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CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.
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The consequences of short-term disuse are well known, but effective countermeasures remain elusive. This study investigated the effects of neuromuscular electrical stimulation (NMES) during 5 days of bed rest on retaining lower limb muscle mass and muscle function in healthy young and old participants. One leg received NMES of the quadriceps muscle (3 × 30min/day) (NMES), and the other served as a control (CON). Isometric quadriceps strength (MVC), rate of force development (RFD), lower limb lean mass, and muscle thickness were assessed pre-and post-intervention. Muscle thickness remained unaltered with NMES in young and increased in old following bed rest, while it decreased in CON legs. In old participants, mid-thigh lean mass (MTLM) was preserved with NMES while decreased in CON legs. In the young, only a tendency to change with bed rest was detected for MTLM. MVC and early-phase RFD decreased in young and old, irrespective of NMES. In contrast, late-phase RFD was retained in young participants with NMES, while it decreased in young CON legs, and in the old, irrespective of NMES. NMES during short-term bed rest preserved muscle thickness but not maximal muscle strength. While young and old adults demonstrated similar adaptive responses in preventing the loss of skeletal muscle thickness, RFD was retained in the young only.
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Repouso em Cama , Força Muscular , Humanos , Repouso em Cama/efeitos adversos , Masculino , Força Muscular/fisiologia , Adulto , Feminino , Idoso , Músculo Quadríceps/fisiologia , Músculo Quadríceps/inervação , Músculo Esquelético/fisiologia , Estimulação Elétrica/métodos , Terapia por Estimulação Elétrica/métodos , Adulto Jovem , Contração Isométrica/fisiologia , Envelhecimento/fisiologia , Pessoa de Meia-IdadeRESUMO
A non-exercise method equation using seismocardiography for estimating VÌO2peak (SCG VÌO2peak) has previously been validated in healthy subjects. However, the performance of the SCG VÌO2peak within a trained population is unknown, and the ability of the model to detect changes over time is not well elucidated. Forty-seven sub-elite football players were tested at the start of pre-season (SPS) and 36 players completed a test after eight weeks at the end of the pre-season (EPS). Testing included an SCG VÌO2peak estimation at rest and a graded cardiopulmonary exercise test (CPET) on a treadmill for determination of VÌO2peak. Agreement between SCG VÌO2peak and CPET VÌO2peak showed a large underestimation at SPS (bias ± 95% CI: -9.9 ± 1.8, 95% Limits of Agreement: 2.2 to -22.0 mL·min-1 kg-1). At EPS no interaction (p = 0.3590) but a main effect of time (p < 0.0001) and methods (p < 0.0001) was observed between SCG and CPET VÌO2peak. No correlation in VÌO2peak changes was observed between SCG and CPET (r = -20.0, p = 0.2484) but a fair agreement in classifying the correct directional change in VÌO2peak with the SCG method was found (Cohen's κ coefficient = 0.28 ± 0.25). Overall, the SCG VÌO2peak method lacks accuracy and despite being able to estimate group changes, it was incapable of detecting individual changes in VÌO2peak following a pre-season period in sub-elite football players. The SCG algorithm needs to be further adjusted and the accuracy and precision improved for the method to be applicable for use within a trained population.
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Teste de Esforço , Consumo de Oxigênio , Futebol , Humanos , Teste de Esforço/métodos , Futebol/fisiologia , Adulto Jovem , Masculino , Consumo de Oxigênio/fisiologia , Adulto , Atletas , AdolescenteRESUMO
High-resolution respirometry (HRR) can assess peripheral blood mononuclear cell (PBMC) bioenergetics, but no standardized medium for PBMC preparation and HRR analysis exist. Here, we study the effect of four different media (MiR05, PBS, RPMI, Plasmax) on the count, size, and HRR (Oxygraph-O2k) of intact PBMCs. Remarkably, the cell count was 21 % higher when PBMCs were resuspended in MiR05 than in PBS or Plasmax, causing O2 flux underestimation during HRR due to inherent adjustments. Moreover, smaller cell size and cell aggregation was observed in MiR05. Based on our findings, we propose that Plasmax, PBS or RPMI is more suitable than MiR05 for HRR of intact PBMCs. We provide oxygen solubility factors for Plasmax and PBS and encourage further optimization of a standardized HRR protocol for intact PBMCs.
