Publications by authors named "Elaine Vieira"

42 Publications

Metformin Improves Autonomic Nervous System Imbalance and Metabolic Dysfunction in Monosodium L-Glutamate-Treated Rats.

Front Endocrinol (Lausanne) 2021 4;12:660793. Epub 2021 Jun 4.

Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, Brazil.

Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21-100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.
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http://dx.doi.org/10.3389/fendo.2021.660793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212417PMC
June 2021

High plasma renin activity associates with obesity-related diabetes and arterial hypertension, and predicts persistent hypertension after bariatric surgery.

Cardiovasc Diabetol 2021 06 9;20(1):118. Epub 2021 Jun 9.

Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142, Milan, Italy.

Background: Information about the renin-angiotensin-aldosterone system (RAAS) in obese individuals before and after bariatric surgery is scarce. Aim of this study was to analyze the RAAS in severely obese subjects, in relation to anthropometric and metabolic variables, with special reference to glucose tolerance.

Methods: 239 subjects were evaluated at baseline, and 181 one year after bariatric surgery [laparoscopic gastric banding (LAGB)].

Results: At baseline, renin (plasma renin activity, PRA) was increased from normal to glucose tolerance and more in diabetes, also correlating with ferritin. After LAGB, the decrease of PRA and aldosterone was significant in hypertensive, but not in normotensive subjects, and correlatied with decrease of ferritin. PRA and glucose levels were predictive of persistent hypertension 1 year after LAGB.

Conclusions: These data support the role of RAAS in the pathophysiology of glucose homeostasis, and in the regulation of blood pressure in obesity. Ferritin, as a proxy of subclinical inflammation, could be another factor contributing to the cross-talk between RAAS and glucose metabolism.
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http://dx.doi.org/10.1186/s12933-021-01310-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191118PMC
June 2021

Prevalence of sexual dysfunction in women with pulmonary hypertension and associated factors.

Heart Lung 2021 Jun 6;50(5):714-719. Epub 2021 Jun 6.

Paulista Nursing School, Federal University of São Paulo. Electronic address:

Background: Pulmonary hypertension is a progressive, and disabling disease, however, there is little knowledge about impaired sexual function in this population.

Aim: To identify the prevalence of sexual dysfunction and the association between sexual dysfunction level and sociodemographic and clinical characteristics.

Methods: A cross-sectional study with 71 women diagnosed with pulmonary hypertension without signs of clinical decompensation was carried out. Sexual function was assessed using the Female Sexual Function Index (FSFI) and functional capacity was assessed by 6-minute walk test. The relationships between sociodemographic and clinical characteristics with sexual function was performed using statistical tests. A p-value <0.05 was considered as significant.

Results: 71.8% of patients self-reported sexual dysfunction as indicated as a score of <26.55 points on FSFI. Women with sexual dysfunction were older, higher average age of their last menstruation, had worse functional class, shorter distance covered and worse Borg score at the end of the 6-minute walk test.

Conclusion: There is evident impairment of sexual function self-reported by women with pH and the association of this condition with a decline in functional capacity was identified.
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http://dx.doi.org/10.1016/j.hrtlng.2021.04.018DOI Listing
June 2021

The influence of time of day on the performance of adolescent swimmers.

Chronobiol Int 2021 Aug 11;38(8):1177-1185. Epub 2021 Apr 11.

Postgraduate Program on Physical Education, Universidade Católica de Brasília, Taguatinga, Brazil.

The study aimed to investigate the effects of time-of-day, chronotype, and sex differences on the relationships between anxiety, depression, sleep quality, and swimming performance of normally diurnally active adolescent athletes. Thirty-three competitive swimmers, 20 boys (14.8 ± 1.60 y) and 13 girls (14.4 ± 1.51 y) from two different swimming centers participate in the study. They performed 50 m and 400 m front crawl trials twice, at 08:00 h and 18:00 h, with an interval of 48 h in a 50 m swimming pool. Chronotype, depression, anxiety levels, and sleep quality were accessed by questionnaires. No effect of time-of-day was observed in girls for the 50 and 400 m trials. The swimming performance of boys was similar in the 50 m trials independent of time-of-day, but in the 400 m trial the performance time was better in the evening compared to morning. The best evening performance was observed among N-types. Linear regression analysis of the data of all participants revealed a positive correlation between sleep quality and anxiety level ( = .016; R = 0.1769) and sleep quality and depression level ( = .006; R = 0.2192). There was no correlation between chronotype and sleep quality in either sex ( = .4044; R = 0.0232). We conclude that time-of-day can influence the performance of adolescent swimmers that differs with the distance of the trial and by sex. We also demonstrated the importance of sleep quality among adolescents swimmers as a factor that can influence anxiety and depression and thus consequently affect their performance.
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http://dx.doi.org/10.1080/07420528.2021.1912074DOI Listing
August 2021

Clock Genes, Inflammation and the Immune System-Implications for Diabetes, Obesity and Neurodegenerative Diseases.

