Diabetes Mellitus, Type 2 Clinical Trial
— EDUGUTIONOfficial title:
Efficacy of a Nutritional Education Strategy and Role of Physical Exercise on the Modulation of Muscle Metabolism Through the Gut Microbiota in Type 2 Diabetics (THE EDUGUTION PROJECT)
We hypothesize that the combination of a nutritional education intervention with a HIIT-based physical exercise program improve muscle metabolism through positive modifications of gut microbiota in people with T2DM, leading to better glycaemia/insulinaemia levels, reduction of body fat mass and improving quality of life. The project is a randomized controlled clinical trial in 120 participants with T2DM and obesity, which aims to determine the efficacy of a nutritional education program and the role of physical exercise type on health related variables. The participants will be of both sexes with age between 40 and 55 years, belonging to the Province of Cádiz. The design has two 12-week interventions; the main factor has 2 levels: participants who receive the nutritional education (EDU) and controls (CG); the second factor has 3 levels: high-intensity interval training (HIIT), moderate intensity continuous training (MICT), and controls (INACT). Therefore, participants will be randomized into 6 groups (n=20), adjusted by gender (≈50% in each group): EDU+HIIT, EDU+MICT, EDU+INACT, CG+HIIT, CG+MICT, CG+INACT. The outcome variables, which will be measured before and after the intervention, will include: dietary intake assessment, physical activity assessment, quality of life, faecal samples, blood samples, blood pressure, appetite assessment, muscle biopsy samples, body composition and fluids, basal metabolism, maximal fat oxidation test and cardiorespiratory fitness.
Status | Recruiting |
Enrollment | 120 |
Est. completion date | August 31, 2024 |
Est. primary completion date | September 1, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 40 Years to 55 Years |
Eligibility | Inclusion Criteria: - Non smoking - Non-alcoholic (<3 standard drinks per day) - Body mass index >25 kg/m maintaining the habitual dietary patterns without a body mass reduction higher than 2% during the last 6 months - Not being insulin dependent - Absence of injury, disease or disability or other known medical condition which could affect the ability to successfully participate in physical exercise tests - Absence of cardiovascular disease (angina, peripheral or cerebro-vascular disease, etc.). - Absence of neurologic and psychiatric diseases. - Absence of respiratory diseases (pulmonary hypertension, Chronic obstructive pulmonary disease, etc.). - Absence of other metabolic diseases (hyper/hypo parathyroidism, hyper/hypothyroidism, Cushing's disease, Type 1 diabetes, etc.) - Absence of active inflammatory bowel disease - Absence of kidney disease - Absence of tumours - Absence of coagulation dysfunction - Not under treatment with medications k known to affect glucose metabolism, recent steroid treatment (within 6 months), or hormone replacement therapy - Be able to understand a communication in Spanish or English. Exclusion Criteria: - They do not attend more than 2 or 4 consecutive sessions of nutritional counselling or physical training respectively. - The lose more than 4 or 6 sessions in total of nutritional counselling or physical training respectively. |
Country | Name | City | State |
---|---|---|---|
Spain | Facultad de Ciencias de la Educación | Puerto Real | Cadiz |
Lead Sponsor | Collaborator |
---|---|
University of Cadiz | Ministerio de Ciencia e Innovación, Spain |
Spain,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Assessed gut microbiota population | For the DNA extraction, fecal samples will be homogenized in a Stomacher-400 mixer. The DNA will be extracted using a mini QIAamp DNA stool kit (QIAGEN, Barcelona, Spain) as indicated by the manufacturer. Quantification is performed with a NanoDrop ND-1000 spectrophotometer (Thermo Fisher Scientific, DE, USA). For sequencing analysis, DNA extracted is amplified by Polymerase Chain Reaction (PCR). All PCRs will be performed in 25 µl of reaction volumes containing 12.5 µl of the KAPA HiFi Hotstart 2X prepared mixture (KAPA Biosystems, Woburn, MA), 5 µl of each direct and reverse primer (1 µM) and 2.5 µl of extracted DNA (10 ng) under standardized cycling conditions. PCR cleaning will be performed with beads and PCR products combined with AMPure XP beads (Beckman Coulter, USA). Determine gut microbiota composition and characterization, for classification of phylum, genus, and species of bacteria. Specifically the Firmicutes/Bacteroidetes ratio. | 12 weeks | |
Primary | Assessed changes in Insulin Resistance | They will be determined using the ELISA technique for the concentration of insulin. The Homeostatic Model Assessment for Insulin Resistance insulin sensitivity index (HOMA-IR) will be calculated. | 12 weeks | |