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Tamanho Celular , Meios de Cultura , Leucócitos Mononucleares , Leucócitos Mononucleares/metabolismo , Humanos , Meios de Cultura/química , Respiração CelularRESUMO
PURPOSE: In Football, the high-intensity running bouts during matches are considered decisive. Interestingly, recent studies showed that peak fat oxidation rates (PFO) are higher in football players than other athletes. This study aimed to investigate whether PFO increases following a pre-season. Secondarily, and due to COVID-19, we investigated whether PFO is related to the physical performance in a subgroup of semi-professional male football players. METHODS: Before and after 8 weeks of pre-season training, 42 sub-elite male football players (18 semi-professionals and 24 non-professionals) had a dual-energy x-ray absorptiometry scan and performed a graded exercise test on a treadmill for the determination of PFO, the exercise intensity eliciting PFO (Fatmax) and peak oxygen uptake (VÌO2peak). Additionally, the semi-professional players performed a Yo-Yo Intermittent Recovery Test level 2 (YYIR2) before and after pre-season training to determine football-specific running performance. RESULTS: PFO increased by 11 ± 10% (mean ± 95% CI), p = 0.031, and VÌO2peak increased by 5 ± 1%, p < 0.001, whereas Fatmax was unchanged (+12 ± 9%, p = 0.057), following pre-season training. PFO increments were not associated with increments in VÌO2peak (Pearson's r2 = 0.00, p = 0.948) or fat-free mass (FFM) (r2 = 0.00, p = 0.969). Concomitantly, YYIR2 performance increased in the semi-professional players by 39 ± 17%, p < 0.001, which was associated with changes in VÌO2peak (r2 = 0.35, p = 0.034) but not PFO (r2 = 0.13, p = 0.244). CONCLUSIONS: PFO, VÌO2peak, and FFM increased following pre-season training in sub-elite football players. However, in a subgroup of semi-professional players, increments in PFO were not associated with improvements in YYIR2 performance nor with increments in VÌO2peak and FFM.
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Desempenho Atlético , Corrida , Futebol , Humanos , Masculino , Teste de Esforço , Oxigênio , Estações do AnoRESUMO
INTRODUCTION: Liver fat (LF) and visceral adipose tissue (VAT) content decreases with training, however, this has mainly been investigated in sedentary obese or healthy participants. The aim of this study was to investigate the effects of repeated prolonged exercise on LF and VAT content in well-trained older men and to compare baseline LF and VAT content to recreationally active older men. METHOD: A group of five well-trained older men were tested before and after cycling a total distance of 2558 km in 16 consecutive days. VAT content and body composition was measured using DXA before a bicycle ergometer test was performed to determine maximal fat oxidation (MFO), maximal oxygen consumption ( VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ ), and the relative intensity at which MFO occurred (Fatmax). LF content was measured on a separate day using MRI. For comparison of baseline values, a control group of eight healthy age- and BMI-matched recreationally active men were recruited. RESULTS: The well-trained older men had lower VAT (p = 0.02), and a tendency toward lower LF content (p = 0.06) compared with the control group. The intervention resulted in decreased LF content (p = 0.02), but VAT, fat mass, and lean mass remained unchanged. VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ , MFO, and Fatmax were not affected by the intervention. CONCLUSION: The study found that repeated prolonged exercise reduced LF content, but VAT and VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ remained unchanged. Aerobic capacity was aligned with lower LF and VAT in older active men.
