Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia.

Type 2 diabetes (T2D) is a complex multifactorial disease that emerges from the combination of genetic and environmental factors, and obesity, lifestyle, and aging are the most relevant risk factors. Hyperglycemia is the main metabolic feature of T2D as a consequence of insulin resistance and ß-cell dysfunction. Among the cellular alterations induced by hyperglycemia, the overproduction of reactive oxygen species (ROS) and consequently oxidative stress, accompanied by a reduced antioxidant response and impaired DNA repair pathways, represent essential mechanisms underlying the pathophysiology of T2D and the development of late complications. Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation are also closely correlated with insulin resistance and ß-cell dysfunction. This review focus on the mechanisms by which oxidative stress, mitochondrial dysfunction, ER stress, and inflammation are involved in the pathophysiology of T2D, highlighting the importance of the antioxidant response and DNA repair mechanisms counteracting the development of the disease. Moreover, we indicate evidence on how nutritional interventions effectively improve diabetes care. Additionally, we address key molecular characteristics and signaling pathways shared between T2D and Alzheimer's disease (AD), which might probably be implicated in the risk of T2D patients to develop AD.

High Fasting Glycemia Predicts Impairment of Cardiac Autonomic Control in Adults With Type 2 Diabetes: A Case-Control Study.

Introduction: Type 2 diabetes (T2D) is characterized by a metabolic disorder that elevates blood glucose concentration. Chronic hyperglycemia has been associated with several complications in patients with T2D, one of which is cardiac autonomic dysfunction that can be assessed from heart rate variability (HRV) and heart rate recovery (HRR) response, both associated with many aspects of health and fitness, including severe cardiovascular outcomes. Objective: To evaluate the effects of T2D on cardiac autonomic modulation by means of HRV and HRR measurements. Materials and Methods: This study has an observational with case-control characteristic and involved ninety-three middle-aged adults stratified into two groups (control group - CG, n = 34; diabetes group - DG, n = 59). After signing the free and informed consent form, the patients were submitted to the evaluation protocols, performed biochemical tests to confirm the diagnosis of T2D, collection of R-R intervals for HRV analysis and cardiopulmonary effort test to quantify HRR. Results: At rest, the DG showed a reduction in global HRV (SDNN= 19.31 ± 11.72 vs CG 43.09 ± 12.74, p < 0.0001), lower parasympathetic modulation (RMSSD= 20.49 ± 14.68 vs 52.41 ± 19.50, PNN50 = 4.76 ± 10.53 vs 31.24 ± 19.24, 2VD%= 19.97 ± 10.30 vs 28.81 ± 9.77, p < 0.0001 for both indices) and higher HRrest when compared to CG. After interruption of physical exercise, a slowed heart rate response was observed in the DG when compared to the CG. Finally, a simple linear regression showed that fasting glycemia was able to predict cardiac autonomic involvement in volunteers with T2D. Conclusion: Patients with T2D presented lower parasympathetic modulation at rest and slowed HRR after physical exercise, which may be associated with higher cardiovascular risks. The findings show the glycemic profile as an important predictor of impaired cardiac autonomic modulation.

Gestational diabetes mellitus and obesity are related to persistent hyperglycemia in the postpartum period / Diabetes mellitus gestacional e obesidade estão relacionados à hiperglicemia persistente no período pós-parto

Abstract Objective To evaluate the obstetric and sociodemographic characteristics of gestational diabetic women who maintained hyperglycemia in the postpartum period (6-12 weeks postpartum). Methods This is a longitudinal cohort study with women who have had gestational diabetes and/or macrosomic children between March 1st, 2016 and March 1st, 2017. Between 6 and 12 weeks after birth, women who had gestational diabetes collected fasting glycemia, glucose tolerance test, and glycated hemoglobin results. The data were collected from medical records and during an interview in the first postpartum consultation. A statistical analysis was performed using frequency, percentage, Chi- Squared test, Fisher exact test, Mann-Whitney test, and multivariate Poisson regression. The significance level adopted for the statistical tests was 5%. Results One hundred and twenty-two women were included. Most of the women were younger than 35 years old (70.5%), white, multiparous, and with no history of gestational diabetes. Thirteen percent of the participants developed persistent hyperglycemia. A univariate analysis showed that maternal age above 35 years, being overweight, having grade 1 obesity and weight gain under 5 kg was related to the persistence of hyperglycemia in the postpartum period. Conclusion Maternal age above 35 years, obesity and overweight, and the diagnosis of gestational diabetes in the first trimester of pregnancy are associated with hyperglycemia during the postpartum period.

