Therapeutic Strategies for Type 2 Diabetes Based on Lifestyle Changes: Plant-based Diet and Physical Exercise

Обзор

The study evaluates the impact of a strict vegetarian diet combined with regular physical exercise and the use of probiotics on metabolic, inflammatory, and epigenetic parameters in patients with type 2 diabetes. It aims to determine the influence of these interventions on gut microbiota, glycemic control, body composition, insulin resistance, and quality of life.

Подробное описание

This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the effects of a strict vegetarian diet (SVD) combined with regular physical exercise (RPE), with or without probiotic supplementation, on key metabolic and physiological parameters in patients with type 2 diabetes mellitus (T2DM). Participants will be monitored for changes in glycemic control, insulin resistance (IR), liver function (elastography and ultrasound), metabolomic profile, muscle composition (biopsy), cholesterol efflux, and gene expression.

Glycemic Control Glycemic control will be assessed through glycated hemoglobin (HbA1c), fasting glucose, fructosamine, and oral meal tolerance test (OMTT). A standardized dietary test (500 kcal plant-based meal) will be conducted at baseline and post-intervention, measuring postprandial glucose, insulin, proinsulin, C-peptide, and incretin hormones (GLP-1, GIP).

Insulin Resistance (IR) IR will be evaluated using HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and fasting insulin levels. The study will also analyze inflammatory markers (TNF-α, IL-1β, IL-6, IFN-γ), as chronic low-grade inflammation plays a crucial role in IR development.

Elastography and Ultrasound (US) Liver ultrasound and transient elastography (FibroScan®) will be performed to assess hepatic steatosis and fibrosis, which are highly prevalent in T2DM. The effects of dietary and probiotic interventions on liver fat content, liver stiffness, and metabolic liver function will be analyzed.

Metabolome Analysis Metabolomic profiling will be conducted through mass spectrometry-based analysis of fasting and postprandial plasma samples. The study will evaluate amino acids, lipids, short-chain fatty acids, bile acids, ketone bodies, and glycolysis-related metabolites to understand how dietary and microbiome changes influence metabolic pathways in T2DM.

Muscle Biopsy A vastus lateralis muscle biopsy will be performed in a subgroup of participants (n=24). Samples will be analyzed for fiber composition, extracellular matrix remodeling, mitochondrial function, and inflammatory markers. The role of microRNAs (miR-29a, miR-29b, miR-1, miR-133a/b, miR-206) in muscle insulin sensitivity will also be investigated.

Cholesterol Efflux HDL functionality will be assessed by measuring cholesterol efflux capacity from macrophages exposed to participants' serum. This analysis will provide insight to cardiovascular risk modulation by diet and probiotics in T2DM.

Gene Expression Analysis Peripheral blood lymphocytes will be analyzed for expression of inflammation-related genes (TNF-α, IL-6, IL-1β, IFN-γ, TLR4, TLR5) and longevity-related genes (SIRT1, FOXO1, PGC-1α, P53). These markers will help determine how dietary and probiotic interventions influence immune response, cellular aging, and metabolic regulation.

Microbiota analysis This study will assess how a strict vegetarian diet and probiotic supplementation influence gut microbiota composition and functionality in individuals with T2DM. Stool samples will be collected before and after the intervention (4 weeks) and analyzed using 16S rRNA sequencing (NGS platforms: Ion Torrent PGM or Illumina MiSeq).

Microbiota diversity (alpha and beta diversity metrics) and the relative abundance of key bacterial taxa (Bacteroides, Firmicutes, Akkermansia, Prevotella, Bifidobacterium, Lactobacillus) will be evaluated. Functional analysis will include metagenomic predictions (PICRUSt2), short-chain fatty acid (SCFA) production, and microbial metabolic pathways.

The impact of probiotic supplementation (B. breve BR03, B. breve B632, B. longum 04, L. reuteri LRE11) will be assessed by comparing gut microbiota changes between the probiotic and placebo groups, focusing on butyrate-producing bacteria, lactate-utilizing species, and intestinal barrier integrity markers.

The intervention will last four weeks, followed by 12 months of telemedicine follow-up. This study aims to provide new insights into the role of lifestyle interventions in metabolic regulation, inflammation, and gut microbiota modulation in T2DM, potentially offering novel therapeutic strategies beyond pharmacological approaches.

Вмешательства

• Пищевая добавка Probiotic Supplementation
  Participants will follow the same strict vegetarian diet and regular physical exercise as in Intervention 1. Additionally, they will receive a probiotic supplement, taken twice daily for four weeks. This aims to evaluate the metabolic impact of probiotics in type 2 diabetes.
• Пищевая добавка Placebo Administration
  Participants will follow a strictly plant-based diet rich in fiber and bioactive compounds, with controlled macronutrient distribution. Regular physical exercise includes supervised aerobic and resistance training sessions. The intervention lasts four weeks. Instead of probiotic supplementation, participants will receive a placebo, administered in the same manner as the probiotic group to maintain blinding.