Primary | Muscle biopsy samples: mRNA expression by quantitative real-time PCR (Transcriptomic) | The mRNA levels of Glucose Transporter GLUT4, IRS1, PI 3-Kinase, PGC1-alpha, SIRT1, Mitofusin 1, Mitofusin 2, Complex I, III, IV, V of mitochondria (Nd1, Cyb, Co1, Atp6), CPT1B, and OPA1 will be analysed, for that, total RNA will be isolated from tissues (frozen muscle biopsies) an Illustra MiniRNA Spin kit (GE Healthcare). Then, cDNA will be obtained using a PrimeScript™ RT Master Mix (Perfect Real Time) (Takara), following the manufacturer's instructions. Relative quantification of mRNA will be performed using a Corbett RotorGene by using 6.5 ng of cDNA, forward and reverse primers at 100 nM each, and a SYBR Green PCR Master Mix Reagent kit (Life Technologies) in 10 µL of reaction. The mRNA levels will be normalized to those of housekeeping genes (b-actin, a-tubulin) and expressed as fold change. | 12 weeks | |
Primary | Muscle biopsy samples: Western blot analysis (Proteomic) | Frozen muscle tissue will be homogenized in protein extraction buffer (RIPA buffer with phosphatase inhibitors and protease inhibitors). Protein concentration will be determined using a BCA protein assay kit (Thermoscientific). Then, samples will be separated on SDS-PAGE gels, and then transferred onto PVDF membranes (Millipore). The following primary antibodies will be used Rabbit polyclonal to PGC1 alpha, Rabbit monoclonal [EPR19274] to DRP1, Rabbit monoclonal [E104] to SIRT1, Rabbit monoclonal [EP2109Y] to AKT1 (phospho S473), Rabbit polyclonal to TIM44, Rabbit polyclonal to Glucose Transporter GLUT4, Rabbit polyclonal to IRS1, Rabbit polyclonal to AKT1, Rabbit monoclonal [EPR5683] to AMPK alpha 2 (phospho T172), Rabbit polyclonal to CPT1B, Total OXPHOS Human WB Antibody Cocktail, Rabbit polyclonal to Mitofusin 1, Rabbit polyclonal to OPA1, Mouse monoclonal [12C4F12] to MTCO2, Rabbit polyclonal to IRS1 (phospho S312), Rabbit polyclonal to AMPK alpha 2, Mouse monoclonal [6A | 12 weeks | |
Primary | Muscle biopsy samples: Citrate synthase (CS) activity assay (Mitochondrial content marker) | Therefore, skeletal muscle (5 mg) will be homogenized in 100 µl cold CelLytic MT (Sigma) at pH 7.4 and protease inhibitor cocktail. The homogenized sample will be centrifuged at 12,000xg for 10 min and the supernatant containing the protein collected. After, 8 µg of protein, as determined by BCA protein assay. In addition to protein, the reaction mixture contained 1X assay buffer, 300 µM acetyl CoA and 100 µM 5,5'-Dithiobis-(2-nitrobenzoic acid). The reaction starts by adding 500 µM Oxaloacetate. CS activity is measured by continuous spectrophotometric rate determination at 412 nm, according to manufacturer instructions. Each sample will be run in triplicate. | 12 weeks | |
Primary | Assessed changes from Appetite assessment | Since appetite feeling modulates nutritional behavior, the evaluation of appetite among the intervention groups can improve the quality of the study from a comprehensive perspective. After a period of 8-10 hours of fasting, an analog visual scale (AVS) will be completed in order to ensure the appetite felt by the participant in the morning. The AVS runs from 1 to 10, being the lowest value no appetite at all, and the maximum full appetite. | 12 weeks | |
Primary | Assessed changes from Body composition: Fatmass and Fat-free mass. | Body composition will be estimated using a multifrequency bioimpedance of 8 electrodes previously validated (TANITAMC780MA). The calculation of impedance can estimate the fat mass and fat-free mass in kilograms. The patients will wear light clothing and will assume a posture in accordance with the manufacturers' instructions. Other previous considerations will be followed 24 hours before the measure: (i) to refrain from vigorous exercise, (ii) to take alcoholic drinks, (iii) to take energy drinks, and (iv) to be in a fasting state for at least 8 hours. Hydration status will be controlled through a urine color scale from clear to dark during the 7 days before assessment for adjusting variables. | 12 weeks | |
Secondary | Assessed changes from dietary intake: Frequency of consumption | Dietary intake assessment by trained surveyors in a personal interview, using a Food Frequency Questionnaire (FFQ). The FFQ has been previously validated in Mediterranean population of Spain, and provides qualitative frequency of consumption over the last year. In addition, a semi-quantitative analysis of total energy, macro and micro nutrients will be performed. The results will be analysed through the DIAL® software for Windows, version 3.7.1.0, estimating the average of total energy in kilocalories, macro and micro nutrients in grams for each participant. | 12 weeks | |