Resumo Objetivo Avaliar características sociodemográficas e obstétricas de mulheres com diabetes gestacional que mantêm hiperglicemia no período pós-parto (6-12 semanas pós-parto). Métodos Este é um estudo longitudinal de coorte com mulheres com diagnóstico de diabetes gestacional e/ou macrossomia fetal entre 1° de março de 2016 a 1° de março de 2017. As mulheres coletaram glicemia de jejum, teste de tolerância a glicose e hemoglobina glicada entre 6 a 12 semanas pós-parto. Os dados foram coletados de prontuários médicos e durante entrevista na primeira consulta de revisão pós-parto. Uma análise estatística foi realizada através do cálculo de frequências, porcentagens, teste do qui-quadrado, teste exato de Fisher, teste de Mann-Whitney e regressão multivariada de Poisson. A significância estatística adotada foi de 5%. Resultados Cento e vinte e duas mulheres foram incluídas. A maioria delas tinha menos de 35 anos de idade (70,5%), eram brancas, multíparas, e não tinham história de diabetes gestacional. Treze por cento das participantes desenvolveu hiperglicemia persistente. A análise univariada mostrou que os fatores relacionados com a persistência de hiperglicemia no período pós-natal foram: idade materna acima de 35 anos, sobrepeso, obesidade grau 1 e ganho de peso abaixo de 5 quilos. A análisemultivariada incluiu o diagnóstico no primeiro trimestre como fator de risco para hiperglicemia persistente. Conclusão Mulheres acima de 35 anos, obesidade, sobrepeso e diagnóstico de diabetes gestacional no primeiro trimestre estão relacionados com hiperglicemia persistente no período pós-parto.

Gestational Diabetes Mellitus and Obesity are Related to Persistent Hyperglycemia in the Postpartum Period.

OBJECTIVE: To evaluate the obstetric and sociodemographic characteristics of gestational diabetic women who maintained hyperglycemia in the postpartum period (6-12 weeks postpartum). METHODS: This is a longitudinal cohort study with women who have had gestational diabetes and/or macrosomic children between March 1st, 2016 and March 1st, 2017. Between 6 and 12 weeks after birth, women who had gestational diabetes collected fasting glycemia, glucose tolerance test, and glycated hemoglobin results. The data were collected from medical records and during an interview in the first postpartum consultation. A statistical analysis was performed using frequency, percentage, Chi-Squared test, Fisher exact test, Mann-Whitney test, and multivariate Poisson regression. The significance level adopted for the statistical tests was 5%. RESULTS: One hundred and twenty-two women were included. Most of the women were younger than 35 years old (70.5%), white, multiparous, and with no history of gestational diabetes. Thirteen percent of the participants developed persistent hyperglycemia. A univariate analysis showed that maternal age above 35 years, being overweight, having grade 1 obesity and weight gain under 5 kg was related to the persistence of hyperglycemia in the postpartum period. CONCLUSION: Maternal age above 35 years, obesity and overweight, and the diagnosis of gestational diabetes in the first trimester of pregnancy are associated with hyperglycemia during the postpartum period.