Первичные конечные точки

• Change in Body Mass Index (BMI) [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Waist, Abdominal, and Hip Circumference [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Waist-to-Hip Ratio (WHR) [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Functional Aerobic Capacity (1-Mile Walk Test) [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Functional Mobility (Up and Go Test) [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Fasting Blood Glucose [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Postprandial Glucose Levels [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Glycated Hemoglobin (HbA1c) [Срок оценки: Baseline and 4 weeks post-intervention]

Вторичные конечные точки (12)

• Change in Liver Enzymes (AST, ALT, GGT) [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Standard Lipid Profile [Срок оценки: Baseline and 4 weeks post-intervention]
• HDL Function and Lipid Profile [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in C-Reactive Protein (CRP) Levels [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Plasma Cytokine Levels [Срок оценки: Baseline and 4 weeks post-intervention]
• Metabolomic and Biochemical Markers [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in expression of Metabolism- and Inflammation-Related microRNAs [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Expression of Inflammatory Genes [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Inflammatory Gene Expression in Lymphocytes and Skeletal Muscle [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Fasting Insulin, Proinsulin, and C-Peptide Levels [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Insulin Resistance Assessed by HOMA-IR [Срок оценки: Baseline and 4 weeks post-intervention]
• Change in Incretin Hormone Levels (GLP-1 and GIP) [Срок оценки: Baseline and 4 weeks post-intervention]

Критерии участия

Критерии включения

• Have a medical diagnosis of type 2 diabetes for a maximum of 5 years.
• Be omnivorous; Have a Body Mass Index (BMI) ≥ 25 kg/m2 and < 40 kg/m2;
• Be between the ages of 45 and 70, both genders.
• Women should be in the postmenopausal stage;
• Use no more than three hypoglycemic medications in total;
• Have the availability for a four-week consecutive hospitalization at CSVN.

Критерии исключения

• Be using insulin, anti-obesity medications, antibiotics, and/or probiotic supplements in the 2 months preceding data collection;
• Use of alcohol or tobacco;
• Have limited mobility and a previous diagnosis of cardiopulmonary diseases;
• Report current or previous (within the past two months) diarrhea during screening;
• Have liver or kidney failure and uncontrolled endocrine disorders (hypothyroidism, hypogonadism, and adrenal insufficiency);
• Have eating disorders or have undergone bariatric surgery.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Бразилия · 1 центр

• Universidade de São Paulo (USP) — São Paulo

Публикации

• Guasch-Ferre M, Hruby A, Toledo E, Clish CB, Martinez-Gonzalez MA, Salas-Salvado J, Hu FB. Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis. Diabetes Care. 2016 May;39(5):833-46. doi: 10.2337/dc15-2251. PMID 27208380
• Nikiforova VJ, Giesbertz P, Wiemer J, Bethan B, Looser R, Liebenberg V, Ruiz Noppinger P, Daniel H, Rein D. Glyoxylate, a new marker metabolite of type 2 diabetes. J Diabetes Res. 2014;2014:685204. doi: 10.1155/2014/685204. Epub 2014 Nov 27. PMID 25525609
• Koutnikova H, Genser B, Monteiro-Sepulveda M, Faurie JM, Rizkalla S, Schrezenmeir J, Clement K. Impact of bacterial probiotics on obesity, diabetes and non-alcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2019 Mar 30;9(3):e017995. doi: 10.1136/bmjopen-2017-017995. PMID 30928918
• Miraghajani M, Dehsoukhteh SS, Rafie N, Hamedani SG, Sabihi S, Ghiasvand R. Potential mechanisms linking probiotics to diabetes: a narrative review of the literature. Sao Paulo Med J. 2017 Mar-Apr;135(2):169-178. doi: 10.1590/1516-3180.2016.0311271216. PMID 28538869
• Heppner KM, Perez-Tilve D. GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front Neurosci. 2015 Mar 20;9:92. doi: 10.3389/fnins.2015.00092. eCollection 2015. PMID 25852463
• Firouzi S, Majid HA, Ismail A, Kamaruddin NA, Barakatun-Nisak MY. Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial. Eur J Nutr. 2017 Jun;56(4):1535-1550. doi: 10.1007/s00394-016-1199-8. Epub 2016 Mar 17. PMID 26988693
• Hopper I, Billah B, Skiba M, Krum H. Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomised controlled clinical trials. Eur J Cardiovasc Prev Rehabil. 2011 Dec;18(6):813-23. doi: 10.1177/1741826711421687. Epub 2011 Aug 30. PMID 21878448
• Jardine MA, Kahleova H, Levin SM, Ali Z, Trapp CB, Barnard ND. Perspective: Plant-Based Eating Pattern for Type 2 Diabetes Prevention and Treatment: Efficacy, Mechanisms, and Practical Considerations. Adv Nutr. 2021 Dec 1;12(6):2045-2055. doi: 10.1093/advances/nmab063. PMID 34113961

Идентификаторы

NCT: NCT06959043 · Cappesq

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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