Secondary | Assessed changes from dietary intakes: 24 hours dietary recalls | Dietary intake assessment by trained surveyors in a personal interview, using three 24h dietary recalls (24HR). The results will be analysed through the DIAL® software for Windows, version 3.7.1.0, estimating the average of total energy in kcal, macro and micro nutrients in grams for each participant. | 12 weeks | |
Secondary | Assessed changes from accelerometry: Physical activity time | Physical activity assessment will be carried out through accelerometers (direct method) at the wrist during 7consecutive days. The data generated by the accelerometers will be analysed by using ActiLife 6.6.2 software (ActiGraph, Florida; USA), using Freedson (1998) cut-points for adults and Choi's validation. The software calculates in the base the movements of the accelerometer's time of light, moderate, and vigorous physical activity in minutes. | 12 weeks | |
Secondary | Assessed changes from physical activity | Physical activity assessment will be estimated by the participant's self-reported International Physical Activity Questionnaire Short Version (IPAQ-SF) previously validated in Spain. The IPAQ-SF calculates moderate and vigorous activity time in minutes per week. | 12 weeks | |
Secondary | Assessed changes from resting fat oxidation | Basal Metabolism will be assessed to determine the Resting Fat Oxidation of each participant before and after the 12-week intervention, since its importance as a health indicator and relationship with obesity. Therefore, Oxygen uptake (VO2), carbon dioxide production (VCO2) will be registered at resting conditions on a bed in a supine position during 30 min. Resting indirect calorimetry will be measured using a gas analyser of an open circuit, Jaeger MasterScreen CPX® (CareFusion, San Diego, USA). Heart Rate will be measured continuously over the test with Polar Team 2 (Polar Electro Inc., Lake Success, NY). Resting Fat Oxidation in grams per minute will be calculated by the indirect equation proposed by Frayn. | 12 weeks | |
Secondary | Assessed changes from cardiorespiratory fitness | Maximum VO2 test: To determine the maximal oxygen consumption (VO2max) during exercise in liters per minute, a gradual test on cycloergometer (Lode Excalibur, Netherlands) will be performed. The gas exchange will be measured by Jaeger MasterScreen CPX® (CareFusion, San Diego, USA)The test will be continuing the MFO from the load when the respiratory quotient reaches a stable value of 1 or higher. Once this point is reached, 15 Watts increments will occur every minute until exhaustion is reached, until achieving the VO2max. Throughout the test a cadence of 80 r.p.m. will be maintained. Heart rate will be recorded in beats per minute. | 12 weeks | |
Secondary | Assessed changes from maximal fat oxidation | Maximal fat oxidation test (MFO) to determine the maximal fat oxidation during exercise (MFO), a gradual test on cycloergometer (Lode Excalibur, Netherlands) will be performed. The test will begin with a load of 15 Watts, increasing 15Watts every 3 minutes until the respiratory quotient reaches a stable value of 1 or higher. Throughout the test a cadence of 80 r.p.m. will be maintained. Calculation in the base of expired gases will be made for the estimation of grams per minute of fat oxidation. | 12 weeks | |
Secondary | Assessed changes from self-reported quality of life | Self-reported quality of life will be registered by applying the Short Form 36-health survey (SF-36) questionnaire previously validated in Spain. The SF-36 is a generic measure of quality of life and has been evaluated for a wide variety of medical conditions, including diabetes. The SF-36 includes 36 questions that evaluate 8 subscales, scores for each scale range from 0 to 100, with higher scores indicating higher level of function or wellbeing. The physical component summary is derived from the 4 subscales of physical functioning, role physical, bodily pain, and general health; while the mental component summary is derived from the subscales of vitality, social functioning, role emotional, and mental health. | 12 weeks | |
Secondary | Assessed changes from blood pressure | Systolic and diastolic blood pressures will be recorded three times by using the validated Omron HEM 742 blood pressure monitoring device with the participant seated, back supported in chair and feet flat on floor without legs crossed, after they rested 5 minutes. The guidelines of the Hypertension and Cardiology European Societies and the Spanish one will be used to classify blood pressure stages of participants. | 12 weeks |
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