OBJETIVO: Avaliar características sociodemográficas e obstétricas de mulheres com diabetes gestacional que mantêm hiperglicemia no período pós-parto (6­12 semanas pós-parto). MéTODOS: Este é um estudo longitudinal de coorte com mulheres com diagnóstico de diabetes gestacional e/ou macrossomia fetal entre 1° de março de 2016 a 1° de março de 2017. As mulheres coletaram glicemia de jejum, teste de tolerância a glicose e hemoglobina glicada entre 6 a 12 semanas pós-parto. Os dados foram coletados de prontuários médicos e durante entrevista na primeira consulta de revisão pós-parto. Uma análise estatística foi realizada através do cálculo de frequências, porcentagens, teste do qui-quadrado, teste exato de Fisher, teste de Mann-Whitney e regressão multivariada de Poisson. A significância estatística adotada foi de 5%. RESULTADOS: Cento e vinte e duas mulheres foram incluídas. A maioria delas tinha menos de 35 anos de idade (70,5%), eram brancas, multíparas, e não tinham história de diabetes gestacional. Treze por cento das participantes desenvolveu hiperglicemia persistente. A análise univariada mostrou que os fatores relacionados com a persistência de hiperglicemia no período pós-natal foram: idade materna acima de 35 anos, sobrepeso, obesidade grau 1 e ganho de peso abaixo de 5 quilos. A análise multivariada incluiu o diagnóstico no primeiro trimestre como fator de risco para hiperglicemia persistente. CONCLUSãO: Mulheres acima de 35 anos, obesidade, sobrepeso e diagnóstico de diabetes gestacional no primeiro trimestre estão relacionados com hiperglicemia persistente no período pós-parto.

Muscular strength and cardiovascular risk factors in adults: a systematic review.

OBJECTIVE: The purpose of this study was to identify and summarize the relationships between MS and individual components of metabolic syndrome (MetS) [high waist circumference (WC), high blood pressure (BP), high systolic blood pressure (SBP), high diastolic blood pressure (DBP), high triglycerides (TG), fasting blood glucose (GL) and low HDL cholesterol levels (HDL-C)] in adults. METHODS: A systematic review was performed on six electronic databases (Lilacs, Pubmed, Scielo, Scopus, Sportdiscus, and Web of Knowledge), with complimentary searches in reference lists. The databases were investigated without restrictions regarding the period of publication. RESULTS: Of the 6,833 articles initially identified, 17 were included, with data on 43,343 adults. Higher MS values were associated with lower WC values. Different results in relation to the association between MS and BP, MS and SBP, and MS and DBP were verified. In addition, inconclusive results were verified in the relationship between MS and TG, MS and HDL-C, and MS and GL. CONCLUSION: Higher MS values were related with lower WC in adults. More evidence from longitudinal studies with high methodological rigor is needed to elucidate the relationship between MS and CVD among adults.

Diabetes y COVID-19, una relación de ida y vuelta / Diabetes and COVID-19, one relation to go and comeback

Diabetic patients are at risk of developing unfavorably from SARS-COV19 disease, especially when they have poor glycemic control. On the other hand, in the case of diabetic patients with severe COVID, they evolve with severe hyperglycemia, often difficult to manage. Marked hyperglycemia has also been described in people without a known history of previous diabetes, even there have been reported cases of insulin-dependent diabetes debut in days after the disease. The aim of this review is to analyze possible mechanisms involved in the relationship between COVID-19 and DIABETES.

Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation.

Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. Excess glucose is responsible for inducing redox imbalance and both systemic and intrarenal inflammation, playing a critical role in the pathogenesis of diabetic kidney disease, which is currently the leading cause of dialysis in the world. The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. Despite the disparate mechanisms involved in renal damage related to diabetes mellitus, the metabolic mechanisms involving oxidative/inflammatory pathways are widely accepted. The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. The present study presents an update on metabolic pathways that involve redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of diabetic kidney disease.

Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation / Doença Renal do Diabetes: Cross-Linking entre Hiperglicemia, Desequilíbrio Redox e Inflamação

Abstract Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. Excess glucose is responsible for inducing redox imbalance and both systemic and intrarenal inflammation, playing a critical role in the pathogenesis of diabetic kidney disease, which is currently the leading cause of dialysis in the world. The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. Despite the disparate mechanisms involved in renal damage related to diabetes mellitus, the metabolic mechanisms involving oxidative/inflammatory pathways are widely accepted. The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. The present study presents an update on metabolic pathways that involve redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of diabetic kidney disease.

