Effects of vildagliptin compared with glibenclamide on glucose variability after a submaximal exercise test in patients with type 2 diabetes: study protocol for a randomized controlled trial, DIABEX VILDA

Background: Cardiovascular disease, endothelial dysfunction, and oxidative stress are common complications among patients with type 2 diabetes (T2DM). in addition to the average blood glucose concentration, glycemic variability may be an important factor for the development of chronic diabetes complications. Patients with T2DM are treated with various types of oral glucose-lowering drugs. Exercise is considered to benefit the health of both healthy and unhealthy individuals, which has been confirmed by a number of scientific research studies in which the participants' health improved. Our general aim in this study will be to evaluate glucose variability after submaximal exercise test in patients receiving treatment with either vildagliptin or glibenclamide. the specific aims of this study are to evaluate the oxidative stress, endothelial function, and metabolic and cardiovascular responses to exercise under treatment with vildagliptin or glibenclamide. All these responses are important in patients with T2DM.Methods/Design: This study is a PROBE (Prospective, Randomized, Open-label, Blinded-Endpoint) design clinical trial. the estimated sample needed is 20 patients with T2DM. in addition to the routine treatment (metformin), patients will receive a second drug orally for 12 weeks: the METV group will receive metformin plus vildagliptin (50 mg twice daily), and the METG group will receive metformin plus glibenclamide (5 to 10 mg twice daily.). Before and after intervention, evaluation of glycemic variability, endothelial function, oxidative stress, and metabolic and cardiovascular response will be performed at rest, during and after a submaximal exercise test (30 minutes, with an intensity based at 10% under the heart rate at the second threshold).Discussion: in addition to drug treatment, exercise is recommended for treatment of glycemic control in patients with T2DM, especially for its beneficial effects on blood glucose and HbA1c. Few studies have determined the effects of the association between exercise and oral glucose-lowering drugs. the study will be conducted to assess the metabolic and cardiovascular responses at rest, and during and after submaximal exercise in patients receiving one of two oral glucose-lowering drugs (vildagliptin or glibenclamide).Novartis(R)Hosp Clin Porto Alegre, Exercise Pathophysiol Res Lab, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Div Cardiol, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Div Endocrinol, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Dept Sci & Technol, Inst Sci & Technol, Sao Jose Dos Campos, SP, BrazilUniv Fed Rio Grande do Sul, Fac Med, Dept Internal Med, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Dept Sci & Technol, Inst Sci & Technol, Sao Jose Dos Campos, SP, BrazilWeb of Scienc

Neuropeptides in the posterodorsal medial amygdala modulate central cardiovascular reflex responses in awake male rats

The rat posterodorsal medial amygdala (MePD) links emotionally charged sensory stimuli to social behavior, and is part of the supramedullary control of the cardiovascular system. We studied the effects of microinjections of neuroactive peptides markedly found in the MePD, namely oxytocin (OT, 10 ng and 25 pg; n=6/group), somatostatin (SST, 1 and 0.05 mu M; n=8 and 5, respectively), and angiotensin II (Ang II, 50 pmol and 50 fmol; n=7/group), on basal cardiovascular activity and on baroreflex- and chemoreflex-mediated responses in awake adult male rats. Power spectral and symbolic analyses were applied to pulse interval and systolic arterial pressure series to identify centrally mediated sympathetic/parasympathetic components in the heart rate variability (HRV) and arterial pressure variability (APV). No microinjected substance affected basal parameters. On the other hand, compared with the control data (saline, 0.3 mu L; n=7), OT (10 ng) decreased mean AP (MAP(50)) after baroreflex stimulation and increased both the mean AP response after chemoreflex activation and the high-frequency component of the HRV. OT (25 pg) increased overall HRV but did not affect any parameter of the symbolic analysis. SST (1 mu M) decreased MAP(50), and SST (0.05 mu M) enhanced the sympathovagal cardiac index. Both doses of SST increased HRV and its low-frequency component. Ang II (50 pmol) increased HRV and reduced the two unlike variations pattern of the symbolic analysis (P<0.05 in all cases). These results demonstrate neuropeptidergic actions in the MePD for both the increase in the range of the cardiovascular reflex responses and the involvement of the central sympathetic and parasympathetic systems on HRV and APV.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPERGSUniv Fed Ciencias Saude Porto Alegre, Dept Ciencias Basicas Saude Fisiol, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Programa Posgrad Neurociencias, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, SP, BrazilUniv Fed Ciencias Saude Porto Alegre, Dept Fisioterapia, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, SP, BrazilCNPq: 501041/2012-5FAPERGS: 1016957Web of Scienc