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Exercício Físico , Gordura Intra-Abdominal , Masculino , Humanos , Idoso , Obesidade/metabolismo , Fígado/diagnóstico por imagem , Teste de Esforço , Tecido Adiposo/metabolismo , Consumo de OxigênioRESUMO
BACKGROUND: The aim of this study was to investigate the effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in younger and older men. METHODS: "Young" (aged 30 years, n = 7) and "old" (aged 65 years, n = 7) trained men were exposed to an exercise intervention of 15 consecutive days biking 7 to 9 hours/day at 63% and 65% of maximal heart rate (young and old, respectively), going from Copenhagen, Denmark to Palermo, Italy. Adipose tissue was sampled from both the gluteal and abdominal depot before and after the intervention. Mitochondrial respiration was measured by high-resolution respirometry, and adipose inflammation was assessed by immunohistochemical staining of paraffin embedded sections. RESULTS: An increased number of CD163+ macrophages was observed in both the gluteal and abdominal depot (P < .01). In addition, an increased mitochondrial respiration was observed in the abdominal adipose tissue from men in the young group with complex I (CIp) stimulated respiration, complex I + II (CI+IIp) stimulated respiration and the capacity of the electron transport system (ETS) (P < .05), and in the older group an increase in CIp and CI+IIp stimulated respiration (P < .05) was found. CONCLUSION: Overall, we found a positive effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in both young and old trained men, and no sign of attenuated function in adipose tissue with age.
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Tecido Adiposo , Respiração , Masculino , Humanos , Idoso , Terapia por Exercício , Macrófagos , InflamaçãoRESUMO
Thirteen percent of the Danish population are treated with a statin-half of these are in primary prevention, and most are > 65 years old. Statins have known muscular side effects (i.e., myalgia) correlated to reduced muscle performance. This study examines if years of statin treatment in older people introduce subclinical muscle discomfort and loss of muscle mass and strength. In total, 98 participants (71.1 ± 3.6 years (mean ± SD)), who were in primary prevention treatment for elevated plasma cholesterol with a statin, were included in this study. Statin treatment was discontinued for 2 months and then re-introduced for 2 months. Primary outcomes included muscle performance and myalgia. Secondary outcomes included lean mass and plasma cholesterol. Functional muscle capacity measured as a 6-min walk test increased after discontinuation (from 542 ± 88 to 555 ± 91 m, P < 0.05) and remained increased after re-introduction (557 ± 94 m). Similar significant results were found with a chair stand test (15.7 ± 4.3 to 16.3 ± 4.9 repetitions/30 s) and a quadriceps muscle test. Muscle discomfort during rest did not change significantly with discontinuation (visual analog scale from 0.9 ± 1.7 to 0.6 ± 1.4) but increased (P < 0.05) with the re-introduction (to 1.2 ± 2.0) and muscle discomfort during activity decreased (P < 0.05) with discontinuation (from 2.5 ± 2.6 to 1.9 ± 2.3). After 2 weeks of discontinuation, low-density lipoprotein cholesterol increased from 2.2 ± 0.5 to 3.9 ± 0.8 mM and remained elevated until the re-introduction of statins (P < 0.05). Significant and lasting improvements in muscle performance and myalgia were found at the discontinuation and re-introduction of statins. The results indicate a possible statin-related loss of muscle performance in older persons that needs further examination.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Doenças Musculares , Humanos , Idoso , Idoso de 80 Anos ou mais , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Mialgia/induzido quimicamente , Mialgia/complicações , Mialgia/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Doenças Musculares/complicações , Doenças Musculares/tratamento farmacológico , LDL-ColesterolRESUMO
Background: Low cardiorespiratory fitness (ie, peak oxygen consumption [V.O2peak]) is associated with cardiovascular disease and all-cause mortality and is recognized as an important clinical tool in the assessment of patients. Cardiopulmonary exercise test (CPET) is the gold standard procedure for determination of V.O2peak but has methodological challenges as it is time-consuming and requires specialized equipment and trained professionals. Seismofit is a chest-mounted medical device for estimating V.O2peak at rest using seismocardiography. Objective: The purpose of this study was to investigate the validity and reliability of Seismofit V.O2peak estimation in a healthy population. Methods: On 3 separate days, 20 participants (10 women) underwent estimations of V.O2peak with Seismofit (×2) and Polar Fitness Test (PFT) in randomized order and performed a graded CPET on a cycle ergometer with continuous pulmonary gas exchange measurements. Results: Seismofit V.O2peak showed a significant bias of -3.1 ± 2.4 mL·min-1·kg-1 (mean ± 95% confidence interval) and 95% limits of agreement (LoA) of ±10.8 mL·min-1·kg-1 compared to CPET. The mean absolute percentage error (MAPE) was 12.0%. Seismofit V.O2peak had a coefficient of variation of 4.5% ± 1.3% and an intraclass correlation coefficient of 0.95 between test days and a bias of 0.0 ± 0.4 mL·min-1·kg-1 with 95% LoA of ±1.6 mL·min-1·kg-1 in test-retest. In addition, Seismofit showed a 2.4 mL·min-1·kg-1 smaller difference in 95% LoA than PFT compared to CPET. Conclusion: The Seismofit is highly reliable in its estimation of V.O2peak. However, based on the measurement error and MAPE >10%, the Seismofit V.O2peak estimation model needs further improvement to be considered for use in clinical settings.
