Insulin ResistanceNCCNPDMENANCT04810572
Nutraceutical Composition Containing Natural Products Derivatives on the Modulation of the Endocrine Neuroimmune Axis
A study testing Composition with Silymarin and Low-mineral composition without Silymarin in people with Insulin Resistance and Inflammatory Bowel Diseases, run by University of Sao Paulo General Hospital at 1 site in Brazil.
Trial summary
The use of natural products in the prevention or treatment of chronic diseases is an emerging field in current medicine. And studying the mechanisms of actions by which natural products act in our bodies contributes to the rational use of these products. Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance, Inflammatory Bowel Diseases, Overweight and Obesity
- What is being tested?
- Composition with Silymarin and Low-mineral composition without Silymarin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 162 participants
- Where
- 1 siteBrazil
- Study dates
- 20 May 2021to 19 Dec 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy (healthy) and sedentary volunteers: people without chronic use of drugs for chronic inflammatory diseases that require the use of corticosteroids or NSAIDs (Non-Steroidal Anti-inflammatories) for a period of more than 15 days. BMI (Body Mass Index) of 24.9 Kg / m2.
- Sedentary overweight/obesity grade 1 volunteer: overweight people, with a BMI of 25.0 to 29.9 kg / m2; and grade 1 obesity with a BMI of 30.0 and 34.9 kg / m2, with or without dyslipidemia and/or non-insulin-dependent type 2 diabetics.
Who cannot join
- Volunteers who are allergic to some of the components of the nutraceutical formulation, who use insulin, corticosteroids, and NSAIDs for more than 15 days, AIDS, hepatitis, patients undergoing chemotherapy.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Evaluation of the Effects of a Nutraceutical Composition Containing Derivatives From Natural Products on the Modulation of the Endocrine Neuroimmune Axis - Translational Study.
The use of natural products in the prevention or treatment of chronic diseases is an emerging field in current medicine. And studying the mechanisms of actions by which natural products act in our bodies contributes to the rational use of these products. And the combination of different natural products such as prebiotics (FOS- fructooligosaccharides, GOS-Galactooligosaccharides and beta-glucans derived from yeast), herbal medicine (Silybum marianum), and minerals (Se-selenium, Zn-Zinc, and Mg-Magnesium), o which would result in a synergistic association between them can contribute to achieving not only preventive effects but treatment for chronic diseases such as diabetes and obesity. The present study aims to study the effects of a composition containing natural products on factors and markers that are part of mitochondrial biogenesis and the neuroimmune-endocrine system in healthy volunteers and that present grade 1 overweight/obesity.
Read the detailed description
Obesity and diabetes are chronic diseases characterized by increased visceral adipose tissue and sub-acute inflammation. These conditions can lead to insulin resistance, hyperglycemia, oxidative stress], and lipotoxicity, and lead to the development of metabolic syndrome. Previous work has shown that these comorbidities, as well as high levels of glucocorticoids, can modulate the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory response. In some cases, these conditions and responses perturb neuroimmune endocrine system homeostasis.
Another potential outcome arising from inflammation, insulin resistance, hyperglycemia, and lipotoxicity is a nonalcoholic fatty liver disease (NAFLD), a chronic liver disease that often coexists with obesity-related type 2 diabetes. Previous studies have demonstrated that NAFLD compromises glycemic and lipid homeostasis. The hyperglycemia and the lipotoxicity drive the metabolic pathways of the cell towards gluconeogenesis, glycolysis, and de novo lipogenesis, and the subsequent increase in free fatty acid (FFA) production can cause oxidative stress.
Previous studies have shown that non-pharmacological interventions can be used as strategies for treating and/or preventing inflammatory and metabolic diseases. Furthermore, exploiting specific proteins and transcription factors that target the mitochondria represents potential mechanisms for these interventions.
Along these lines, natural products and derivatives thereof, often referred to as natural medicines, have been gaining notoriety as sources of effective therapeutics. For example, polyphenols present in plants can be metabolized to form propionic acid, which is later transformed into another metabolite, butyrate. As reviewed by Juárez-Hernández et al., Na-butyrate and synthetic derivatives thereof increase prebiotic lactobacilli and bifidobacteria growth in the colon, consequently improving thermogenesis and energy expenditure, ultimately reducing hepatic lipid deposition, improving triacylglycerol content and insulin resistance and protecting against metabolic impairment, as well as liver inflammation and/or damage. Furthermore, butyrate can induce the expression of fibroblast growth factor 21 (FGF-21), which plays a vital role in stimulating hepatic fatty acid β-oxidation. In this sense, prebiotics may be a promising treatment for chronic inflammatory and metabolic diseases in humans.