Int J Mol Sci 2020 Dec 21;21(24). Epub 2020 Dec 21.

Laboratory of Cardiovascular and Dysmetabolic diseases, IRCCS MultiMedica, 20138 Milan, Italy.

Inflammation is a common feature of several diseases, including obesity, diabetes and neurodegenerative disorders. Circadian clock genes are expressed and oscillate in many cell types such as macrophages, neurons and pancreatic β cells. During inflammation, these endogenous clocks control the temporal gating of cytokine production, the antioxidant response, chemokine attraction and insulin secretion, among other processes. Deletion of clock genes in macrophages or brain-resident cells induces a higher production of inflammatory cytokines and chemokines, and this is often accompanied by an increased oxidative stress. In the context of obesity and diabetes, a high-fat diet disrupts the function of clock genes in macrophages and in pancreatic β cells, contributing to inflammation and systemic insulin resistance. Recently, it has been shown that the administration of natural and synthetic ligands or pharmacological enhancers of the circadian clock function can selectively regulate the production and release of pro-inflammatory cytokines and improve the metabolic function in vitro and in vivo. Thus, a better understanding of the circadian regulation of the immune system could have important implications for the management of metabolic and neurodegenerative diseases.
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http://dx.doi.org/10.3390/ijms21249743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766955PMC
December 2020

Resistance training improves sleep quality, redox balance and inflammatory profile in maintenance hemodialysis patients: a randomized controlled trial.

Sci Rep 2020 07 16;10(1):11708. Epub 2020 Jul 16.

Graduate Program of Physical Education, Catholic University of Brasilia (USB), EPTC, QS07, LT1 s/n. Bloco G Sala 117, Águas Claras, Taguatinga, Brasília, DF, 71966-700, Brazil.

Patients in maintenance hemodialisys (HD) present sleep disorders, increased inflammation, unbalanced redox profiles, and elevated biomarkers representing endothelial dysfunction. Resistance training (RT) has shown to mitigate the loss of muscle mass, strength, improve inflammatory profiles, and endothelial function while decreasing oxidative stress for those in HD. However, the relation between those factors and sleep quality are inadequately described. The aim of this study was to verify the effects of 3 months of RT on sleep quality, redox balance, nitric oxide (NO) bioavailability, inflammation profile, and asymmetric dimethylarginine (ADMA) in patients undergoing HD. Our primary goal was to describe the role of RT on sleep quality. Our secondary goal was to evaluate the effect of RT on NO, metabolism markers, and inflammatory and redox profiles as potential mechanisms to explain RT-induced sleep quality changes. Fifty-five men undergoing maintenance hemodialysis were randomized into either a control (CTL, n = 25) and RT group (RTG; n = 30). Participants in the RT group demonstrated an improvement in sleep pattern, redox, inflammatory profiles, and biomarkers of endothelial function (NO and ADMA). This group also increased muscle strength (total workload in RT exercises of upper and lower limbs). These findings support that RT may improve the clinical status of HD patients by improving their sleep quality, oxidative and inflammatory parameters.
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http://dx.doi.org/10.1038/s41598-020-68602-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367305PMC
July 2020

Time-of-Day Effects on Short-Duration Maximal Exercise Performance.

Sci Rep 2020 06 11;10(1):9485. Epub 2020 Jun 11.

Postgraduate Program on Physical Education, Universidade Católica de Brasília, Brasília, DF, Brazil.

Time-of-day dependent fluctuations in exercise performance have been documented across different sports and seem to affect both endurance and resistance modes of exercise. Most of the studies published to date have shown that the performance in short-duration maximal exercises (i.e. less than 1 min - e.g. sprints, jumps, isometric contractions) exhibits diurnal fluctuations, peaking between 16:00 and 20:00 h. However, the time-of-day effects on short duration exercise performance may be minimized by the following factors: (1) short exposures to moderately warm and humid environments; (2) active warm-up protocols; (3) intermittent fasting conditions; (4) warming-up while listening to music; or (5) prolonged periods of training at a specific time of day. This suggests that short-duration maximal exercise performance throughout the day is controlled not only by body temperature, hormone levels, motivation and mood state but also by a versatile circadian system within skeletal muscle. The time of day at which short-duration maximal exercise is conducted represents an important variable for training prescription. However, the literature available to date lacks a specific review on this subject. Therefore, the present review aims to (1) elucidate time-of-day specific effects on short-duration maximal exercise performance and (2) discuss strategies to promote better performance in short-duration maximal exercises at different times of the day.
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http://dx.doi.org/10.1038/s41598-020-66342-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289891PMC
June 2020

Prognostic value of six-minute walk distance at a South American pulmonary hypertension referral center.

