agudo do miocárdio / The prevalence of diabetes and stress hyperglycemia in the acute myocardial infarction patients

OBJETIVOS: Determinar a prevalência do diabetes melito (DM) e da hiperglicemia de estresse (HE) em pacientes com infarto agudo do miocárdio (IAM) admitidos em unidade de emergência cardiológica. MÉTODOS: Análise retrospectiva de 2.262 pacientes com IAM, avaliando, além da prevalência de diabetes referido, o diagnosticado e a hiperglicemia de estresse. RESULTADOS: Apesar de referido em 12,1 por cento dos pacientes (H: 10,7 por cento, M: 15,8 por cento), o DM ocorria efetivamente em 24,8 por cento (H: 22,9 por cento, M: 29,7 por cento) e a HE em 13,6 por cento (H: 14,3 por cento, M: 11,7 por cento) dos indivíduos dessa população. Portanto, alterações glicêmicas ocorreram em 37,4 por cento dos indivíduos com IAM (H: 37,2 por cento, M: 41,4 por cento). Nos pacientes com DM, observou-se maior precocidade etária do IAM, maior prevalência de óbitos (DM: 20,7 por cento, ND:13,8 por cento, HE: 13,4 por cento) e de procedimentos cirúrgicos (ND: 33,8 por cento, HE: 18,0 por cento, DM: 21,7 por cento). CONCLUSÃO: A elevada prevalência de DM e hiperglicemia de estresse observada em nosso estudo indica que as alterações glicêmicas constituem um dos mais importantes fatores de risco para o IAM.

OBJECTIVES: To evaluate in our population the real prevalence of diabetes (DM) and stress hyperglycemia (HE) in patients with myocardial infarction (IAM) admitted in a cardiologic emergency unit. METHODS: A retrospective analysis of 2262 patients with AMI evaluating the prevalence of DM (referred and diagnosed) and stress hyperglycemia. RESULTS: Besides 12,1 percent of subjects were previously referred to be diabetic (men: 10.7 percent and women: 15.8 percent), diabetes was effectively diagnosed in 24,8 percent (M: 22,9 percent, W: 29,7 percent) and stress hyperglycemia in 13,6 percent HE of the patients (M: 14,3 percent, W: 11,7 percent) indicating that glycemic alterations were effectively observed in 37.2. percent of the patients with IAM (M: 37,2 percent, W: 41,4 percent). In DM subjects IAM events occurred earlier, total intra-hospital mortality was higher (DM: 20.7 percent, ND: 13,8 percent, HE: 13,4 percent) and less surgical procedures were performed (ND 33.8 percent, DM: 21.7 percent, HE: 18.0 percent). CONCLUSION: The elevated DM and stress hyperglycemia prevalence observed in our study indicates that glycemic alterations is one of the most important risk factors for IAM.

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1: [revisão] / Adjunctive therapies to glycaemic control of type 1 diabetes mellitus: [review]

Desde o Diabetes Control and Complications Trial (DCCT), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. Entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. O objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. Outros modos de ação [pirenzepina, fator de crescimento insulina-símile (IGF-1) e peptídeo semelhante ao glucagon 1 (GLP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5 por cento a 1 por cento na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1 percent, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Doença cardiovascular no diabetes melito tipo 1: [revisão] / Cardiovascular disease in type 1 diabetes mellitus: [review]

O risco de doença arterial coronariana (DAC) nos pacientes com diabetes melito tipo 1 (DM1) é conhecido desde o final dos anos 1970, sendo atualmente a principal causa de mortalidade na população adulta com diabetes tipo 1 de longa duração. A patogênese do processo aterosclerótico nesta doença ainda é obscura, acreditando-se que a hiperglicemia desenvolva aí um papel importante, entretanto vários estudos epidemiológicos mostraram que a associação entre doença coronariana e glicemia, em pacientes com DM1 seja fraca. Dados recentes do estudo DCCT/EDIC mostram que o grupo que recebeu tratamento insulínico intensificado durante o DCCT desenvolveu graus menores de aterosclerose, relacionado aos valores reduzidos de HbA1c durante a fase ativa do estudo, com melhor proteção nos pacientes mais jovens e com menor duração da doença. Há também evidências de que os benefícios são maiores nos pacientes sem nefropatia quando comparados aos com doença renal. Outros fatores de risco importante para o desenvolvimento de DAC em pacientes com DM1 são os mesmos descritos para DM2, incluindo os componentes da síndrome metabólica e marcadores de resistência insulínica. Sugere-se que pacientes com DM1 devam ter o melhor controle glicêmico possível, desde o início da sua doença acrescido de vigilância e tratamento rígido dos fatores de riscos clássicos para DAC, principalmente naqueles com história familiar de DM2.

The association between type 1 diabetes and coronary heart disease has become very clear since the late 1970. It has been demonstrated that there is an important increased risk in morbidity and mortality caused by coronary artery disease in young adults with type 1 diabetes compared with the non diabetic population. The underlying pathogeneses is still poorly understood. While the role of glycemic control in the development of microvascular disease complication is well established its role in CVD in patients with DM1 remains unclear with epidemiologic studies reporting conflicting data. Recent findings from the DCCT/EDIC showed that prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced level of HbA1c during the DCCT. The improvement of glycemic control itself appeared to be particularly effective in younger patients with shorter duration of the disease. Other analyses suggested the glycemia may have a stronger effect on CAD in patients without than in those with albuminúria. Other major determinants of coronary artery disease are the components of metabolic syndrome and the surrogate measure of insulin resistence: eGDR. It is proposed that patients with DM1 should have aggressive medical therapy, risk factor modification and careful monitoring not only of his blood sugar but also of the other processes involved in the atherosclerotic process, mostly the ones with family history of type 2 diabetes.