Resumo A hiperglicemia crônica é o ponto-chave das complicações macro e microvasculares associadas ao diabetes mellitus. O excesso de glicose é responsável por induzir desequilíbrio redox e inflamação sistêmica e intra-renal, desempenhando um papel crítico na patogênese da doença renal do diabetes, configurada atualmente como a principal causa de doença renal dialítica em todo o mundo. A patogênese da doença é complexa, multifatorial e, não totalmente elucidada, estando vários fatores e mecanismos associados ao seu desenvolvimento, progressão e desfechos clínicos. Apesar dos mecanismos díspares envolvidos nos danos renais durante o diabetes, os caminhos metabólicos pela via oxidativa/inflamatória são amplamente aceitos e discutidos. As evidências acentuam que o estado hiperglicêmico crônico desencadeia o estresse oxidativo e a inflamação mediada por diversas vias metabólicas alteradas em um ciclo-vicioso de autoperpetuação, promovendo aumento da injúria celular e progressão para a doença renal dialítica. O presente artigo traz, portanto, uma atualização sobre os caminhos metabólicos que envolvem o desequilíbrio redox e a inflamação induzidos pela exposição crônica à hiperglicemia na patogênese da doença renal do diabetes.

Hyperglycemia induces mechanical hyperalgesia and depolarization of the resting membrane potential of primary nociceptive neurons: Role of ATP-sensitive potassium channels.

Cumulating data suggests that ion channel alterations in nociceptive neurons might be involved in the development of diabetic painful neuropathy. In the present study we investigated the involvement of ATP-sensitive potassium (K+ATP) channels in the acute effect of high glucose solution in vitro and in vivo. High glucose concentrations depolarized cultured nociceptive neurons and depolarization was blocked by the K+ATP opener, diazoxide or by insulin. Glucose injection at the rat dorsal root ganglia (L5) resulted in acute mechanical hyperalgesia that was blocked by diazoxide. Mannitol injection indicates that osmolarity changes are not responsible for glucose effect. Therefore, this study suggests that K+ATP channels expressed in peripheral sensory neurons might be involved in the development of diabetic painful neuropathy. Since sulfonylureas, that act by blocking K+ATP are used for diabetes treatment, it is important to evaluate the possible side effects of such drugs at primary sensory neurons.

Improvements cardiometabolic risk factors in Latin American Amerindians (the Mapuche) with concurrent training.

Our aim was to investigate the effects of 12 weeks of CT (ie, high-intensity interval and resistance training) in Mapuche adults from Chile and in their peers of European descent. In total, 96 hyperglycemic adult women (mean age 46 years [95% confidence interval; 38, 53]) were divided in four groups: Mapuche CT (Map-CT, n = 14) or control group (Map-CG, n = 44), and European CT (Eur-CT, n = 14) or control group (Eur-CG, n = 23). The following endpoints were analyzed at baseline and after 12 weeks: anthropometric (body mass, body mass index, waist circumference), body composition (fat mass, muscle mass, lean mass), cardiovascular (systolic [SBP]/diastolic [DBP] blood pressure), metabolic (blood fasting glucose and total cholesterol), and muscle strength (handgrip of dominant/non-dominant arm). There were significant positive changes in body mass, body fat, and muscle mass (P < 0.0001) in both Map-CT and Eur-CT groups, whereas waist circumference was decreased significantly only in the Eur-CT group (P < 0.0001). Both Map-CT and Eur-CT groups showed decreased levels of fasting glucose (P < 0.05) and total cholesterol after the intervention (P < 0.0001). Also, both Map-CT (P < 0.05) and Eur-CT (P = 0.01) groups showed a lowered SBP. Finally, significant increases were observed after training in handgrip strength (dominant arm) in Map-CT and Eur-CT groups (both P < 0.0001). CT led to similar improvements in cardiometabolic risk factors for metabolic syndrome development in Mapuche and European participants, with additional improvements in other anthropometric, body composition, cardiovascular, metabolic, and muscle strength parameters related to the prevention of metabolic syndrome. These results suggest future more complex studies.

Intermediate hyperglycaemia to predict progression to type 2 diabetes (ELSA-Brasil): an occupational cohort study in Brazil.