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BACKGROUND: Adjuvant chemo- and radiotherapy cause cellular damage to tumorous and healthy dividing cells. Chemotherapy has been shown to cause mitochondrial respiratory dysfunction in non-tumorous tissues, but the effects on human peripheral blood mononuclear cells (PBMCs) remain unknown. AIM: We aimed to investigate mitochondrial respiration of PBMCs before and after adjuvant chemo- and radiotherapy in postmenopausal patients with early breast cancer (EBC) and relate these to metabolic parameters of the patients. METHODS: Twenty-three postmenopausal women diagnosed with EBC were examined before and shortly after chemotherapy with (n = 18) or without (n = 5) radiotherapy. Respiration (O2 flux per million PBMCs) was assessed by high-resolution respirometry of intact and permeabilized PBMCs. Clinical metabolic characteristics and mitochondrial DNA (mtDNA) content of PBMCs (mtDN relative to nuclear DNA) were furthermore assessed. RESULTS: Respiration of intact and permeabilized PBMCs from EBC patients significantly increased with adjuvant chemo- and radiotherapy (p = 6 × 10-5 and p = 1 × 10-7 , respectively). The oxygen flux attributed to specific mitochondrial complexes and respiratory states increased by 17-43% compared to before therapy initiation. Similarly, PBMC mtDNA content increased by 40% (p = 0.002). Leukocytes (p = 0.0001), hemoglobin (p = 0.0003), and HDL cholesterol (p = 0.003) concentrations decreased whereas triglyceride (p = 0.01) and LDL (p = 0.02) concentrations increased after treatment suggesting a worsened metabolic state. None of the metabolic parameters or the mtDNA content of PBMCs correlated significantly with PBMC respiration. CONCLUSION: This study shows that mitochondrial respiration and mtDNA content in circulating PBMCs increase after adjuvant chemo- and radiotherapy in postmenopausal patients with EBC. Besides the increased mtDNA content, a shift in PBMC subpopulation proportions towards cells relying on oxidative phosphorylation, who may be less sensitive to chemotherapy, might influence the increased mitochondrial respiration observed iafter chemotherapy.
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Neoplasias da Mama , Leucócitos Mononucleares , Humanos , Feminino , Leucócitos Mononucleares/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , RespiraçãoRESUMO
CONTEXT: Prior to this study, it is known that type 2 diabetes is linked to obesity and a sedentary lifestyle, leading to inadequate ß-cell function and insulin resistance. Limited research has explored the metabolic effects of combining exercise training with antidiabetic medications, particularly focusing on insulin secretion in patients with type 2 diabetes and moderately preserved ß-cell function. OBJECTIVE: The effect of the interaction of semaglutide and physical training on pancreatic ß-cell secretory function is unknown in patients with type 2 diabetes. METHODS: Thirty-one patients with type 2 diabetes underwent 12 weeks of aerobic training alone or concurrent to treatment with semaglutide. Patients randomly allocated to concurrent semaglutide and training were treated with semaglutide for 20 weeks before the training and evaluated at inclusion and again before and after the training intervention. Patients randomized to training were evaluated before and after training. The primary outcome was a change in insulin secretory capacity with training, evaluated by a 2-stepped hyperglycemic (20 and 30 mM) clamp. RESULTS: Training increased the incremental area under the curve for insulin from 21 to 27 nM × 2 hours (ratio 1.28, 95% CI 1.02-1.60) during clamp step 1 and from 40 to 64 nM × 2 hours (ratio 1.61, 95% CI 1.25-2.07) during step 2. Semaglutide treatment increased insulin secretion from 16 to 111 nM × 2 hours (ratio 7.10, 95% CI 3.68-13.71), and from 35 to 447 nM × 2 hours (ratio 12.74, 95% CI 5.65-28.71), correspondingly. Semaglutide and training increased insulin secretion from 130 to 171 nM × 2 hours (ratio 1.31, 95% CI 1.06-1.63), and from 525 to 697 nM × 2 hours (ratio 1.33, 95% CI 1.02-1.72), correspondingly. The median increase in total insulin secretion with the combination was 134 nM × 2 hours greater (95% CI 108-232) than with training. CONCLUSION: The combination of aerobic training and semaglutide treatment synergistically improved ß-cell secretory function. (ClinicalTrials.gov number, ID NCT04383197).