The efficacy of prebiotic compounds, such as fructooligosaccharides (FOS), galacto-oligosaccharides (GOS) and yeast β-glucans, minerals including magnesium, zinc, selenium, and plants like Silybum marianum (L.) Gaerth. (Silymarin), have been evaluated for the treatment of specific diseases. However, most of these studies only describe the effects of the supplements being administered alone. Thus, the present study monitored the synergic effects of a novel supplement formulation containing prebiotics, yeast β-glucans, minerals, and silymarin on lipid metabolism, inflammatory and mitochondrial proteins in eutrophic, and overweight/obesity I volunteer.
- Being tested
- Composition with Silymarin, Low-mineral composition without Silymarin
- Medical subject headings
- Insulin Resistance, Inflammatory Bowel Diseases, Overweight, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Composition with SilymarinDietary supplement
Also called Patent number: BR 10 2020 016156 3
Volunteers will receive supplementation for 180 days. They took 4 capsules daily. Two capsules in the morning and two capsules at night.
There will be blood and feces collection at zero time, before supplementation, after 30, 90 and 180 days from the beginning of supplementation.
Low-mineral composition without SilymarinDietary supplement
Volunteers will receive supplementation for 180 days. They took 4 capsules daily. Two capsules in the morning and two capsules at night.
There will be blood and feces collection at zero time, before supplementation, after 30, 90 and 180 days from the beginning of supplementation.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 - composition with Silymarin (L5-Plus) | Active comparator | This group compound with healthy and overweight/obese-I will receive the composition with Silymarin (Silybum marianum), in a diary dose of 140 mg for 180 days.
The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). Receives: Dietary Supplement: Composition with Silymarin; Dietary Supplement: Low-mineral composition without Silymarin |
| Group 2 - composition without Silymarin (L5-Plus) | Active comparator | This group compound with healthy and overweight/obese-I will receive the composition without Silymarin (Silybum marianum), in a diary dose for 180 days.
The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). Receives: Dietary Supplement: Composition with Silymarin; Dietary Supplement: Low-mineral composition without Silymarin |
| Group3 - Low-mineral composition without Silymarin (L5) | Active comparator | This group compound with healthy and overweight/obese-I will receive the composition without Silymarin (Silybum marianum), in a diary dose for 180 days.
The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). Receives: Dietary Supplement: Composition with Silymarin; Dietary Supplement: Low-mineral composition without Silymarin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change Lipid Profile Baseline after 4, 12 and 24 weeks of intervention.
The serum levels of cholesterol (mg/dL), triglycerides (mg/dL), and high-density lipoprotein cholesterol (HDL-c) (mg/dL) will be measured with a commercially available kit (Bioclin, Belo Horizonte, MG, Brazil).
Measured: Baseline and 4, 12 and 24 weeks.
Change Lymphocyte Phenotype at 4, 12 and 24 weeks after intervention.
Lymphocytes will be isolated from 12 mL of whole blood. Anticoagulated blood is layered onto Histopaque-1077. During centrifugation, erythrocytes are aggregated by polysucrose and rapidly sediment. Lymphocytes and other mononuclear cells remain at the plasma/ Histopaque-1077 interface.
Single-cell suspensions with lymphocyte will be incubated with the human antibodies indicated:
- T helper type 1 (Th1) cells are a subset of CD4+ effector T cells (cell surface expression of IL-12 R beta 2, IL-27 R alpha/WSX-1, IFN-gamma R2, IL-18 R, CCR5, and CXCR3);
- T helper type 2 (Th2) cells are a subset of CD4+ effector T cells (cell surface markers CCR3, CCR4, CCR8, CXCR4, and ST2/IL-1 R4).
- T helper type 9 (Th9) cells are a subset of CD4+ effector T cells [helper cell subsets including T-bet (Th1 cells), GATA-3 (Th2 cells), ROR gamma t (Th17 cells), or FoxP3 (regulatory T cells)].
Cells will be analyzed in a FACSCalibur (BD Biosciences, San Diego, CA).
Measured: Baseline and 4, 12 and 24 weeks.
Change Serum Cortisol Level Baseline after 4, 12 and 24 weeks of intervention.
Serum cortisol (pg/ml) will be measured by Elisa Kit (Cayman Chemical, Ann Arbor, MI, USA), according to the recommendations of the manufacturer.
Measured: Baseline and 4, 12 and 24 weeks.
Change Gut Microbiota Baseline after 4, 12 and 24 weeks of intervention.
For analysis of the gut microbiota, stool samples will be collected (approximately 15g) in a sterile plastic tube kit (ColOff®) and kept frozen at -80°C until the DNA extraction procedure. The material will not be collected in cases of watery stools or when the evacuation was not spontaneous (use of laxatives for evacuation). At the time of stool collection, none of the participants should be using or has used antibiotics for at least one month. Samples will be collected before bowel preparation for surgery, if necessary. Genomic DNA will be extracted from the fecal contents using the QIAamp DNA Stool Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions and the microbiota composition analysis will be performed by 16S rRNA gene sequencing on the Illumina MiSeq platform.