Pulm Circ 2020 Apr-Jun;10(2):2045894019888422. Epub 2020 May 18.

Department of Medicine, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil.

Six-minute walk distance (6MWD) assessment is recommended for pulmonary arterial hypertension multidimensional risk stratification. However, current 6MWD cut-off values were mainly derived from North American and European pulmonary arterial hypertension registries. Therefore, it is unknown if such cut-off values broadly apply to other geographical populations. In this study, we aimed to identify 6MWD cut-off values for Brazilian pulmonary arterial hypertension patients and to contrast our findings to current international Pulmonary Hypertension guidelines recommendations. One-hundred four consecutive pulmonary arterial hypertension patients were allocated in groups according to their 6MWD, considering 50 m as a clinically relevant 6MWD difference. Next, patients were categorized into different 6MWD ranges based on similar survival rates in each group: < 250 m, 250-400 m, and >400 m. The study outcome was all-cause mortality and transplantation according to the 6MWD range. Survival was truncated at five years. Median follow-up period was 4.35 years (0.48-5.00). Survival rates at 1, 2, 3, and 5 years were 96%, 89%, 81%, and 73%, respectively. Cox analyses adjusted for age, sex, and pulmonary arterial hypertension etiology showed that 6MWD < 250 m and >400 m were associated with higher and lower risk of all-cause mortality and transplantation. According to Harrell's c-statistic, the prognostic discrimination of the 6MWD cut-off value identified by the current study was 0.70 while international Pulmonary Hypertension guidelines 6MWD cut-offs value was 0.61. In conclusion, our findings suggest that 6MWD geographical variations should be considered when assessing risk stratification in pulmonary arterial hypertension.
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http://dx.doi.org/10.1177/2045894019888422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235667PMC
May 2020

Modified BODE Index to Predict Mortality in Individuals With COPD: The Role of 4-Min Step Test.

Respir Care 2020 Jul 28;65(7):977-983. Epub 2020 Jan 28.

All authors are affiliated with Pulmonary Function and Exercise Physiology Unit, Division of Respiratory Diseases, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil.

Background: The BODE (body mass index, air-flow obstruction, dyspnea, exercise capacity) index is a composite prognostic marker that predicts mortality in COPD. It includes body mass index, air-flow obstruction, dyspnea score, and exercise capacity by using the 6-min walk distance. However, a 30-m-long corridor is necessary to perform the test and this limits its use in clinical practice. Step tests may elicit distinct physiologic responses compared with the 6-min walk test but are easy to perform in the office setting. We sought to investigate whether a 4-min step test would be a suitable surrogate of the 6-min walk test, in a modified BODE step index (simplified BODE index), to predict mortality in COPD.

Methods: Individuals with COPD performed a self-paced 4-min step test, and the simplified BODE index was calculated by replacing the 6-min walk distance by the number of steps climbed. Cutoff values were determined by receiver operating characteristic curve analysis as follows: score 0 for >60 steps; score 1 for 50-60 steps; score 2 for 40-49 steps; and score 3 for <40 steps.

Results: A total of 186 individuals with COPD were enrolled from 2011 to 2016 (60% males; mean ± SD age, 65 ± 9 y; mean ± SD FEV, 50 ± 17 L). There were 36 deaths among the study cohort. The simplified BODE index was a prognostic marker, independent of cardiovascular comorbidities and oxygen desaturation (HR 1.12, confidence interval (CI) [1.03-1.22]). Individuals with simplified BODE index scores ≥ 7 were at higher risk of death from any cause ( < .001, log-rank test).

Conclusions: This was the first study, to our knowledge, to show that the 4-min step test as a surrogate of exercise capacity in the BODE index (simplified BODE index) is an independent predictor of mortality in COPD and may help to spread its use among practicing physicians.
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http://dx.doi.org/10.4187/respcare.06991DOI Listing
July 2020

Moderate exercise training since adolescence reduces Walker 256 tumour growth in adult rats.