BACKGROUND: The burden of diabetes is increasing worldwide and diabetes can be prevented with intervention in people with impaired glucose tolerance (IGT). Intermediate hyperglycaemia defined without an oral glucose tolerance test as impaired fasting glucose (IFG) and high HbA1c are also used to characterise risk. We aimed to assess the prognostic properties of five definitions of intermediate hyperglycaemia (also known as prediabetes) on the basis of their ability to predict who will progress to diabetes. METHODS: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is an occupational cohort study of active or retired civil servants, aged 35-74 years, recruited from public universities and research institutes in six state capital cities in Brazil. We excluded participants who provided insufficient information to ascertain diabetes status, those without information on relevant covariates, and those with diabetes. We classified type 2 diabetes on the basis of self-report, medication use, measures of fasting plasma glucose (FPG), 2 h plasma glucose, and HbA1c. We used five laboratory definitions of intermediate hyperglycaemia: IGT (2 h plasma glucose ≥7·8 mmol/L [≥140 mg/dL]); IFG based on American Diabetes Association (ADA) criteria (FPG ≥5·5 mmol/L [≥100 mg/dL]); IFG based on WHO criteria (FPG ≥6·1 mmol/L [≥110 mg/dL]); HbA1c based on ADA criteria (HbA1c ≥39 mmol/mol [5·7%]); and HbA1c based on International Expert Committee criteria, IEC-HbA1c, (HbA1c ≥42 mmol/mol [6·0%]). We estimated risk of each definition using Cox regression and overall predictability (area under the receiver operating characteristic curve [AUC]) using logistic regression. FINDINGS: We recruited 15 105 participants from Aug 18, 2008, to Dec 20, 2010, and followed up for a mean of 3·7 (SD 0·63) years. Diabetes incidence rate was 2·0 per 100 person-years (95% CI 1·8-2·1). Among the 11 199 eligible participants, 6563 (59%) presented with some form of intermediate hyperglycaemia. ADA-IFG (4870/11 199 [43·5%), IEC-HbA1c (1005 [9·0%]), and ADA-HbA1c (2299 [20·5%]) poorly predicted diabetes (3·5-3·6 per 100 person-years). WHO-IFG (1140 [10·2%]) and IGT (2245 [20·0%]) predicted greater conversion (7·5 per 100 person-years and 5·8 per 100 person-years, respectively). All definitions presented either low sensitivity or specificity. Combinations of tests improved prognostic properties, with the combination of IGT or WHO-IFG showing the best, but still insufficient, predictability (sensitivity 67·7%, 95% CI 64·5-70·1; specificity 77·9%, 77·1-78·7). The AUC for the three underlying glycaemic tests was 65·0% (95% CI 63·0-66·9) for HbA1c, 74·6% (72·7-76·4) for FPG, and 77·1% (75·4-78·8) for 2 h plasma glucose, whereas the AUC for a score composed of clinical information was 71·6% (69·8-73·3). When this score was combined with results of an oral glucose tolerance test, the AUC reached 82·4% (80·9-83·9). INTERPRETATION: IFG based on WHO criteria and IGT predict diabetes progression better than do the other three definitions of intermediate hyperglycaemia, but their sensitivity is low. IFG based on ADA criteria has better sensitivity than the others, but classifies almost half of adults as having intermediate hyperglycaemia and poorly predicts diabetes. Combining glycaemic results with clinical information improves prognostic properties of those at risk. FUNDING: The Brazilian Ministry of Health (Science and Technology Department), the Brazilian Ministry of Science, Technology and Innovation (Financiadora de Estudos e Projetos and Conselho Nacional de Desenvolvimento Científico e Tecnológico), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES).

Involvement of Intracellular pH in Vascular Insulin Resistance.

The maintenance of the pH homeostasis is maintained by several mechanisms including the efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia, protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation, and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.

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

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.

Diabetes mellitus tipo 2 y cardiopatía isquémica: fisiopatología, regulación génica y futuras opciones terapéuticas / Type II diabetes and ischemic heart disease: pathophysiology, gen regulation and future therapeutic options

Resumen: En los últimos años, la diabetes mellitus tipo 2 (DM2) ha evolucionado en forma epidémica, experimentando un rápido crecimiento y afectando a millones de individuos a nivel mundial. La cardiopatía isquémica es la principal causa de mortalidad en los pacientes diabéticos, quienes poseen un mayor riesgo cardiovascular respecto a los no diabéticos. La DM2 y la cardiopatía isquémica se caracterizan por ser prevenibles, sin embargo, existen diversos factores de riesgo comunes que contribuyen a su desarrollo. Los mecanismos que explican la ateroesclerosis acelerada y el incremento de riesgo de enfermedades cardiovasculares en los pacientes diabéticos tipo 2 incluyen a la hiperglicemia, dislipidemia y la inflamación del endotelio vascular. La diabetes es resultado de una interacción compleja entre la genética y el medio ambiente. Recientemente se han descrito varios genes implicados en el desarrollo de la diabetes y cardiopatía isquémica y que podrían significar nuevas opciones terapéuticas. En este artículo se revisa la relación entre ambas patologías, los mecanismos moleculares y el descubrimiento de factores de riesgo genéticos comunes y su implicancia en el desarrollo de nuevos blancos terapéuticos.