Measured: Baseline and 4, 12 and 24 weeks.
Change Haemogram Parameters Baseline after 4, 12 and 24 weeks of intervention.
Anticoagulated blood will be used to do the complete blood count performed using basic laboratory equipment or an automated hematology analyzer, which counts cells and collects information on their size and structure.
Total red blood count (RBC), Haemoglobin (HGB). Haematocrit (HCT), Mean Cell Volume (MCV), Mean Cell Haemoglobin (MCH), Mean Cell Haemoglobin Concentration (MCHC), and platelets (mm3).
Measured: Baseline and 4, 12 and 24 weeks.
Change Leucogram Parameters Baseline after 4, 12 and 24 weeks of intervention.
Anticoagulated blood will be used to do the complete blood count performed using basic laboratory equipment or an automated hematology analyzer, which counts cells and collects information on their size and structure.
Assessment of leukocyte numbers: Total WBC count (all cell types), relative (%) and absolute (cells/uL) differential leukocyte count (WBC separated by type). Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils.
Measured: Baseline and 4, 12 and 24 weeks.
Change Circadian Rhythms Over time of Intervention.
The first version of the Portuguese language questionnaire, "Morningness-Eveningness-Stability Scale - improved by Horne e Ostberg" (QMV-H\&O), had 20 items (19 items translated from English language questionnaire and a 20th added by us).
The total of the items is divided in three subscales, each one composed of five items: Morning Affect, Eveningness, and Distinctness. The items related to the Morning Affect subscale measure morningness preferences (early schedules), whereas the items of the Eveningness subscale assess evening preferences (late schedules). The remaining five items constitute the Distinctness subscale, that is, the amplitude dimension of this instrument. Each item is responded using a 5-points Likert scale and scored with 1-5 points, although some of them are reverse coded. The previous validation studies mentioned in the Introduction have revealed good indexes, such as Cronbach' alpha values for the three subscales ranging between 0.69 to 0.87.
Measured: Baseline and 4, 12 and 24 weeks.
Change Quality of Life Assessments Over time of Intervention.
One of the instruments that is regularly used to measure QOL, is the World Health Organization Quality of Life instrument - 100 items (WHOQOL-100; WHOQOL Group, 1998b), a cross-culturally developed generic instrument. It was created by the World Health Organization Quality of Life Group (WHOQOL Group), that defined QOL as "an individual's perception of his/her position in life in the context of the culture and value systems in which he/she lives and in relation to his/her goals, expectations, standards and concerns" (WHOQOL group, 1995). The WHOQOL-BREF contains 26 items; one item from each of the 24 facets contained in the original WHOQOL-100 and two items were retrieved from the 'Overall QOL and General health' facet. The WHOQOL-BREF covers four domains: Physical health, Psychological health, Social relationships, and Environment.
Measured: Baseline and 4, 12 and 24 weeks.
Change Sleep Patterns Over time of Intervention.
Sleep patterns will be evaluated using the Brazilian Portuguese Version of the Mini-Sleep Questionnaire (MSQ-BR).
It is composed of a ten-item self-report scale that measures frequencies of sleep difficulty. Insomnia is evaluated by four questions which assess difficulty in falling asleep, mid-sleep awakenings, early awakening in the morning, and hypnotic medication use (MSQ-BR insomnia). For evaluation of hypersomnia, the questions include snoring, feeling tired upon awakening, excessive daytime sleepiness, and restless sleep (MSQ-BR hypersomnia). Answers are given on a seven-point scale ranging from 1 (never) to 7 (always). The total sum of scores is divided into four levels of sleep difficulties: 10-24 points, good sleep quality; 25-27 points, mild sleep difficulties; 28-30 points, moderate sleep difficulties; and ≥31 points, severe sleep difficulties. The total score offers an estimate of sleep quality, with higher scores reflecting more sleeping problems.
Measured: Baseline and 4, 12 and 24 weeks.
Change Sleep Quality Over Time of Intervention.
The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality over a 1-month period. The questionnaire consists of 19 self-rated questions and 5 questions that should be answered by bedmates or roommates. The latter questions are used only for clinical information. The 19 questions categorized into 7 components, graded on a score that ranges from 0 to 3. The PSQI components are as follows: subjective sleep quality (C1), sleep latency (C2), sleep duration (C3), habitual sleep efficiency (C4), sleep disturbances (C5), use of sleeping medication(C6), and daytime dysfunction (C7). The sum of scores for these 7components yields one global score, which ranges from 0 to 21, where the highest score indicates the worst sleep quality. A global PSQIscore greater than 5 indicates major difficulties in at least 2 components or moderate difficulties in more than 3 components.
Measured: Baseline and 4, 12 and 24 weeks.
Change Sleepiness Patterns Over time of Intervention.
Excessive daytime sleepiness (EDS) is defined as an increased propensity to fall asleep under circumstances that the affected individual and others would consider inappropriate. A Portuguese-language version of the Epworth sleepiness scale (ESS) will be applied to volunteers.
The ESS is based on questions referring to eight such situations, some known to be very soporific; others less so. The questionnaire, which is self-administered. Subjects are asked to rate on a scale of 0-3 how likely they would be to doze off or fall asleep in the eight situations, based on their usual way of life in recent times. A distinction is made between dozing off and simply feeling tired. If a subject has not been in some of the situations recently, he is asked, nonetheless, to estimate how each might affect him.
Measured: Baseline and 4, 12 and 24 weeks.
Secondary outcomes (1)
Change Body Mass Index (BMI) Over time of Intervention.
Body Mass Index (BMI) - weight in kilograms divided by the square of height in meters (kg/m^2) .
Measured: Baseline and 4, 12 and 24 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Mar 2021
- Study start20 May 2021
- Primary completion20 May 2022
- Study completion19 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Insulin ResistanceStudies of the same condition, open and under way.
- More trials run by University of Sao Paulo General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 162 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University of Sao Paulo
- Responsible party
- Principal investigator, Ana Flávia Marçal Pessoa, University of Sao Paulo General Hospital
- Investigators
- Ana Flavia M Pessoa, Ph.D, Principal investigator, University of São Paulo - Medical School - FMUSP
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04810572
- Sponsor's protocol ID
- 39984320.5.0000.0068
- Acronym
- NCCNPDMENA
- Status last verified
- Jan 2024
- First submitted
- 20 Feb 2021
- Last updated
- 1 Feb 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P. Insulin regulation of gluconeogenesis. Ann N Y Acad Sci. 2018 Jan;1411(1):21-35. doi: 10.1111/nyas.13435. Epub 2017 Sep 3.
PubMed 28868790Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, Salom C, Jover A, Mora V, Roldan I, Sola E, Rocha M, Victor VM. Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. J Clin Med. 2019 Sep 4;8(9):1385. doi: 10.3390/jcm8091385.
PubMed 31487953Kutlu O, Kaleli HN, Ozer E. Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2018 Aug 29;2018:8543763. doi: 10.1155/2018/8543763. eCollection 2018.
PubMed 30228976Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013 Jun;18(6):692-9. doi: 10.1038/mp.2012.144. Epub 2012 Oct 23.
PubMed 23089630Hao H, Zheng X, Wang G. Insights into drug discovery from natural medicines using reverse pharmacokinetics. Trends Pharmacol Sci. 2014 Apr;35(4):168-77. doi: 10.1016/j.tips.2014.02.001. Epub 2014 Feb 28.
PubMed 24582872Juarez-Hernandez E, Chavez-Tapia NC, Uribe M, Barbero-Becerra VJ. Role of bioactive fatty acids in nonalcoholic fatty liver disease. Nutr J. 2016 Aug 2;15(1):72. doi: 10.1186/s12937-016-0191-8.
PubMed 27485440Sabater-Molina M, Larque E, Torrella F, Zamora S. Dietary fructooligosaccharides and potential benefits on health. J Physiol Biochem. 2009 Sep;65(3):315-28. doi: 10.1007/BF03180584.
PubMed 20119826Torres DPM, Goncalves MDPF, Teixeira JA, Rodrigues LR. Galacto-Oligosaccharides: Production, Properties, Applications, and Significance as Prebiotics. Compr Rev Food Sci Food Saf. 2010 Sep;9(5):438-454. doi: 10.1111/j.1541-4337.2010.00119.x.
PubMed 33467830Abenavoli L, Izzo AA, Milic N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res. 2018 Nov;32(11):2202-2213. doi: 10.1002/ptr.6171. Epub 2018 Aug 6.
PubMed 30080294Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.
PubMed 2748771Bertolazi AN, Fagondes SC, Hoff LS, Dartora EG, Miozzo IC, de Barba ME, Barreto SS. Validation of the Brazilian Portuguese version of the Pittsburgh Sleep Quality Index. Sleep Med. 2011 Jan;12(1):70-5. doi: 10.1016/j.sleep.2010.04.020. Epub 2010 Dec 9.
PubMed 21145786Vagos P, Rodrigues PFS, Pandeirada JNS, Kasaeian A, Weidenauer C, Silva CF, Randler C. Factorial Structure of the Morningness-Eveningness-Stability-Scale (MESSi) and Sex and Age Invariance. Front Psychol. 2019 Jan 17;10:3. doi: 10.3389/fpsyg.2019.00003. eCollection 2019.