Heart rate variability in normal and pathological sleep

Sleep is a physiological process involving different biological systems, from molecular to organ level; its integrity is essential for maintaining health and homeostasis in human beings. Although in the past sleep has been considered a state of quiet, experimental and clinical evidences suggest a noteworthy activation of different biological systems during sleep. A key role is played by the autonomic nervous system (ANS), whose modulation regulates cardiovascular functions during sleep onset and different sleep stages. Therefore, an interest on the evaluation of autonomic cardiovascular control in health and disease is growing by means of linear and non-linear heart rate variability (HRV) analyses. the application of classical tools for ANS analysis, such as HRV during physiological sleep, showed that the rapid eye movement (REM) stage is characterized by a likely sympathetic predominance associated with a vagal withdrawal, while the opposite trend is observed during non-REM sleep. More recently, the use of non-linear tools, such as entropy-derived indices, have provided new insight on the cardiac autonomic regulation, revealing for instance changes in the cardiovascular complexity during REM sleep, supporting the hypothesis of a reduced capability of the cardiovascular system to deal with stress challenges. Interestingly, different HRV tools have been applied to characterize autonomic cardiac control in different pathological conditions, from neurological sleep disorders to sleep disordered breathing (SDB). in summary, linear and non-linear analysis of HRV are reliable approaches to assess changes of autonomic cardiac modulation during sleep both in health and diseases. the use of these tools could provide important information of clinical and prognostic relevance.European Regional Development Fund-Project FNUSA-ICRCUniv Milan, L Sacco Hosp, Dept Biomed & Clin Sci L Sacco, Div Med & Pathophysiol, I-20157 Milan, ItalyOsped Niguarda Ca Granda, Ctr Epilepsy Surg C Munari, Ctr Sleep Med, Dept Neurosci, Milan, ItalyUniversidade Federal de São Paulo, Inst Sci & Technol, Dept Sci & Technol, São Paulo, BrazilUniv Fdn Cardiol, Inst Cardiol Rio Grande do Sul, Porto Alegre, RS, BrazilFdn S Maugeri, Sleep Med Unit, Veruno, ItalySt Annes Univ Hosp, Int Clin Res Ctr, Brno, Czech RepublicUniversidade Federal de São Paulo, Inst Sci & Technol, Dept Sci & Technol, São Paulo, BrazilEuropean Regional Development Fund-Project FNUSA-ICRC: CZ.1.05/1.1.00/02.0123Web of Scienc

Short-term complexity of cardiac autonomic control during sleep: REM as a potential risk factor for cardiovascular system in aging.

peer reviewedINTRODUCTION: Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects. METHODS: A polysomnographic study was performed in 12 healthy young (21.1+/-0.8 years) and 12 healthy older subjects (64.9+/-1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1-2 (S1-2), Stage 3-4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE(min) measuring the minimum amount of information that cannot be derived from the knowledge of previous values. RESULTS: Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE(min). In the older group, SE(3) and CCE(min) were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE(min). This decrease of entropy measures was more evident during REM sleep. CONCLUSION: Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events

Aerobic and combined exercise sessions reduce glucose variability in type 2 diabetes : crossover randomized trial

Purpose: To evaluate the effects of aerobic (AER) or aerobic plus resistance exercise (COMB) sessions on glucose levels and glucose variability in patients with type 2 diabetes. Additionally, we assessed conventional and non-conventional methods to analyze glucose variability derived from multiple measurements performed with continuous glucose monitoring system (CGMS). Methods: Fourteen patients with type 2 diabetes (5662 years) wore a CGMS during 3 days. Participants randomly performed AER and COMB sessions, both in the morning (24 h after CGMS placement), and at least 7 days apart. Glucose variability was evaluated by glucose standard deviation, glucose variance, mean amplitude of glycemic excursions (MAGE), and glucose coefficient of variation (conventional methods) as well as by spectral and symbolic analysis (non-conventional methods). Results: Baseline fasting glycemia was 139605 mg/dL and HbA1c 7.960.7%. Glucose levels decreased immediately after AER and COMB protocols by ,16%, which was sustained for approximately 3 hours. Comparing the two exercise modalities, responses over a 24-h period after the sessions were similar for glucose levels, glucose variance and glucose coefficient of variation. In the symbolic analysis, increases in 0 V pattern (COMB, 67.067.1 vs. 76.066.3, P = 0.003) and decreases in 1 V pattern (COMB, 29.165.3 vs. 21.565.1, P = 0.004) were observed only after the COMB session. Conclusions: Both AER and COMB exercise modalities reduce glucose levels similarly for a short period of time. Th

Effect of excercise on glucose variability in healthy subjects : randomized crossover trial

The aim of this study was to evaluate the acute effect of aerobic (AER) and eccentric (ECC) exercise on glucose variability, correlating it with circulating markers of inflammation and oxidative stress in healthy subjects. Sixteen healthy subjects (32 ± 12 years old) wore a continuous glucose monitoring system for three days. Participants randomly performed single AER and ECC exercise sessions. Glucose variability was evaluated by glucose variance (VAR), glucose coefficient of variation (CV%) and glucose standard deviation (SD). Blood samples were collected to evaluate inflammatory and oxidative stress markers. When compared with the preexercise period of 0-6 h, all the indices of glucose variability presented comparable reductions 12-18 h after both exercises (ΔAER: VAR= 151.5, ΔCV% = 0.55 and ΔSD = 3.1 and ECC: ΔVAR = 221.2 , ΔCV% = 3.7 and ΔSD = 6.5). Increased interleukin-6 (IL-6) levels after AER (68.5%) and ECC (30.8%) (P<0.001) were observed, with no differences between sessions (P = 0.459). Uric acid levels were increased after exercise sessions (3% in AER and 4% in ECC, P = 0.001). In conclusion, both AER and ECC exercise sessions reduced glucose variability in healthy individuals. Inflammatory cytokines, such as IL-6, and stress oxidative markers might play a role in underlying mechanisms modulating the glucose variability responses to exercise (clinicalTrials.gov NCT02262208)

Efeito da dieta rica em colesterol sobre a oxidação de lipídeos plasmáticos em camundongos knockout para o receptor de LDL

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Chronic treatment with ivabradine does not affect cardiovascular autonomic control in rats.

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ? 16 bpm vs. IVA: 260 ? 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ? 9 bpm vs. IVA: 326 ? 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ? 4.6 vs. IVA: 29.8 ? 6.4; p > 0.05); HF (nu) (VEH: 75.1 ? 3.7 vs. IVA: 69.2 ? 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91? 0.02 vs. IVA: 0.88 ? 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ? 12 bpm vs. IVA: 207 ? 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ? 16 vs. IVA: 120 ? 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ? 4 vs. IVA: 77 ? 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart