RESUMO
The optimal timing between meal ingestion and simple physical activity for improving blood glucose control is unknown. This study compared the effects of physical activity on postprandial interstitial glucose responses when the activity was conducted either immediately before, immediately after, or 30 min after breakfast. Forty-eight adults were randomized to three separate physical activity interventions: standing still (for 30 min), walking (for 30 min), and bodyweight exercises (3 sets of 10 squats, 10 push-ups, 10 lunges, 10 sit-ups). In each intervention, 16 participants completed four trials (A to D) during which a 500 kcal mixed nutrient liquid breakfast meal was consumed. Interstitial glucose responses were recorded using continuous glucose monitoring for 2 h after the meal. The activity was completed either after the glucose monitoring period (trial A; control) or immediately before (trial B), immediately after (trial C), or 30 min after (trial D) the breakfast. Mean, coefficient of variance (CV), and area under the curve (AUC) for glucose were calculated and compared between the four trials. Walking and bodyweight exercises immediately after the meal improved mean, CV, and AUC glucose (P ≤ 0.05 vs. control), while standing immediately after the meal only improved AUC glucose (P ≤ 0.05 vs. control) and nearly improved mean glucose (P = 0.06). Mean, CV, and AUC glucose were not affected by standing, walking, or bodyweight exercise conducted immediately before, or 30 min after the meal (all P > 0.05 vs. control). Energy intake (diet records) and energy expenditure (Actigraph) were consistent throughout the studies and did not influence the findings. Low- to moderate-intensity activity should be implemented soon after eating to improve glucose control following breakfast. The type of activity appears less important than the timing. These findings will help optimize exercise-meal timing in general health guidelines. ClinicalTrials.gov Identifier: NCT03730727.
Assuntos
Desjejum/fisiologia , Hiperglicemia/prevenção & controle , Condicionamento Físico Humano/métodos , Adulto , Glicemia/metabolismo , Metabolismo Energético , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Posição Ortostática , CaminhadaRESUMO
Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index (DI(OGTT)) that is a measure of pancreatic ß-cell insulin secretory compensation for changing insulin sensitivity. We conducted an observational study of n = 187 subjects, representing the entire glucose tolerance continuum from normal glucose tolerance to type 2 diabetes. OGTT-derived insulin sensitivity (S(I OGTT)) was calculated using a novel multiple-regression model derived from insulin sensitivity measured by hyperinsulinemic euglycemic clamp as the independent variable. We also validated the novel S(I OGTT) in n = 40 subjects from an independent data set. Plasma C-peptide responses during OGTT were used to determine oral glucose-stimulated insulin secretion (GSIS(OGTT)), and DI(OGTT) was calculated as the product of S(I OGTT) and GSIS(OGTT). Our novel S(I OGTT) showed high agreement with clamp-derived insulin sensitivity (typical error = +3.6%; r = 0.69, P < 0.0001) and that insulin sensitivity was lowest in subjects with impaired glucose tolerance and type 2 diabetes. GSIS(OGTT) demonstrated a significant inverse relationship with S(I OGTT). GSIS(OGTT) was lowest in normal glucose-tolerant subjects and greatest in those with impaired glucose tolerance. DI(OGTT) was sequentially lower with advancing glucose intolerance. We hereby derive and validate a novel OGTT-derived measurement of insulin sensitivity across the entire glucose tolerance continuum and demonstrate that ß-cell compensation for changing insulin sensitivity can be readily calculated from clinical variables collected during OGTT.
Assuntos
Alostase , Diabetes Mellitus Tipo 2/diagnóstico , Intolerância à Glucose/diagnóstico , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Estado Pré-Diabético/diagnóstico , Glicemia/análise , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Técnica Clamp de Glucose , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Ohio , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/fisiopatologiaRESUMO
We demonstrated use of ChatGPT4 for efficient group formation in undergraduate medical education. ChatGPT4 created balanced groups considering students' backgrounds in microbiology, physiology, genetics, and immunology considerably faster than manual efforts. Manual refinements included gender balance and discipline distribution. Improvements included ChatGTP's ability to further incorporate GPA and MCAT scores.
RESUMO
Although long-distance running, such as ultramarathons and multistage races, is increasingly popular, it maybe potentially harmful to health, despite sparse evidence. We studied 8 experienced recreational runners participating in a multiple-marathon running event in which 7 marathons were completed on consecutive days. Fasting blood chemistry and body composition were assessed before and 20-24 hours after the race. The total finish time for the 7 marathons ranged between 23:25:42 and 34:25:21 (hours:minutes:seconds). Only minor increases in circulating skeletal muscle cell damage markers, liver cell damage markers, and inflammatory markers occurred after the race. No other significant adverse biochemical effects were observed. The homeostasis model assessment of insulin resistance decreased markedly, and an improved lipid profile was found. A decrease in fat mass and increase in lean body mass was observed, resulting in no overall weight changes. In summary, the race did not cause any major adverse effects, whereas some traditional markers of cardiovascular disease improved acutely after the race.
Assuntos
Biomarcadores/sangue , Composição Corporal , Corrida/fisiologia , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Fatores de Coagulação Sanguínea/metabolismo , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Colesterol/sangue , Jejum , Feminino , Hematócrito , Hemoglobinas/metabolismo , Homeostase , Humanos , Insulina/sangue , L-Lactato Desidrogenase/sangue , Lipase/sangue , Masculino , Pessoa de Meia-Idade , Mioglobina/sangue , Orosomucoide/metabolismo , Albumina Sérica/metabolismo , Fatores de Tempo , gama-Glutamiltransferase/sangueRESUMO
Abdominal obesity associates with cardiometabolic disease and an accumulation of lipids in the visceral adipose depot, whereas lipid accumulation in the subcutaneous depot is more benign. We aimed to further investigate whether the adipogenic properties where cell-intrinsic, or dependent on a depot-specific or obesity-produced microenvironment. We obtained visceral and subcutaneous biopsies from non-obese women (n = 14) or women living with morbid obesity (n = 14) and isolated adipose stem and progenitor cells (ASPCs) from the stromal vascular fraction of non-obese (n = 13) and obese (n = 13). Following in vitro differentiation into mature adipocytes, we observed a contrasting pattern with a lower gene expression of adipogenic markers and a higher gene expression of immunogenic markers in the visceral compared to the subcutaneous adipocytes. We identified the immunogenic factor BST2 as a marker for visceral ASPCs. The effect of obesity and insulin resistance on adipogenic and immunogenic markers in the in vitro differentiated cells was minor. In contrast, differentiation with exogenous Tumor necrosis factor resulted in increased immunogenic signatures, including increased expression of BST2, and decreased adipogenic signatures in cells from both depots. Our data, from 26 women, underscore the intrinsic differences between human visceral and subcutaneous adipose stem and progenitor cells, suggest that dysregulation of adipocytes in obesity mainly occurs at a post-progenitor stage, and highlight an inflammatory microenvironment as a major constraint of human adipogenesis.
RESUMO
Muscle specific miRNAs, myomiRs, have been shown to control muscle development in vitro and are differentially expressed at rest in diabetic skeletal muscle. Therefore, we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemiceuglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. The subjects increased their endurance capacity, VO2max (l min−1) by 17.4% (P < 0.001), and improved insulin sensitivity by 19% (P < 0.01). While myomiR expression remained stable during a hyperinsulinaemiceuglycaemic clamp, an acute bout of exercise increased mir-1 (P < 0.05) and mir-133a (P < 0.05) expression before, but not after, training. In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05). Interestingly, all myomiRs reverted to their pre-training expression levels 14 days after ceasing the training programme. Components of major pathways involved in endurance adaptation such as MAPK and TGF-ß were predicted to be targeted by the myomiRs examined. Tested predicted target proteins included Cdc42 and ERK 1/2. Although these proteins were downregulated between post-training period and 2 weeks of cessation, an inverse correlation between myomiR and target proteins was not found. In conclusion, our data suggest myomiRs respond to physiological stimuli, but their role in regulating human skeletal muscle adaptation remains unknown.
Assuntos
Exercício Físico/fisiologia , MicroRNAs/fisiologia , Músculo Esquelético/fisiologia , Resistência Física/fisiologia , Adulto , Análise de Variância , Western Blotting , Composição Corporal/fisiologia , Técnica Clamp de Glucose , Humanos , Masculino , Consumo de Oxigênio/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The temporal changes in skeletal muscle mitochondrial content and lipid metabolism that precede type 2 diabetes are largely unknown. Here we examined skeletal muscle mitochondrial fatty acid oxidation (MitoFAOX) and markers of mitochondrial gene expression and protein content in sedentary 20- and 40-wk-old hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF-SED) rats. Changes in OLETF-SED rats were compared with two groups of rats who maintained insulin sensitivity: age-matched OLETF rats given access to voluntary running wheels (OLETF-EX) and sedentary, nonobese Long-Evans Tokushima Otsuka (LETO-SED) rats. As expected, glucose tolerance tests revealed insulin resistance at 20 wk that progressed to type 2 diabetes at 40 wk in the OLETF-SED, whereas both the OLETF-EX and LETO-SED maintained whole body insulin sensitivity. At 40 wk, complete MitoFAOX (to CO(2)), beta-hydroxyacyl-CoA dehydrogenase activity, and citrate synthase activity did not differ between OLETF-SED and LETO-SED but were significantly (P < 0.05) higher in OLETF-EX compared with OLETF-SED rats. Genes controlling skeletal muscle MitoFAOX (PGC-1alpha, PPARdelta, mtTFA, cytochrome c) were not different between OLETF-SED and LETO-SED at any age. Compared with the OLETF-SED, the OLETF-EX rats had significantly (P < 0.05) higher skeletal muscle PGC-1alpha, cytochrome c, and mtTFA mRNA levels at 20 and 40 wk and PPARdelta at 40 wk; however, protein content for each of these markers did not differ between groups at 40 wk. Limited changes in skeletal muscle mitochondria were observed during the transition from insulin resistance to type 2 diabetes in the hyperphagic OLETF rat. However, diabetes prevention through increased physical activity appears to be mediated in part through maintenance of skeletal muscle mitochondrial function.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos/metabolismo , Mitocôndrias Musculares/metabolismo , Atividade Motora/fisiologia , Músculo Esquelético/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Western Blotting , Composição Corporal/fisiologia , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Resistência à Insulina/fisiologia , Mitocôndrias Musculares/enzimologia , Músculo Esquelético/enzimologia , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/química , RNA Mensageiro/genética , Distribuição Aleatória , Ratos , Ratos Endogâmicos OLETF , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
BACKGROUND & AIMS: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model. METHODS: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group). RESULTS: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals. CONCLUSIONS: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.
Assuntos
Fígado Gorduroso/fisiopatologia , Resistência à Insulina/fisiologia , Obesidade/fisiopatologia , Tecido Adiposo/fisiopatologia , Animais , Compostos Azo , Composição Corporal , Modelos Animais de Doenças , Ingestão de Energia , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Masculino , Mitocôndrias Hepáticas/fisiologia , Mitocôndrias Hepáticas/ultraestrutura , Oxirredução , Ácido Palmítico/metabolismo , Ratos , Ratos Long-Evans , Valores de Referência , Superóxido Dismutase/metabolismoRESUMO
Using the hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat, we sought to determine if progression to type 2 diabetes alters visceral white adipose tissue (WAT) mitochondrial content and if these changes are modified through prevention of type 2 diabetes with daily exercise. At 4 weeks of age, OLETF rats began voluntary wheel running (OLETF-EX) while additional OLETF rats (OLETF-SED) and Long-Evans Tokushima Otsuka (LETO-SED) rats served as obese and lean sedentary controls, respectively, for 13, 20 and 40 weeks of age (n = 6-8 for each group at each age). OLETF-SED animals displayed insulin resistance at 13 and 20 weeks and type 2 diabetes by 40 weeks. OLETF-SED animals gained significantly (P < 0.001) more weight and omental fat mass compared with OLETF-EX and LETO-SED. Markers of WAT mitochondrial protein content (cytochrome c, COXIV-subunit I, and citrate synthase activity) significantly increased (P < 0.05) from 13 to 40 weeks in the LETO-SED, but were significantly attenuated in the OLETF-SED rats. Daily exercise normalized WAT cytochrome c and COXIV-subunit I protein content in the OLETF-EX to the healthy LETO-SED animals. In conclusion, increases in omental WAT mitochondrial content between 20 and 40 weeks of age in LETO control animals are attenuated in the hyperphagic, obese OLETF rat. These alterations occurred in conjunction with the progression from insulin resistance to type 2 diabetes and were prevented with daily exercise. Reduced ability to increase WAT mitochondrial content does not appear to be a primary cause of insulin resistance, but may play a key role in the worsening of the disease condition.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Gordura Intra-Abdominal/fisiopatologia , Gordura Intra-Abdominal/ultraestrutura , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Condicionamento Físico Animal/métodos , Adaptação Fisiológica , Animais , Humanos , Esforço Físico , Ratos , Ratos Long-Evans , VoliçãoRESUMO
Physical inactivity is associated with the increased risk of developing chronic metabolic diseases. To understand early alterations caused by physical inactivity, we utilize an animal model in which rats are transitioned from daily voluntary wheel running to a sedentary condition. In the hours and days following this transition, adipose tissue mass rapidly increases, due in part to increased lipogenesis. However, whether a concurrent decrease in fatty acid oxidative capacity (FAO) in skeletal muscle, liver, and adipose tissue occurs during this period is unknown. Following 6 wk of access to voluntary running wheels (average distance of approximately 6 km a night), rats were rapidly transitioned to a sedentary state by locking the wheels for 5 h (WL5) or 173 h (WL173). Complete ([(14)C]palmitate oxidation to (14)CO(2)) and incomplete ([(14)C]palmitate oxidation to (14)C-labeled acid soluble metabolites) was determined in isolated mitochondrial and whole homogenate preparations from skeletal muscle and liver and in isolated adipocytes. Strikingly, the elevated complete FAO in the red gastrocnemius at WL5 fell to that of rats that never ran (SED) by WL173. In contrast, hepatic FAO was elevated at WL173 above both WL5 and SED groups, while in isolated adipocytes, FAO remained higher in both running groups (WL5 and WL173) compared with the SED group. The alterations in muscle and liver fat oxidation were associated with changes in carnitine palmitoyl transferase-1 activity and inhibition, but not significant changes in other mitochondrial enzyme activities. In addition, peroxisome proliferator-activated receptor coactivator-1alpha mRNA levels that were higher in both skeletal muscle and liver at WL5 fell to SED levels at WL173. This study is the first to demonstrate that the transition from high to low daily physical activity causes rapid, tissue-specific changes in FAO.
Assuntos
Tecido Adiposo/metabolismo , Metabolismo Energético , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Ácido Palmítico/metabolismo , Esforço Físico , Adaptação Fisiológica , Tecido Adiposo/enzimologia , Animais , Composição Corporal , Carnitina O-Palmitoiltransferase/metabolismo , Ingestão de Alimentos , Fígado/enzimologia , Masculino , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Musculares/enzimologia , Músculo Esquelético/enzimologia , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The purpose of this study was to delineate potential mechanisms initiating the onset of hepatic steatosis following the cessation of daily physical activity. Four-week-old, hyperphagic/obese Otsuka Long-Evans Tokushima Fatty rats were given access to voluntary running wheels for 16 weeks to prevent the development of hepatic steatosis. The animals were then suddenly transitioned to a sedentary condition as wheels were locked (wheel lock; WL) for 5 h (WL5), 53 h (WL53) or 173 h (WL173). Importantly after the cessation of daily exercise (5-173 h), no changes occurred in body weight, fat pad mass (omental and retroperitoneal), food intake, serum insulin, hepatic triglycerides or in the exercise-suppressed hepatic stearoyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma protein content. However, complete hepatic fatty acid oxidation and mitochondrial enzyme activities were highest at WL5 and WL53 and dropped significantly to SED levels by WL173. In addition, cessation of daily exercise quickly increased the hepatic protein contents of fatty acid synthase and acetyl-coenzyme A carboxylase (ACC), reduced ACC phosphorylation status, and dramatically increased hepatic malonyl-CoA concentration. This study is the first to show that the sudden cessation of daily exercise in a hyperphagic/obese model activates a subgroup of precursors and processes known to initiate hepatic steatosis, including decreased hepatic mitochondrial oxidative capacity, increased hepatic expression of de novo lipogenesis proteins, and increased hepatic malonyl CoA levels; each probably increasing the susceptibility to non-alcoholic fatty liver disease.
Assuntos
Fígado Gorduroso/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Ácidos Graxos/metabolismo , Masculino , Oxirredução , Ratos , Ratos Endogâmicos OLETF , TempoRESUMO
The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a model of hyperphagic obesity in which the animals retain the desire to run voluntarily. Running wheels were provided for 4-wk-old OLETF rats for 16 wk before they were killed 5 h (WL5), 53 h (WL53), or 173 h (WL173) after the wheels were locked. Sedentary (SED) OLETF rats that were not given access to running wheels served as age-matched cohorts. Epididymal fat pad mass, adipocyte volume, and adipocyte number were 58%, 39%, and 47% less, respectively, in WL5 than SED rats. Contrary to cessation of daily running in Fischer 344 x Brown Norway rats, epididymal fat did not increase during the first 173 h of running cessation in the OLETF runners. Serum insulin and glucose levels were 77% and 29% less, respectively, in WL5 than SED rats. Oil red O staining for intramyocellular lipid accumulation was not statistically different among groups. However, lipid peroxidation levels, as determined by total trans-4-hydroxy-2-nonenal (4-HNE) and 4-HNE normalized to oil red O, was higher in epitrochlearis muscles of SED than WL5, WL53, and WL173 rats. mRNA levels of glutathione S-transferase-alpha type 4, an enzyme involved in cellular defense against electrophilic compounds such as 4-HNE, were higher in epitrochlearis muscle of WL53 than WL173 and SED rats. In contrast, 4-HNE levels in omental fat were unaltered. Epitrochlearis muscle palmitate oxidation and relative transcript levels for peroxisome proliferator-activated receptor-delta and peroxisome proliferator-activated receptor-gamma coactivator type 1 were surprisingly not different between runners and SED rats. In summary, voluntary running was associated with lower levels of lipid peroxidation in skeletal muscle without significant changes in intramyocellular lipids or mitochondrial markers in OLETF rats at 20 wk of age. Therefore, even in a genetic animal model of extreme overeating, daily physical activity promotes improved health of skeletal muscle.
Assuntos
Hiperinsulinismo/prevenção & controle , Peroxidação de Lipídeos , Músculo Esquelético/metabolismo , Obesidade/prevenção & controle , Esforço Físico , Tecido Adiposo/patologia , Envelhecimento/metabolismo , Aldeídos/metabolismo , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Insulina/sangue , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/enzimologia , Obesidade/metabolismo , Obesidade/patologia , Oxirredução , PPAR gama/genética , PPAR gama/metabolismo , Ácido Palmítico/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Endogâmicos OLETF , Corrida , Especificidade da Espécie , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Aumento de PesoRESUMO
Physical inactivity and excessive postprandial hyperglycemia are two major independent risk factors for type 2 diabetes and cardiovascular-related mortality. Current health policy guidelines recommend at least 150 min of physical activity per week coupled with reduced daily sedentary behavior by interrupting prolonged sitting with bouts of light activity every 30-min. This evidence-based strategy promotes health and quality of life. Since modern lifestyle enforces physical inactivity through motorized transportation and seated office working environments, this review examines the practical strategies (standing, walking, stair climbing, and strength-based circuit exercises) for reducing sitting time and increasing activity during the workday. Furthermore, since postprandial hyperglycemia poses the greatest relative risk for developing type 2 diabetes and its cardiovascular complications, this review examines a novel hypothesis that interrupting sitting time would be best focused on the postprandial period in order to optimize blood glucose control and maximize cardiometabolic health. In doing so, we aim to identify the science gaps which urgently need filling if we are to optimize healthcare policy in this critical area.
RESUMO
Previously, inducing inactivity for 53 h after 21 days of voluntary running resulted in a 25 and 48% increase in epididymal and omental fat pad weights, respectively, while rats continued to eat more than a group that never had access to a running wheel (J Physiol 565: 911-925, 2005). We wanted to test the hypothesis that inactivity, independent of excessive caloric intake, could induce an increase in fat pad mass. Twenty-one-day-old rats were given access to voluntary running wheels for 42-43 days so that they were running approximately 9 km/day in the last week of running, after which wheels were locked for 5, 53, or 173 h (WL5, WL53, WL173) before the rats were killed. During the 53 and 173 h of inactivity, one group of animals was pair fed (PF) to match sedentary controls, whereas the other continued to eat ad libitum (AL). Epididymal and retroperitoneal fat masses were significantly increased in the WL173-PF vs. the WL5 group, whereas epididymal, perirenal, and retroperitoneal fat masses were all significantly increased in the WL173-AL group compared with the WL5 group. Additionally, hyperplasia, and not hypertrophy, of the epididymal fat mass was responsible for the increase at WL173-AL as demonstrated by a significant increase in cell number vs. WL5, with no change in cell diameter or volume. Thus two important findings have been elucidated: 1) increases in measured abdominal fat masses occur in both AL and PF groups at WL173, and 2) adipocyte expansion via hyperplasia occurred with an ad libitum diet following cessation of voluntary running.
Assuntos
Abdome/fisiopatologia , Tecido Adiposo/fisiopatologia , Adiposidade , Hiperplasia/fisiopatologia , Atividade Motora , Abdome/patologia , Adaptação Fisiológica , Tecido Adiposo/patologia , Animais , Hiperplasia/patologia , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344RESUMO
Dietary restriction (DR) is a robust intervention that extends lifespan and slows the onset of age-related diseases in diverse organisms. While significant progress has been made in attempts to uncover the genetic mechanisms of DR, there are few studies on the effects of DR on the metabolome. In recent years, metabolomic profiling has emerged as a powerful technology to understand the molecular causes and consequences of natural aging and disease-associated phenotypes. Here, we use high-resolution mass spectroscopy and novel computational approaches to examine changes in the metabolome from the head, thorax, abdomen, and whole body at multiple ages in Drosophila fed either a nutrient-rich ad libitum (AL) or nutrient-restricted (DR) diet. Multivariate analysis clearly separates the metabolome by diet in different tissues and different ages. DR significantly altered the metabolome and, in particular, slowed age-related changes in the metabolome. Interestingly, we observed interacting metabolites whose correlation coefficients, but not mean levels, differed significantly between AL and DR. The number and magnitude of positively correlated metabolites was greater under a DR diet. Furthermore, there was a decrease in positive metabolite correlations as flies aged on an AL diet. Conversely, DR enhanced these correlations with age. Metabolic set enrichment analysis identified several known (e.g., amino acid and NAD metabolism) and novel metabolic pathways that may affect how DR effects aging. Our results suggest that network structure of metabolites is altered upon DR and may play an important role in preventing the decline of homeostasis with age.