PubMed 30705648Falavigna A, de Souza Bezerra ML, Teles AR, Kleber FD, Velho MC, da Silva RC, Mazzochin T, Santin JT, Mosena G, de Braga GL, Petry FL, de Lessa Medina MF. Consistency and reliability of the Brazilian Portuguese version of the Mini-Sleep Questionnaire in undergraduate students. Sleep Breath. 2011 Sep;15(3):351-5. doi: 10.1007/s11325-010-0392-x. Epub 2010 Jul 24.
PubMed 20652835Fleck MP, Louzada S, Xavier M, Chachamovich E, Vieira G, Santos L, Pinzon V. [Application of the Portuguese version of the instrument for the assessment of quality of life of the World Health Organization (WHOQOL-100)]. Rev Saude Publica. 1999 Apr;33(2):198-205. doi: 10.1590/s0034-89101999000200012. Portuguese.
PubMed 10413938Bech P. Quality of life measurement in the medical setting. Eur Psychiatry. 1995;10 Suppl 3:83s-5s. doi: 10.1016/0924-9338(96)80085-X.
PubMed 19698400
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Effects of a Nutraceutical Composition Containing Derivatives From Natural Products on the Modulation of the Endocrine Neuroimmune Axis - Translational Study.
- ClinicalTrials.gov ID
- NCT04810572
- Acronym / sponsor ID
- NCCNPDMENA / 39984320.5.0000.0068
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 162 participants (actual)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Collaborators
- University of Sao Paulo
- Study start
- 20 May 2021 (actual)
- Primary completion
- 20 May 2022 (actual)
- Study completion
- 19 Dec 2022 (actual)
- First posted
- 23 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The use of natural products in the prevention or treatment of chronic diseases is an emerging field in current medicine. And studying the mechanisms of actions by which natural products act in our bodies contributes to the rational use of these products. And the combination of different natural products such as prebiotics (FOS- fructooligosaccharides, GOS-Galactooligosaccharides and beta-glucans derived from yeast), herbal medicine (Silybum marianum), and minerals (Se-selenium, Zn-Zinc, and Mg-Magnesium), o which would result in a synergistic association between them can contribute to achieving not only preventive effects but treatment for chronic diseases such as diabetes and obesity. The present study aims to study the effects of a composition containing natural products on factors and markers that are part of mitochondrial biogenesis and the neuroimmune-endocrine system in healthy volunteers and that present grade 1 overweight/obesity.
Detailed description
Obesity and diabetes are chronic diseases characterized by increased visceral adipose tissue and sub-acute inflammation. These conditions can lead to insulin resistance, hyperglycemia, oxidative stress], and lipotoxicity, and lead to the development of metabolic syndrome. Previous work has shown that these comorbidities, as well as high levels of glucocorticoids, can modulate the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory response. In some cases, these conditions and responses perturb neuroimmune endocrine system homeostasis.
Another potential outcome arising from inflammation, insulin resistance, hyperglycemia, and lipotoxicity is a nonalcoholic fatty liver disease (NAFLD), a chronic liver disease that often coexists with obesity-related type 2 diabetes. Previous studies have demonstrated that NAFLD compromises glycemic and lipid homeostasis. The hyperglycemia and the lipotoxicity drive the metabolic pathways of the cell towards gluconeogenesis, glycolysis, and de novo lipogenesis, and the subsequent increase in free fatty acid (FFA) production can cause oxidative stress.
Previous studies have shown that non-pharmacological interventions can be used as strategies for treating and/or preventing inflammatory and metabolic diseases. Furthermore, exploiting specific proteins and transcription factors that target the mitochondria represents potential mechanisms for these interventions.
Along these lines, natural products and derivatives thereof, often referred to as natural medicines, have been gaining notoriety as sources of effective therapeutics. For example, polyphenols present in plants can be metabolized to form propionic acid, which is later transformed into another metabolite, butyrate. As reviewed by Juárez-Hernández et al., Na-butyrate and synthetic derivatives thereof increase prebiotic lactobacilli and bifidobacteria growth in the colon, consequently improving thermogenesis and energy expenditure, ultimately reducing hepatic lipid deposition, improving triacylglycerol content and insulin resistance and protecting against metabolic impairment, as well as liver inflammation and/or damage. Furthermore, butyrate can induce the expression of fibroblast growth factor 21 (FGF-21), which plays a vital role in stimulating hepatic fatty acid β-oxidation. In this sense, prebiotics may be a promising treatment for chronic inflammatory and metabolic diseases in humans.