J Physiol 2019 08 18;597(15):3905-3925. Epub 2019 Jun 18.

Laboratory of Microorganisms Genetics and Mutagenesis, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, PR, Brazil.

Key Points: Cancer growth, cell proliferation and cachexia index can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins in adolescence. Walker 256 tumour-bearing rats who started exercise training during adolescence did not revert the basal low glycaemia and insulinaemia observed before tumour cell inoculation. The moderate exercise training improved glucose tolerance and peripheral insulin sensitivity only in rats exercised early in adolescence. The chronic effects of our exercise protocol are be beneficial to prevent cancer cachexia and hold clear potential as a nonpharmacological therapy of insulin sensitization.

Abstract: We tested the hypothesis that moderate exercise training, performed early, starting during adolescence or later in life during adulthood, can inhibit tumour cell growth as a result of changes in biometric and metabolic markers. Male rats that were 30 and 70 days old performed a treadmill running protocol over 8 weeks for 3 days week , 44 min day and at 55-65% . After the end of training, a batch of rats was inoculated with Walker 256 carcinoma cells. At 15 days after carcinoma cell inoculation, the tumour was weighed and certain metabolic parameters were evaluated. The data demonstrated that physical performance was better in rats that started exercise training during adolescence according to the final workload and . Early or later moderate exercise training decreased the cachexia index, cell proliferation and tumour growth; however, the effects were more pronounced in rats that exercised during adolescence. Low glycaemia, insulinaemia and tissue insulin sensitivity was not reverted in Walker 256 tumour-bearing rats who trained during adolescence. Cancer growth can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins during adolescence. In addition, improvement in glucose-insulin homeostasis might be involved in this process.
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http://dx.doi.org/10.1113/JP277645DOI Listing
August 2019

Inspiratory muscle weakness contributes to exertional dyspnea in chronic thromboembolic pulmonary hypertension.

PLoS One 2018 27;13(9):e0204072. Epub 2018 Sep 27.

Pulmonary Circulation Group and Pulmonary Function and Exercise Physiology Unit, Division of Respiratory Diseases, Department of Medicine, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil.

Determination of potentially-reversible factors contributing to exertional dyspnea remains an unmet clinical need in chronic thromboembolic pulmonary hypertension (CTEPH). Therefore, we aimed to evaluate the influence of inspiratory muscle weakness (IMW) on exercise capacity and dyspnea during effort in patients with CTEPH. We performed a prospective cross-sectional study that included thirty-nine consecutive patients with CTEPH (48 ± 15 yrs, 61% female) confirmed by right heart catheterization that underwent an incremental cardiopulmonary exercise test, 6-minute walk test and maximum inspiratory pressure (MIP) measurement. MIP < 70%pred was found in 46% of patients. On a multiple linear regression analysis, MIP was independently associated with 6MWD and [Formula: see text]. Patients with MIP < 70% presented greater [Formula: see text] than those with MIP ≥ 70%. Additionally, they also presented stronger sensations of dyspnea throughout exercise, even when adjusted for ventilation. At rest and at different levels of exercise, mean inspiratory flow (VT/TI) was significantly higher in patients with MIP < 70%. In conclusion, IMW is associated with a rapid increase of dyspnea, higher inspiratory load and poor exercise capacity in patients with CTEPH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204072PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160017PMC
March 2019

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

Front Physiol 2018 8;9:465. Epub 2018 May 8.

Department of Physiology, State University of Maringá, Maringá, Brazil.

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55-65% VO until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.
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http://dx.doi.org/10.3389/fphys.2018.00465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953341PMC
May 2018

Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.

Metabolism 2018 08 8;85:250-258. Epub 2018 May 8.

Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil; Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil.

Objective: The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms.

Results: We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn.

Conclusion: Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.
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http://dx.doi.org/10.1016/j.metabol.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145802PMC
August 2018

Protein malnutrition after weaning disrupts peripheral clock and daily insulin secretion in mice.

J Nutr Biochem 2017 12 4;50:54-65. Epub 2017 Sep 4.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil.

Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock.
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http://dx.doi.org/10.1016/j.jnutbio.2017.08.013DOI Listing
December 2017

Maternal low intensity physical exercise prevents obesity in offspring rats exposed to early overnutrition.

Sci Rep 2017 08 9;7(1):7634. Epub 2017 Aug 9.

Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, 87020-900, PR, Brazil.