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Insulina/uso terapêuticoRESUMO
BACKGROUND: Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. OBJECTIVES: In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. METHODS: Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. RESULTS: Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). CONCLUSION: Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Sinvastatina , Masculino , Feminino , Humanos , Sinvastatina/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-6/metabolismo , Estudos Transversais , Mitocôndrias/metabolismo , Tecido Adiposo Branco/metabolismo , Colesterol/metabolismo , Tecido Adiposo/metabolismoRESUMO
It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.
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Miosinas , Miosinas de Músculo Esquelético , Masculino , Humanos , Miosinas de Músculo Esquelético/metabolismo , Miosinas/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Trifosfato de Adenosina/metabolismoRESUMO
The ß2-receptor mediates the metabolic response to epinephrine. This study investigates the impact of the ß2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Twenty-five healthy men selected according to ADRB2 genotype being homozygous for either Gly16 (GG) (n = 12) or Arg16 (AA) (n = 13) participated in 4 trial days (D1-4): D1pre and D4post with epinephrine 0.06 µg kg-1 â min-1 infusion and D2hypo1-2 and D3hypo3 with three periods of hypoglycemia by an insulin-glucose clamp. At D1pre, the insulin (mean ± SEM of area under the curve 44 ± 8 vs. 93 ± 13 pmol â L-1 h; P = 0.0051), glycerol (79 ± 12 vs. 115 ± 14 µmol â L-1 h; P = 0.041), and free fatty acid (724 ± 96 vs. 1,113 ± 140 µmol â L-1 h; P = 0.033) responses to epinephrine were decreased in AA participants compared with GG participants but without a difference in glucose response. There were no differences in response to epinephrine between genotype groups after repetitive hypoglycemia at D4post. The metabolic substrate response to epinephrine was decreased in AA participants compared with GG participants but without a difference between genotype groups after repetitive hypoglycemia. ARTICLE HIGHLIGHTS: This study investigates the impact of the ß2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Healthy men homozygous for either Gly16 (n = 12) or Arg16 (n = 13) participated in the study. Healthy people with the Gly16 genotype have increased metabolic response to epinephrine compared with the Arg16 genotype but without a difference between genotypes after repetitive hypoglycemia.
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Hipoglicemia , Polimorfismo Genético , Masculino , Humanos , Genótipo , Epinefrina , Hipoglicemia/genética , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Insulina Regular HumanaRESUMO
Alternate-day fasting induces oscillations in energy stores. We hypothesized that repeated oscillations increases insulin secretion and sensitivity, and improve metabolic health in patients with obesity with or without type 2 diabetes (T2DM). Twenty-three male patients fasted every other day for 30 h for 6 weeks. Experiments included resting energy expenditure, continuous glucose monitoring, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamp, body composition, hepatic triglyceride content, muscle biopsies which were performed at baseline, during 3 weeks without allowed weight loss, and after additional 3 weeks with weight loss. Bodyweight decreased â¼1% and further â¼3% during weeks one to three and four to six, respectively (p < 0.05). Only minor changes in fat mass occurred in weeks 1-3. With weight loss, visceral fat content decreased by 13 ± 3% and 12 ± 2% from baseline in patients with and without T2DM, respectively (p < 0.05). Hepatic triglyceride content decreased by 17 ± 9% and 36 ± 9% (with diabetes) and 27 ± 8% and 40 ± 8% (without diabetes) from baseline to week 3 and week 6, respectively (all p < 0.05). Muscle lipid and glycogen content oscillated with the intervention. Glucose homeostasis, insulin secretion and sensitivity was impaired in patients with T2DM and did not change without weight loss, but improved (p < 0.05) when alternate day fasting was combined with weight loss. In conclusion, alternate-day fasting is feasible in patients with obesity and T2DM, and decreases visceral fat and liver fat deposits. Energy store oscillations by alternate-day fasting do not improve insulin secretion or sensitivity per se. Clinical Trial registration: (ClinicalTrials.gov), (ID NCT02420054).