Abstracts: In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic and affects millions of people worldwide. Ischemic heart disease (IHD) is the main cause of death among diabetic patients, who have a higher cardiovascular risk than non-diabetics. Both, DM2 and IHD are characterized by being preventable, however there are several common risk factors that contribute to their development. The mechanisms that explain accelerated atherosclerosis and increased risk of cardiovascular diseases in patients with type 2 diabetes mellitus include damage by hyperglycemia, dyslipidemia and inflammation on vascular endothelium. Diabetes is the result of a complex interaction between genetics and the environment, recently, several genes have been identified that appear to be involved in diabetes and ischemic heart disease that could explain its relationship and serve as new therapeutic possibilities. In this article, we review the relationship between diabetes and ischemic heart disease, the molecular mechanisms and the discovery of genetic risk factors common to both diseases and their implication in the development of new therapeutic targets.

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.

Quercetin Prevents Diastolic Dysfunction Induced by a High-Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats.

Alterations in cardiac energy metabolism play a key role in the pathogenesis of diabetic cardiomyopathy. Hypercholesterolemia associated with bioenergetic impairment and oxidative stress has not been well characterized in the cardiac function under glycemic control deficiency conditions. This work aimed to determine the cardioprotective effects of quercetin (QUE) against the damage induced by a high-cholesterol (HC) diet in hyperglycemic rats, addressing intracellular antioxidant mechanisms and bioenergetics. Quercetin reduced HC-induced alterations in the lipid profile and glycemia in rats. In addition, QUE attenuated cardiac diastolic dysfunction (increased E:A ratio), prevented cardiac cholesterol accumulation, and reduced the increase in HC-induced myocyte density. Moreover, QUE reduced HC-induced oxidative stress by preventing the decrease in GSH/GSSG ratio, Nrf2 nuclear translocation, HO-1 expression, and antioxidant enzymatic activity. Quercetin also counteracted HC-induced bioenergetic impairment, preventing a reduction in ATP levels and alterations in PGC-1α, UCP2, and PPARγ expression. In conclusion, the mechanisms that support the cardioprotective effect of QUE in rats with HC might be mediated by the upregulation of antioxidant mechanisms and improved bioenergetics on the heart. Targeting bioenergetics with QUE can be used as a pharmacological approach to modulate structural and functional changes of the heart under hypercholesterolemic and hyperglycemic conditions.

Exercise as an Effective Transgenerational Strategy to Overcome Metabolic Syndrome in the Future Generation: Are We There?

Metabolic syndrome (MetS) consist in a combination of cardiovascular risk factors including elevated blood pressure, dyslipidemia, insulin resistance, hyperglycemia and abdominal obesity. Exercise performed before, during and after pregnancy can exert positive effects to counteract MetS risk factors. Here this review aims to analyze the effects of exercise performed before (fathers and mothers) and after periconception (mothers) by using experimental models and its effects on MetS risk factors in offspring. All selected studies investigated the effects of aerobic exercise before, during and after periconception on MetS risk factors in offspring, while no studies utilizing resistance exercise were found. Exercise performed before, and after periconception exerted preventive effects in the offspring, with regards to MetS risk factors. However, more studies focusing on the dose-response of exercise before, and after periconception may reveal interesting results on MetS risk factor in offspring. Thus, the prevention from chronic degenerative diseases can be improved by mother exercise and might be associated with epigenetic mechanisms, such as DNA methylation, hPTMs (histone post translational modifications), non-coding RNAs (ex: MicroRNAs) which results phenotypic modifications by individual genome reprograming. Otherwise, results from paternal exercise are inconclusive at this time.