Low intensity exercise during pregnancy and lactation may create a protective effect against the development of obesity in offspring exposed to overnutrition in early life. To test these hypotheses, pregnant rats were randomly assigned into 2 groups: Sedentary and Exercised, low intensity, on a rodent treadmill at 30% VO /30-minute/session/3x/week throughout pregnancy and the lactation. Male offspring were raised in small litters (SL, 3 pups/dam) and normal litters (NL, 9 pups/dam) as models of early overnutrition and normal feed, respectively. Exercised mothers showed low mesenteric fat pad stores and fasting glucose and improved glucose-insulin tolerance, VO during lactation and sympathetic activity. Moreover, the breast milk contained elevated levels of insulin. In addition, SL of sedentary mothers presented metabolic dysfunction and glucose and insulin intolerance and were hyperglycemic and hyperinsulinemic in adulthood. SL of exercised mothers showed lower fat tissue accretion and improvements in glucose tolerance, insulin sensitivity, insulinemia and glycemia. The results suggest that maternal exercise during the perinatal period can have a possible reprogramming effect to prevent metabolic dysfunction in adult rat offspring exposed to early overnutrition, which may be associated with the improvement in maternal health caused by exercise.
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http://dx.doi.org/10.1038/s41598-017-07395-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550501PMC
August 2017

Taurine Treatment Modulates Circadian Rhythms in Mice Fed A High Fat Diet.

Sci Rep 2016 11 18;6:36801. Epub 2016 Nov 18.

Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Close ties have been made among certain nutrients, obesity, type 2 diabetes and circadian clocks. Among nutrients, taurine has been documented as being effective against obesity and type 2 diabetes. However, the impact of taurine on circadian clocks has not been elucidated. We investigated whether taurine can modulate or correct disturbances in daily rhythms caused by a high-fat diet in mice. Male C57BL/6 mice were divided in four groups: control (C), control + taurine (C+T), high-fat diet (HFD) and HFD + taurine (HFD+T). They were administered 2% taurine in their drinking water for 10 weeks. Mice were euthanized at 6:00, 12:00, 18:00, and 24:00. HFD mice increased body weight, visceral fat and food intake, as well as higher levels of glucose, insulin and leptin, throughout the 24 h. Taurine prevented increments in food intake, body weight and visceral fat, improved glucose tolerance and insulin sensitivity and reduced disturbances in the 24 h patterns of plasma insulin and leptin. HFD downregulated the expression of clock genes Rev-erbα, Bmal1, and Per1 in pancreatic islets. Taurine normalized the gene and protein expression of PER1 in beta-cells, which suggests that it could be beneficial for the correction of daily rhythms and the amelioration of obesity and diabetes.
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http://dx.doi.org/10.1038/srep36801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114685PMC
November 2016

Acephate exposure during a perinatal life program to type 2 diabetes.

Toxicology 2016 Nov 17;372:12-21. Epub 2016 Oct 17.

Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá-5790, 87020-900 Maringá, PR, Brazil; UPSP-EGEAL Institut Polytechnique LaSalle de Beauvais, BP, 30313-60026 Beauvais Cedex, France.

Acephate has been used extensively as an insecticide in agriculture. Its downstream sequelae are associated with hyperglycemia, lipid metabolism dysfunction, DNA damage, and cancer, which are rapidly growing epidemics and which lead to increased morbidity and mortality rates and soaring health-care costs. Developing interventions will require a comprehensive understanding of which excess insecticides during perinatal life can cause insulin resistance and type 2 diabetes. A Wistar rat animal model suggests that acephate exposure during pregnancy and lactation causes alterations in maternal glucose metabolism and programs the offspring to be susceptible to type 2 diabetes at adulthood. Therapeutic approaches based on preventive actions to food contaminated with insecticides during pregnancy and lactation could prevent new cases of type 2 diabetes.
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http://dx.doi.org/10.1016/j.tox.2016.10.010DOI Listing
November 2016

Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood.

Eur J Nutr 2018 Mar 17;57(2):477-486. Epub 2016 Oct 17.

Department of Physiological Sciences (DCiF) - Biological Science Institute II (ICB-II), Room 220, Federal University of Goiás (UFG) - Campus II, Esperança Avenue s/n, CEP 74690-900, Goiânia, GO, Brazil.

Purpose: Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life.

Methods: Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection.

Results: MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in β-cell function (p < 0.05). MG mothers also showed dyslipidemia (p < 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (p < 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in β-cell function (p < 0.05). Besides, MG offspring showed dyslipidemia (p < 0.05) increasing cardiovascular diseases risk.

Conclusions: Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.
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http://dx.doi.org/10.1007/s00394-016-1330-xDOI Listing
March 2018

Cross-fostering reduces obesity induced by early exposure to monosodium glutamate in male rats.

Endocrine 2017 Jan 26;55(1):101-112. Epub 2016 Apr 26.

Department of Biotechnology, Cell Biology and Genetics, State University of Maringá/UEM, Block H67, room 19, Colombo Avenue 5790, Maringá, PR, Brazil.

Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F) (CTLF), MSG-treated second generation (F) (MSGF), which suckled from their CTL and MSG biological dams, respectively, or CTLF-CR, control offspring suckled by MSG dams and MSGF-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases.
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http://dx.doi.org/10.1007/s12020-016-0965-yDOI Listing
January 2017

Early Effect of Bariatric Surgery on the Circadian Rhythms of Adipokines in Morbidly Obese Women.

Metab Syndr Relat Disord 2016 Feb 28;14(1):16-22. Epub 2015 Oct 28.

3 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) , Madrid, Spain .

Background: The circadian pattern of adipokines is blunted in obese subjects, and we tested the hypothesis that bariatric surgery could normalize the 24-hr pattern of adipokines. Therefore, this study was designed to examine the early impact of the newly designed sleeve gastrectomy with transit bipartition (SGTB) surgery on the circadian pattern of leptin, adiponectin, and resistin in morbidly obese subjects.

Methods: The study group included six morbidly obese women [body mass index (BMI) 41.3 ± 1.53 kg/m(2)] who underwent SGTB and four lean women (BMI 18.61 ± 0.92 kg/m(2)). Blood from all subjects was collected before and 3 months after bariatric surgery every 6 hr throughout the 24-hr period. The circadian pattern of leptin, adiponectin, and resistin was measured by enzyme-linked immunosorbent assay or Luminex techniques.

Results: Lean women exhibited rise of plasma leptin levels at nighttime, whereas obese women had an increase in the overall plasma leptin levels throughout the 24-hr period, lacking the physiological rise of nocturnal leptin levels compared to controls. Obese women had a decrease in 24-hr adiponectin levels and similar plasma resistin levels compared to controls. Three months after SGTB, obese women lost 16.0% (P < 0.005) of their initial body weight and had a decrease in overall 24-hr leptin levels. However, there was no recovery of the nocturnal rise in leptin levels 3 months after SGTB. The 24-hr adiponectin levels were still decreased after SGTB surgery compared to controls, while resistin levels were decreased only during night time after SGTB.

Conclusions: These results suggested that SGTB is an efficient innovative procedure to rapidly decrease 24-hr leptin levels. However, after 3 months, SGTB was not enough to recover the physiological nocturnal rise of leptin levels present in lean subjects.
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http://dx.doi.org/10.1089/met.2015.0051DOI Listing
February 2016

Metabolic surgery and intestinal gene expression: Digestive tract and diabetes evolution considerations.

World J Gastroenterol 2015 Jun;21(22):6990-8

Marcos Ricardo da Silva Rodrigues, Marco Aurelio Santo, Giovani Marino Favero, Elaine Cristina Vieira, Roberto Ferreira Artoni, Viviane Nogaroto, Egberto Gaspar de Moura, Patricia Lisboa, Fabio Quirillo Milleo, Laboratório Multidisciplinar da Universidade Estadual de Ponta Grossa-Campus Uvaranas, Avenida General Carlos Cavalcanti, CEP 84030-900 Ponta Grossa, Paraná, Brazil.

Aim: To investigate the effects of bariatric surgery on metabolic parameters, incretin hormone secretion, and duodenal and ileal mucosal gene expression.

Methods: Nine patients with type 2 diabetes mellitus (T2DM), chronic serum hyperglycemia for more than 2 years, and a body mass index (BMI) of 30-35 kg/m(2) underwent metabolic surgery sleeve gastrectomy with transit bipartition between May 2011 and December 2011. Blood samples were collected pre and 3, 6 and 12 mo postsurgery. Duodenal and ileal mucosa samples were collected pre- and 3 mo postsurgery. Pre- and postoperative blood samples were collected in the fasting state before ingestion of a standard meal (520 kcal) and again 30, 60, 90, and 120 min after the meal to determine hemoglobin A1c (HbA1c) levels and the lipid profile, which consisted of triglyceride and total cholesterol levels. Intestinal gene expression of p53 and transforming growth factor (TGF)-β was analyzed using quantitative reverse-transcription PCR. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were quantified using the enzyme-linked immunoassay method and analyzed pre- and postoperatively. Student's t test or repeated measurements analysis of variance with Bonferroni corrections were performed as appropriate.

Results: BMI values decreased by 15.7% within the initial 3 mo after surgery (31.29 ± 0.73 vs 26.398 ± 0.68, P < 0.05) and then stabilized at 22% at 6 mo postoperative, resulting in similar values 12 mo postoperatively (20-25 kg/m(2)). All of the patients experienced improved T2DM, with 7 patients (78%) achieving complete remission (HbA1c < 6.5%), and 2 patients (22%) achieving improved diabetes (HbA1c < 7.0% with or without the use of oral hypoglycemic agents). At 3 mo postoperatively, fasting plasma glucose had also decreased (59%) (269.55 ± 18.24 mg/dL vs 100.77 ± 3.13 mg/dL, P < 0.05) with no further significant changes at 6 or 12 mo postoperatively. In the first month postoperatively, there was a complete withdrawal of hypoglycemic medications in all patients, who were taking at least 2 hypoglycemic drugs preoperatively. GLP-1 levels significantly increased after surgery (149.96 ± 31.25 vs 220.23 ± 27.55) (P < 0.05), while GIP levels decreased but not significantly. p53 gene expression significantly increased in the duodenal mucosa (P < 0.05, 2.06 fold) whereas the tumor growth factor-β gene expression significantly increased (P < 0.05, 2.52 fold) in the ileal mucosa after surgery.

Conclusion: Metabolic surgery ameliorated diabetes in all of the patients, accompanied by increased anti-proliferative intestinal gene expression in non-excluded segments of the intestine.
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http://dx.doi.org/10.3748/wjg.v21.i22.6990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462741PMC
June 2015

Clock genes, pancreatic function, and diabetes.

Trends Mol Med 2014 Dec 5;20(12):685-93. Epub 2014 Nov 5.

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08033 Barcelona, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández, 03202 Elche, Spain. Electronic address:

Circadian physiology is responsible for the temporal regulation of metabolism to optimize energy homeostasis throughout the day. Disturbances in the light/dark cycle, sleep/wake schedule, or feeding/activity behavior can affect the circadian function of the clocks located in the brain and peripheral tissues. These alterations have been associated with impaired glucose tolerance and type 2 diabetes. Animal models with molecular manipulation of clock genes and genetic studies in humans also support these links. It has been demonstrated that the endocrine pancreas has an intrinsic self-sustained clock, and recent studies have revealed an important role of clock genes in pancreatic β cells, glucose homeostasis, and diabetes.
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http://dx.doi.org/10.1016/j.molmed.2014.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862830PMC
December 2014

Altered clock gene expression in obese visceral adipose tissue is associated with metabolic syndrome.

PLoS One 2014 3;9(11):e111678. Epub 2014 Nov 3.

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; Diabetes and Obesity Research Laboratory, IDIBAPS, Barcelona, Spain; Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain.

Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21-25 kg/m2; n = 21) and morbidly obese women (BMI >40 kg/m2; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111678PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218799PMC
February 2016

REV-ERB ALPHA polymorphism is associated with obesity in the Spanish obese male population.

PLoS One 2014 4;9(8):e104065. Epub 2014 Aug 4.

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; Diabetes and Obesity Research Laboratory, IDIBAPS, Barcelona, Spain.

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m2) and 418 lean (BMI 23.27±1.5 kg/m2). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121274PMC
November 2015

Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle.

J Pineal Res 2014 Sep 22;57(2):155-67. Epub 2014 Jul 22.

Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo (USP), Ribeirão Preto, Brazil; Federal Institute of Science Education and Technology of São Paulo, Sao Paulo, Brazil.

Melatonin has a number of beneficial metabolic actions and reduced levels of melatonin may contribute to type 2 diabetes. The present study investigated the metabolic pathways involved in the effects of melatonin on mitochondrial function and insulin resistance in rat skeletal muscle. The effect of melatonin was tested both in vitro in isolated rats skeletal muscle cells and in vivo using pinealectomized rats (PNX). Insulin resistance was induced in vitro by treating primary rat skeletal muscle cells with palmitic acid for 24 hr. Insulin-stimulated glucose uptake was reduced by palmitic acid followed by decreased phosphorylation of AKT which was prevented my melatonin. Palmitic acid reduced mitochondrial respiration, genes involved in mitochondrial biogenesis and the levels of tricarboxylic acid cycle intermediates whereas melatonin counteracted all these parameters in insulin-resistant cells. Melatonin treatment increases CAMKII and p-CREB but had no effect on p-AMPK. Silencing of CREB protein by siRNA reduced mitochondrial respiration mimicking the effect of palmitic acid and prevented melatonin-induced increase in p-AKT in palmitic acid-treated cells. PNX rats exhibited mild glucose intolerance, decreased energy expenditure and decreased p-AKT, mitochondrial respiration, and p-CREB and PGC-1 alpha levels in skeletal muscle which were restored by melatonin treatment in PNX rats. In summary, we showed that melatonin could prevent mitochondrial dysfunction and insulin resistance via activation of CREB-PGC-1 alpha pathway. Thus, the present work shows that melatonin play an important role in skeletal muscle mitochondrial function which could explain some of the beneficial effects of melatonin in insulin resistance states.
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http://dx.doi.org/10.1111/jpi.12157DOI Listing
September 2014