The efficacy of prebiotic compounds, such as fructooligosaccharides (FOS), galacto-oligosaccharides (GOS) and yeast β-glucans, minerals including magnesium, zinc, selenium, and plants like Silybum marianum (L.) Gaerth. (Silymarin), have been evaluated for the treatment of specific diseases. However, most of these studies only describe the effects of the supplements being administered alone. Thus, the present study monitored the synergic effects of a novel supplement formulation containing prebiotics, yeast β-glucans, minerals, and silymarin on lipid metabolism, inflammatory and mitochondrial proteins in eutrophic, and overweight/obesity I volunteer.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1 - composition with Silymarin (L5-Plus) | Active comparator | Dietary Supplement: Composition with Silymarin, Dietary Supplement: Low-mineral composition without SilymarinThis group compound with healthy and overweight/obese-I will receive the composition with Silymarin (Silybum marianum), in a diary dose of 140 mg for 180 days. The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). |
| Group 2 - composition without Silymarin (L5-Plus) | Active comparator | Dietary Supplement: Composition with Silymarin, Dietary Supplement: Low-mineral composition without SilymarinThis group compound with healthy and overweight/obese-I will receive the composition without Silymarin (Silybum marianum), in a diary dose for 180 days. The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). |
| Group3 - Low-mineral composition without Silymarin (L5) | Active comparator | Dietary Supplement: Composition with Silymarin, Dietary Supplement: Low-mineral composition without SilymarinThis group compound with healthy and overweight/obese-I will receive the composition without Silymarin (Silybum marianum), in a diary dose for 180 days. The formulation of the supplement/composition (Patent number: BR 10 2020 016156 3). |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Healthy (healthy) and sedentary volunteers: people without chronic use of drugs for chronic inflammatory diseases that require the use of corticosteroids or NSAIDs (Non-Steroidal Anti-inflammatories) for a period of more than 15 days. BMI (Body Mass Index) of 24.9 Kg / m2.
- Sedentary overweight/obesity grade 1 volunteer: overweight people, with a BMI of 25.0 to 29.9 kg / m2; and grade 1 obesity with a BMI of 30.0 and 34.9 kg / m2, with or without dyslipidemia and/or non-insulin-dependent type 2 diabetics.
Key exclusion criteria (1 listed)
- Volunteers who are allergic to some of the components of the nutraceutical formulation, who use insulin, corticosteroids, and NSAIDs for more than 15 days, AIDS, hepatitis, patients undergoing chemotherapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Composition with SilymarinAlso: Patent number: BR 10 2020 016156 3Volunteers will receive supplementation for 180 days. They took 4 capsules daily. Two capsules in the morning and two capsules at night. There will be blood and feces collection at zero time, before supplementation, after 30, 90 and 180 days from the beginning of supplementation. | Dietary supplement | Group 1 - composition with Silymarin (L5-Plus), Group 2 - composition without Silymarin (L5-Plus), Group3 - Low-mineral composition without Silymarin (L5) |
| Low-mineral composition without SilymarinVolunteers will receive supplementation for 180 days. They took 4 capsules daily. Two capsules in the morning and two capsules at night. There will be blood and feces collection at zero time, before supplementation, after 30, 90 and 180 days from the beginning of supplementation. | Dietary supplement | Group 1 - composition with Silymarin (L5-Plus), Group 2 - composition without Silymarin (L5-Plus), Group3 - Low-mineral composition without Silymarin (L5) |
Primary outcome
Change Lipid Profile Baseline after 4, 12 and 24 weeks of intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
The serum levels of cholesterol (mg/dL), triglycerides (mg/dL), and high-density lipoprotein cholesterol (HDL-c) (mg/dL) will be measured with a commercially available kit (Bioclin, Belo Horizonte, MG, Brazil).
Change Lymphocyte Phenotype at 4, 12 and 24 weeks after intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Lymphocytes will be isolated from 12 mL of whole blood. Anticoagulated blood is layered onto Histopaque-1077. During centrifugation, erythrocytes are aggregated by polysucrose and rapidly sediment. Lymphocytes and other mononuclear cells remain at the plasma/ Histopaque-1077 interface. Single-cell suspensions with lymphocyte will be incubated with the human antibodies indicated: * T helper type 1 (Th1) cells are a subset of CD4+ effector T cells (cell surface expression of IL-12 R beta 2, IL-27 R alpha/WSX-1, IFN-gamma R2, IL-18 R, CCR5, and CXCR3); * T helper type 2 (Th2) cells are a subset of CD4+ effector T cells (cell surface markers CCR3, CCR4, CCR8, CXCR4, and ST2/IL-1 R4). * T helper type 9 (Th9) cells are a subset of CD4+ effector T cells [helper cell subsets including T-bet (Th1 cells), GATA-3 (Th2 cells), ROR gamma t (Th17 cells), or FoxP3 (regulatory T cells)]. Cells will be analyzed in a FACSCalibur (BD Biosciences, San Diego, CA).