Assuntos
Abdome , Envelhecimento/fisiologia , Restrição Calórica , Privação de Alimentos/fisiologia , Metaboloma , Animais , Drosophila melanogaster/metabolismo , Feminino , Espectrometria de Massas , Análise MultivariadaRESUMO
OBJECTIVE: Cardiorespiratory fitness (VO2max) is associated with glycemic control, yet the relationship between VO2max and the underlying determinants of glycemic control is less clear. Our aim was to determine whether VO2max is associated with insulin sensitivity, insulin secretion, and the disposition index, a measure of compensatory pancreatic ß-cell insulin secretion relative to insulin sensitivity, in subjects representing the entire range of the glucose tolerance continuum. RESEARCH DESIGN AND METHODS: A cohort of subjects (N = 313) with heterogeneous age, sex, BMI, and glycemic control underwent measurements of body composition, HbA1c, fasting glucose, oral glucose tolerance (OGTT), and VO2max. OGTT-derived insulin sensitivity (SiOGTT), glucose-stimulated insulin secretion (GSISOGTT), and the disposition index (DIOGTT) (the product of SiOGTT and GSISOGTT) were measured, and associations between VO2max and these determinants of glycemic control were examined. RESULTS: A low VO2max was associated with high HbA1c (r = -0.33), high fasting glucose (r = -0.34), high 2-h OGTT glucose (r = -0.33), low SiOGTT (r = 0.73), and high early-phase (r = -0.34) and late-phase (r = -0.36) GSISOGTT. Furthermore, a low VO2max was associated with low early- and late-phase DIOGTT (both r = 0.41). Interestingly, relationships between VO2max and either glycemic control or late-phase GSISOGTT deteriorated across the glucose tolerance continuum. CONCLUSIONS: The association between poor cardiorespiratory fitness and compromised pancreatic ß-cell compensation across the entire glucose tolerance continuum provides additional evidence highlighting the importance of fitness in protection against the onset of a fundamental pathophysiological event that leads to type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Consumo de Oxigênio/fisiologia , Análise de Variância , Glicemia/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/prevenção & controle , Jejum/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/fisiopatologia , Hiperglicemia/prevenção & controle , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: Mechanisms explaining exercise-induced ß-cell health are unknown. OBJECTIVE: This study aimed to define the role of muscle contraction and acute exercise-derived soluble humoral mediators on ß-cell health. DESIGN: In vitro models were used. SETTING: University. PARTICIPANTS: Healthy subjects. INTERVENTION(S): Conditioned media (CM) were collected from human skeletal muscle (HSkM) cells treated with or without electrical pulse stimulation (EPS). Antecubital and femoral venous blood serum were collected before and after an exercise bout. CM and sera with or without IL-6 neutralization were used to incubate insulin-producing INS-1 cells and rat islets for 24 h in the presence or absence of proinflammatory cytokines (IL-1ß+IFN-γ). MAIN OUTCOME MEASURE(S): INS-1 and islet apoptosis and accumulated insulin secretion. RESULTS: IL-1ß+IFN-γ increased INS-1 and islet apoptosis and decreased insulin secretion. EPS-treated HSkM cell CM did not affect these variables. Exercise-conditioned antecubital but not femoral sera prevented IL-1ß+IFN-γ-induced INS-1 and islet apoptosis. Femoral sera reduced insulin secretion under normal and proinflammatory conditions in INS-1 but not islet cells. EPS increased HSkM cell IL-6 secretion and exercise increased circulating IL-6 levels in antecubital and femoral serum. IL-6 neutralization demonstrated that muscle-derived IL-6 prevents INS-1 and islet apoptosis in the absence of IL-1ß+IFN-γ, but augments apoptosis under proinflammatory conditions, and that muscle-derived IL-6 supports islet insulin secretion in the absence of IL-1ß+IFN-γ. CONCLUSIONS: Unidentified circulating humoral mediators released during exercise prevent proinflammatory cytokine-induced ß-cell apoptosis. Muscle-derived mediators released during exercise suppress ß-cell insulin secretion. Furthermore, muscle-derived IL-6 seems to prevent ß-cell apoptosis under normal conditions but contributes to ß-cell apoptosis under proinflammatory conditions.