Protein tyrosine phosphatase-1B modulates pancreatic β-cell mass.

PLoS One 2014 28;9(2):e90344. Epub 2014 Feb 28.

Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain ; Universitat de Barcelona, Barcelona, Spain ; Hospital Clinic de Barcelona, Barcelona, Spain.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signalling pathway. It has been demonstrated that PTP1B deletion protects against the development of obesity and Type 2 Diabetes, mainly through its action on peripheral tissues. However, little attention has been paid to the role of PTP1B in β-cells. Therefore, our aim was to study the role of PTP1B in pancreatic β-cells. Silencing of PTP1B expression in a pancreatic β-cell line (MIN6 cells) reveals the significance of this endoplasmic reticulum bound phosphatase in the regulation of cell proliferation and apoptosis. Furthermore, the ablation of PTP1B is able to regulate key proteins involved in the proliferation and/or apoptosis pathways, such as STAT3, AKT, ERK1/2 and p53 in isolated islets from PTP1B knockout (PTP1B (-)/(-)) mice. Morphometric analysis of pancreatic islets from PTP1B (-)/(-) mice showed a higher β-cell area, concomitantly with higher β-cell proliferation and a lower β-cell apoptosis when compared to islets from their respective wild type (WT) littermates. At a functional level, isolated islets from 8 weeks old PTP1B (-)/(-) mice exhibit enhanced glucose-stimulated insulin secretion. Moreover, PTP1B (-)/(-) mice were able to partially reverse streptozotocin-induced β-cell loss. Together, our data highlight for the first time the involvement of PTP1B in β-cell physiology, reinforcing the potential of this phosphatase as a therapeutical target for the treatment of β-cell failure, a central aspect in the pathogenesis of Type 2 Diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938680PMC
October 2014

Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice.

Diabetes 2014 May 31;63(5):1560-71. Epub 2014 Jan 31.

Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the γ3 subunit (AMPKγ3(R225Q)) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3(R225Q) (γ3(R225Q)) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKγ3(R225Q) prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3(R225Q)) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3(R225Q) mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3(R225Q) mice, but not in ob/ob-γ3(R225Q) mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3(R225Q) mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-γ3(R225Q) mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3(R225Q) are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKγ3(R225Q) mutation.
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http://dx.doi.org/10.2337/db13-0670DOI Listing
May 2014

Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

PLoS One 2013 25;8(7):e69939. Epub 2013 Jul 25.

Instituto de Bioingeniería, Universidad Miguel Hernandez de Elche, Elche, Spain.

Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05) and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold) and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001). High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05). AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01) and glucagon release (p<0.05). These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723646PMC
March 2014

Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual β-cells.

Endocrinology 2013 Oct 18;154(10):3515-24. Epub 2013 Jul 18.

Universidad Miguel Hernández, Avenida de la Universidad s/n, 03202 Elche, Spain.

Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese nondiabetic individuals develop a compensatory β-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of β-cell functional adaptations is incompletely understood. Here, we fed female mice with a high-fat diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin-resistant, and mildly glucose-intolerant while fed, and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased β-cell mass and hypertrophy. Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of β-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca²⁺ signals in intact islets, in isolated β-cells, and individual β-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca²⁺ current densities were similar in both groups. Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD β-cells compared with controls. Although this augment was not significant when capacitance increases of the whole β-cell population were normalized to cell size, the exocytotic output varied significantly when β-cells were distributed by size ranges. All these findings indicate that β-cell functional adaptations are present in the islet compensatory response to obesity.
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http://dx.doi.org/10.1210/en.2013-1424DOI Listing
October 2013

Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice.

PLoS One 2012 28;7(3):e33814. Epub 2012 Mar 28.

Departamento de Anatomia, Biologia Celular, Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, UNICAMP, Campinas, Sao Paulo, Brazil.

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr(308) residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit.In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033814PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314682PMC
August 2012