Change Serum Cortisol Level Baseline after 4, 12 and 24 weeks of intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Serum cortisol (pg/ml) will be measured by Elisa Kit (Cayman Chemical, Ann Arbor, MI, USA), according to the recommendations of the manufacturer.
Change Gut Microbiota Baseline after 4, 12 and 24 weeks of intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
For analysis of the gut microbiota, stool samples will be collected (approximately 15g) in a sterile plastic tube kit (ColOff®) and kept frozen at -80°C until the DNA extraction procedure. The material will not be collected in cases of watery stools or when the evacuation was not spontaneous (use of laxatives for evacuation). At the time of stool collection, none of the participants should be using or has used antibiotics for at least one month. Samples will be collected before bowel preparation for surgery, if necessary. Genomic DNA will be extracted from the fecal contents using the QIAamp DNA Stool Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions and the microbiota composition analysis will be performed by 16S rRNA gene sequencing on the Illumina MiSeq platform.
Change Haemogram Parameters Baseline after 4, 12 and 24 weeks of intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Anticoagulated blood will be used to do the complete blood count performed using basic laboratory equipment or an automated hematology analyzer, which counts cells and collects information on their size and structure. Total red blood count (RBC), Haemoglobin (HGB). Haematocrit (HCT), Mean Cell Volume (MCV), Mean Cell Haemoglobin (MCH), Mean Cell Haemoglobin Concentration (MCHC), and platelets (mm3).
Change Leucogram Parameters Baseline after 4, 12 and 24 weeks of intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Anticoagulated blood will be used to do the complete blood count performed using basic laboratory equipment or an automated hematology analyzer, which counts cells and collects information on their size and structure. Assessment of leukocyte numbers: Total WBC count (all cell types), relative (%) and absolute (cells/uL) differential leukocyte count (WBC separated by type). Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils.
Change Circadian Rhythms Over time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
The first version of the Portuguese language questionnaire, "Morningness-Eveningness-Stability Scale - improved by Horne e Ostberg" (QMV-H\&O), had 20 items (19 items translated from English language questionnaire and a 20th added by us). The total of the items is divided in three subscales, each one composed of five items: Morning Affect, Eveningness, and Distinctness. The items related to the Morning Affect subscale measure morningness preferences (early schedules), whereas the items of the Eveningness subscale assess evening preferences (late schedules). The remaining five items constitute the Distinctness subscale, that is, the amplitude dimension of this instrument. Each item is responded using a 5-points Likert scale and scored with 1-5 points, although some of them are reverse coded. The previous validation studies mentioned in the Introduction have revealed good indexes, such as Cronbach' alpha values for the three subscales ranging between 0.69 to 0.87.
Change Quality of Life Assessments Over time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
One of the instruments that is regularly used to measure QOL, is the World Health Organization Quality of Life instrument - 100 items (WHOQOL-100; WHOQOL Group, 1998b), a cross-culturally developed generic instrument. It was created by the World Health Organization Quality of Life Group (WHOQOL Group), that defined QOL as "an individual's perception of his/her position in life in the context of the culture and value systems in which he/she lives and in relation to his/her goals, expectations, standards and concerns" (WHOQOL group, 1995). The WHOQOL-BREF contains 26 items; one item from each of the 24 facets contained in the original WHOQOL-100 and two items were retrieved from the 'Overall QOL and General health' facet. The WHOQOL-BREF covers four domains: Physical health, Psychological health, Social relationships, and Environment.
Change Sleep Patterns Over time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Sleep patterns will be evaluated using the Brazilian Portuguese Version of the Mini-Sleep Questionnaire (MSQ-BR). It is composed of a ten-item self-report scale that measures frequencies of sleep difficulty. Insomnia is evaluated by four questions which assess difficulty in falling asleep, mid-sleep awakenings, early awakening in the morning, and hypnotic medication use (MSQ-BR insomnia). For evaluation of hypersomnia, the questions include snoring, feeling tired upon awakening, excessive daytime sleepiness, and restless sleep (MSQ-BR hypersomnia). Answers are given on a seven-point scale ranging from 1 (never) to 7 (always). The total sum of scores is divided into four levels of sleep difficulties: 10-24 points, good sleep quality; 25-27 points, mild sleep difficulties; 28-30 points, moderate sleep difficulties; and ≥31 points, severe sleep difficulties. The total score offers an estimate of sleep quality, with higher scores reflecting more sleeping problems.