Assuntos
Apoptose/fisiologia , Exercício Físico/fisiologia , Células Secretoras de Insulina/metabolismo , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Estimulação Elétrica , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Interferon gama/farmacologia , Interleucina-1beta/farmacologia , Masculino , Ratos , Ratos Wistar , Adulto JovemAssuntos
Montagem e Desmontagem da Cromatina , Epigênese Genética , Histonas/metabolismo , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Cadeias Pesadas de Miosina/genética , Processamento de Proteína Pós-Traducional , Acetilação , Actinas/genética , Animais , Regulação da Expressão Gênica , Elevação dos Membros Posteriores , Lisina , Metilação , Modelos Animais , Fenótipo , Isoformas de Proteínas , Precursores de RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transcrição GênicaRESUMO
MiRNAs are potent intracellular posttranscriptional regulators and are also selectively secreted into the circulation in a cell-specific fashion. Global changes in miRNA expression in skeletal muscle in response to endurance exercise training have been reported. Therefore, our aim was to establish the miRNA signature in human plasma in response to acute exercise and chronic endurance training by utilizing a novel methodological approach. RNA was isolated from human plasma collected from young healthy men before and after an acute endurance exercise bout and following 12 weeks of endurance training. Global miRNA (742 miRNAs) measurements were performed as a screening to identify detectable miRNAs in plasma. Using customized qPCR panels we quantified the expression levels of miRNAs detected in the screening procedure (188 miRNAs). We demonstrate a dynamic regulation of circulating miRNA (ci-miRNA) levels following 0 hour (miR-106a, miR-221, miR-30b, miR-151-5p, let-7i, miR-146, miR-652 and miR-151-3p), 1 hour (miR-338-3p, miR-330-3p, miR-223, miR-139-5p and miR-143) and 3 hours (miR-1) after an acute exercise bout (P<0.00032). Where ci-miRNAs were all downregulated immediately after an acute exercise bout (0 hour) the 1 and 3 hour post exercise timepoints were followed by upregulations. In response to chronic training, we identified seven ci-miRNAs with decreased levels in plasma (miR-342-3p, let-7d, miR-766, miR-25, miR-148a, miR-185 and miR-21) and two miRNAs that were present at higher levels after the training period (miR-103 and miR-107) (P<0.00032). In conclusion, acute exercise and chronic endurance training, likely through specific mechanisms unique to each stimulus, robustly modify the miRNA signature of human plasma.
Assuntos
Exercício Físico/fisiologia , MicroRNAs/sangue , Resistência Física/fisiologia , Adulto , Regulação para Baixo , Humanos , Masculino , MicroRNAs/genética , Fatores de Tempo , Regulação para CimaRESUMO
Age dependent decline in skeletal muscle function leads to impaired metabolic flexibility in elderly individuals. Physical activity and testosterone treatment have proven efficient strategies for delaying this condition. However, a common molecular pathway has not been identified. Muscle specific miRNAs (myomiRs) regulate metabolic pathways in skeletal muscle, are regulated by physical activity, and have response elements for testosterone in their promoter region. We therefore hypothesized that myomiRs would be regulated in skeletal muscle during aging. We further investigated any potential gender-dependent regulation of these miRNAs. We found that the myomiRs miR-1, miR-133a, and miR-133b were increased in skeletal muscle of elderly men compared to younger men. In addition, miR-133a/133b expression was markedly higher in women compared to men. Elimination of circulating testosterone in men was associated with lower levels of miR-133a and miR-133b. A positive regulatory effect of testosterone on miR-133a/133b expression was confirmed in castrated male C57BL/6J mice and in a model of primary human myocytes. Yet, an improvement of fitness level in the testosterone depleted men resulted in a down-regulation of miR133a/b. In conclusion, alterations in fitness level and circulating testosterone seem to represent two independent regulatory events where testosterone is a specific regulator of miR-133a/b expression.