Cyclosporine A attenuates apoptosis and necrosis after ischemia-reperfusion-induced renal injury in transiently hyperglycemic rats.

PURPOSE:: To investigate the effects of cyclosporine A on renal ischemia-reperfusion injury during transient hyperglycemia in rats. METHODS:: In a model of ischemia-reperfusion-induced renal injury and transiently induced hyperglycemia by intraperitoneal injection of glucose, 2.5 g.kg-1, Wistar rats were anesthetized with either isoflurane or propofol and received intravenous cyclosporine A, 5 mg.kg-1, five minutes before reperfusion. Comparison groups were isoflurane and propofol sham groups and isoflurane and propofol ischemia-reperfusion-induced renal injury. Renal tubular cell viability was quantitatively assessed by flow cytometry after cell culture and classified as early apoptosis, necrotic cells, and intact cells. RESULTS:: Early apoptosis was significantly higher in isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury when compared to both cyclosporine A treated and sham groups. Necrosis percentage was significantly higher in propofol-anesthetized animals subjected to renal ischemia-reperfusion injury. The percentage of intact cells was lower in both, isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury. CONCLUSION:: In a model of ischemia-reperfusion-induced renal injury, cyclosporine A, 5 m.kg-1, administered five minutes before renal reperfusion in rats with acute-induced hyperglycemia under either isoflurano or propofol anesthesia, attenuated early apoptosis and preserved viability in renal tubular cells, regardless of the anesthetic used.

Cyclosporine A attenuates apoptosis and necrosis after ischemia-reperfusion-induced renal injury in transiently hyperglycemic rats

Abstract Purpose: To investigate the effects of cyclosporine A on renal ischemia-reperfusion injury during transient hyperglycemia in rats. Methods: In a model of ischemia-reperfusion-induced renal injury and transiently induced hyperglycemia by intraperitoneal injection of glucose, 2.5 g.kg-1, Wistar rats were anesthetized with either isoflurane or propofol and received intravenous cyclosporine A, 5 mg.kg-1, five minutes before reperfusion. Comparison groups were isoflurane and propofol sham groups and isoflurane and propofol ischemia-reperfusion-induced renal injury. Renal tubular cell viability was quantitatively assessed by flow cytometry after cell culture and classified as early apoptosis, necrotic cells, and intact cells. Results: Early apoptosis was significantly higher in isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury when compared to both cyclosporine A treated and sham groups. Necrosis percentage was significantly higher in propofol-anesthetized animals subjected to renal ischemia-reperfusion injury. The percentage of intact cells was lower in both, isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury. Conclusion: In a model of ischemia-reperfusion-induced renal injury, cyclosporine A, 5 m.kg-1, administered five minutes before renal reperfusion in rats with acute-induced hyperglycemia under either isoflurano or propofol anesthesia, attenuated early apoptosis and preserved viability in renal tubular cells, regardless of the anesthetic used.

Zinc's role in the glycemic control of patients with type 2 diabetes: a systematic review.

Past research has shown the importance of zinc in several metabolic processes, such as the glucidic metabolism. The present systematic review aims to discuss zinc's participation in the glycemic control of type 2 diabetes mellitus (DM2) patients. In order to accomplish that, a systematic search was performed in the Pubmed database using the following indexed and theme-related descriptors: "zinc" AND "type 2 diabetes mellitus", AND MeSH terms related to glycemic control combined with the boolean operator OR. In total, 1078 articles were retrieved from the research, of which 15 articles of original studies conducted with DM2 patients were included, with three being about the effect of mineral supplementation and 12 reporting observational studies. The main findings of these studies consisted of low body contents of zinc and high excretion of zinc in urine. Hyperglycemia was one of the mechanisms that caused these alterations owing to its interference in zinc reabsorption via renal cells. Another evidence was the negative correlation between the glycated hemoglobin percentage (%HbA1c) and the plasma zinc levels. Additionally, it has been observed that zinc supplementation in DM2 patients has improved glycemic control, since the %HbA1c significantly reduced in these individuals. This present review shows the positive effect of adequate zinc levels on glycemic control, whether it is through dietetic ingestion or supplementation, since its role in insulin homeostasis is clear.