Change Sleep Quality Over Time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality over a 1-month period. The questionnaire consists of 19 self-rated questions and 5 questions that should be answered by bedmates or roommates. The latter questions are used only for clinical information. The 19 questions categorized into 7 components, graded on a score that ranges from 0 to 3. The PSQI components are as follows: subjective sleep quality (C1), sleep latency (C2), sleep duration (C3), habitual sleep efficiency (C4), sleep disturbances (C5), use of sleeping medication(C6), and daytime dysfunction (C7). The sum of scores for these 7components yields one global score, which ranges from 0 to 21, where the highest score indicates the worst sleep quality. A global PSQIscore greater than 5 indicates major difficulties in at least 2 components or moderate difficulties in more than 3 components.
Change Sleepiness Patterns Over time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Excessive daytime sleepiness (EDS) is defined as an increased propensity to fall asleep under circumstances that the affected individual and others would consider inappropriate. A Portuguese-language version of the Epworth sleepiness scale (ESS) will be applied to volunteers. The ESS is based on questions referring to eight such situations, some known to be very soporific; others less so. The questionnaire, which is self-administered. Subjects are asked to rate on a scale of 0-3 how likely they would be to doze off or fall asleep in the eight situations, based on their usual way of life in recent times. A distinction is made between dozing off and simply feeling tired. If a subject has not been in some of the situations recently, he is asked, nonetheless, to estimate how each might affect him.
1 secondary outcome
Change Body Mass Index (BMI) Over time of Intervention.
Time frame: Baseline and 4, 12 and 24 weeks.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2024.
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- Background: PubMed 31487953Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, Salom C, Jover A, Mora V, Roldan I, Sola E, Rocha M, Victor VM. Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. J Clin Med. 2019 Sep 4;8(9):1385. doi: 10.3390/jcm8091385.
- Background: PubMed 30228976Kutlu O, Kaleli HN, Ozer E. Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2018 Aug 29;2018:8543763. doi: 10.1155/2018/8543763. eCollection 2018.
- Background: PubMed 23089630Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013 Jun;18(6):692-9. doi: 10.1038/mp.2012.144. Epub 2012 Oct 23.
- Background: PubMed 24582872Hao H, Zheng X, Wang G. Insights into drug discovery from natural medicines using reverse pharmacokinetics. Trends Pharmacol Sci. 2014 Apr;35(4):168-77. doi: 10.1016/j.tips.2014.02.001. Epub 2014 Feb 28.
- Background: PubMed 27485440Juarez-Hernandez E, Chavez-Tapia NC, Uribe M, Barbero-Becerra VJ. Role of bioactive fatty acids in nonalcoholic fatty liver disease. Nutr J. 2016 Aug 2;15(1):72. doi: 10.1186/s12937-016-0191-8.
- Background: PubMed 20119826Sabater-Molina M, Larque E, Torrella F, Zamora S. Dietary fructooligosaccharides and potential benefits on health. J Physiol Biochem. 2009 Sep;65(3):315-28. doi: 10.1007/BF03180584.
- Background: PubMed 33467830Torres DPM, Goncalves MDPF, Teixeira JA, Rodrigues LR. Galacto-Oligosaccharides: Production, Properties, Applications, and Significance as Prebiotics. Compr Rev Food Sci Food Saf. 2010 Sep;9(5):438-454. doi: 10.1111/j.1541-4337.2010.00119.x.
- Background: PubMed 30080294Abenavoli L, Izzo AA, Milic N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res. 2018 Nov;32(11):2202-2213. doi: 10.1002/ptr.6171. Epub 2018 Aug 6.
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- Background: PubMed 21145786Bertolazi AN, Fagondes SC, Hoff LS, Dartora EG, Miozzo IC, de Barba ME, Barreto SS. Validation of the Brazilian Portuguese version of the Pittsburgh Sleep Quality Index. Sleep Med. 2011 Jan;12(1):70-5. doi: 10.1016/j.sleep.2010.04.020. Epub 2010 Dec 9.
- Background: PubMed 30705648Vagos P, Rodrigues PFS, Pandeirada JNS, Kasaeian A, Weidenauer C, Silva CF, Randler C. Factorial Structure of the Morningness-Eveningness-Stability-Scale (MESSi) and Sex and Age Invariance. Front Psychol. 2019 Jan 17;10:3. doi: 10.3389/fpsyg.2019.00003. eCollection 2019.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ana Flavia M Pessoa, Ph.D principal investigator
University of São Paulo - Medical School - FMUSP
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Composition with Silymarin and Low-mineral composition without Silymarin in people with Insulin Resistance and Inflammatory Bowel Diseases, run by University of Sao Paulo General Hospital at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change Lipid Profile Baseline after 4, 12 and 24 weeks of intervention. (time frame: Baseline and 4, 12 and 24 weeks.). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04810572, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2024.