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CONTEXT: Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. OBJECTIVE: We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. METHODS: In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6â pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. RESULTS: During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8â kg/m2; glycated hemoglobin A1c 51 ± 10â mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid ß-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29â °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. CONCLUSION: Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and ß-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.
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Reabsorção Óssea , Diabetes Mellitus Tipo 1 , Masculino , Humanos , Transcriptoma , Tecido Adiposo Marrom/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Estudos Cross-Over , Proteoma/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Tecido Adiposo Branco , Termogênese , Reabsorção Óssea/metabolismoRESUMO
Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduced coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial function has not been investigated in patients treated with statins. To investigate whether concomitant administration of CoQ10 with statins increases the muscle CoQ10 levels and improves the mitochondrial function, and if changes in muscle CoQ10 levels correlate with changes in the intensity of myalgia. 37 men and women in simvastatin therapy with and without myalgia were randomized to receive 400 mg CoQ10 daily or matched placebo tablets for eight weeks. Muscle CoQ10 levels, mitochondrial respiratory capacity, mitochondrial content (using citrate synthase activity as a biomarker), and production of reactive oxygen species were measured before and after CoQ10 supplementation, and intensity of myalgia was determined using the 10 cm visual analogue scale. Muscle CoQ10 content and mitochondrial function were unaltered by CoQ10 supplementation. Individual changes in muscle CoQ10 levels were not correlated with changes in intensity of myalgia. CoQ10 supplementation had no effect on muscle CoQ10 levels or mitochondrial function and did not affect symptoms of myalgia.
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[This corrects the article DOI: 10.2196/35696.].
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Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis.
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Cirurgia Bariátrica , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Tecido Adiposo/patologia , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/patologia , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , Biogênese de Organelas , RespiraçãoRESUMO
BACKGROUND: Individual differences in the rate of aging and susceptibility to disease are not accounted for by chronological age alone. These individual differences are better explained by biological age, which may be estimated by biomarker prediction models. In the light of the aging demographics of the global population and the increase in lifestyle-related morbidities, it is interesting to invent a new biological age model to be used for health promotion. OBJECTIVE: This study aims to develop a model that estimates biological age based on physiological biomarkers of healthy aging. METHODS: Carefully selected physiological variables from a healthy study population of 100 women and men were used as biomarkers to establish an estimate of biological age. Principal component analysis was applied to the biomarkers and the first principal component was used to define the algorithm estimating biological age. RESULTS: The first principal component accounted for 31% in women and 25% in men of the total variance in the biological age model combining mean arterial pressure, glycated hemoglobin, waist circumference, forced expiratory volume in 1 second, maximal oxygen consumption, adiponectin, high-density lipoprotein, total cholesterol, and soluble urokinase-type plasminogen activator receptor. The correlation between the corrected biological age and chronological age was r=0.86 (P<.001) and r=0.81 (P<.001) for women and men, respectively, and the agreement was high and unbiased. No difference was found between mean chronological age and mean biological age, and the slope of the regression line was near 1 for both sexes. CONCLUSIONS: Estimating biological age from these 9 biomarkers of aging can be used to assess general health compared with the healthy aging trajectory. This may be useful to evaluate health interventions and as an aid to enhance awareness of individual health risks and behavior when deviating from this trajectory. TRIAL REGISTRATION: ClinicalTrials.gov NCT03680768; https://clinicaltrials.gov/ct2/show/NCT03680768. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19209.