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Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy.

ABSTRACT: Background: Exercise can ameliorate type II diabetes mellitus (T2DM) by regulating intestinal flora metabolites. However, the detailed mechanism needs to be further explored. Methods: A T2DM model using mice was established by feeding them a high-fat diet and giving them subsequent streptozocin injections. Fasting blood glucose and serum insulin were determined by blood glucose meter and radioimmunoassay, respectively. Intestinal flora was measured by 16sRNA sequencing. SCFA content was measured by gas chromatography (GC) or enzyme-linked immunosorbent assay (ELISA). A fluorescently labeled 2-deoxyglucose (2-NBDG) kit was employed to detect glucose uptake capacity, and western blot was utilized to explore the signaling pathway of insulin resistance and cell autophagy. Results: In the T2DM model, along with a reduction in insulin resistance (IR), exercise reversed the decline of intestinal Bacteroidetes and the increase of Firmicutes. For metabolites of Bacteroides, exercise restored the decline in total intestinal and plasma short-chain fatty acids (SCFAs) in T2DM mice. However, the administration of GLPG0974-the inhibitor of G protein-coupled receptor 43 (GPR43), which is the receptor of SCFAs-abolished exercise-mediated alleviation in IR in vivo and acetate-mediated reduction of skeletal muscle IR (SMIR) in vitro. Mechanistically, exercise induced skeletal muscle cell autophagy, thereby ameliorating SMIR, which was neutralized by GLPG0974 exposure. Conclusions: Exercise-mediated SCFAs-upregulation may ameliorate insulin resistance (IR) through increasing autophagy of skeletal muscle cells by binding to GPR43. This study provides a theoretical basis for targeting gut bacterial metabolites to prevent T2DM.

SUBMITTER: Yang L

PROVIDER: S-EPMC7464264 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy.

Yang Ling L Lin Haiqi H Lin Wentao W Xu Xiaoyang X

Biology 20200803 8

<b>Background</b>: Exercise can ameliorate type II diabetes mellitus (T2DM) by regulating intestinal flora metabolites. However, the detailed mechanism needs to be further explored. <b>Methods</b>: A T2DM model using mice was established by feeding them a high-fat diet and giving them subsequent streptozocin injections. Fasting blood glucose and serum insulin were determined by blood glucose meter and radioimmunoassay, respectively. Intestinal flora was measured by 16sRNA sequencing. SCFA conten ...[more]

PMID: 32756447

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Project description:BackgroundIncreasing evidence suggests that human gut microbiome plays an important role in variation of skeletal muscle mass (SMM). However, specific causal mechanistic relationship of human gut microbiome with SMM remains largely unresolved. Understanding the causal mechanistic relationship may provide a basis for novel interventions for loss of SMM. This study investigated whether human gut microbiome has a causal effect on SMM among Chinese community-dwelling healthy menopausal women.MethodsEstimated SMM was derived from whole-body dual-energy X-ray absorptiometry. We performed integrated analyses on whole-genome sequencing, shotgun metagenomic sequencing, and serum short-chain fatty acids (SCFAs), as well as available host SMM measurements among community-dwelling healthy menopausal women (N = 482). We combined the results with summary statistics from genome-wide association analyses for human gut microbiome (N = 952) and SMM traits (N = 28 330). As a prerequisite for causality, we used a computational protocol that was proposed to measure correlations among gut metagenome, metabolome, and the host trait to investigate the relationship between human gut microbiome and SMM. Causal inference methods were applied to assess the potential causal effects of gut microbial features on SMM, through one-sample and two-sample Mendelian randomization (MR) analyses, respectively.ResultsIn metagenomic association analyses, the increased capacity for gut microbial synthesis of the SCFA butyrate was significantly associated with serum butyrate levels [Spearman correlation coefficient (SCC) = 0.13, P = 0.02] and skeletal muscle index (SCC = 0.084, P = 0.002). Of interest was the finding that two main butyrate-producing bacterial species were both positively associated with the increased capacity for gut microbial synthesis of butyrate [Faecalibacterium prausnitzii (SCC = 0.25, P = 6.6 × 10-7 ) and Butyricimonas virosa (SCC = 0.15, P = 0.001)] and for skeletal muscle index [F. prausnitzii (SCC = 0.16, P = 6.2 × 10-4 ) and B. virosa (SCC = 0.17, P = 2.4 × 10-4 )]. One-sample MR results showed a causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.04, 95% confidence interval 0.029 to 0.051, P = 0.003). Two-sample MR results further confirmed the causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.06, 95% confidence interval 0 to 0.13, P = 0.06).ConclusionsOur results may help the future development of novel intervention approaches for preventing or alleviating loss of SMM.

Project description:ContextThere is substantial evidence that reduced short-chain fatty acids (SCFAs) in the gut are associated with obesity and type 2 diabetes, although findings from clinical interventions that can increase SCFAs are inconsistent.ObjectiveThis systematic review and meta-analysis aimed to assess the effect of SCFA interventions on fasting glucose, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR).Data sourcesRelevant articles published up to July 28, 2022, were extracted from PubMed and Embase using the MeSH (Medical Subject Headings) terms of the defined keywords [(short-chain fatty acids) AND (obesity OR diabetes OR insulin sensitivity)] and their synonyms. Data analyses were performed independently by two researchers who used the Cochrane meta-analysis checklist and the PRISMA guidelines.Data extractionClinical studies and trials that measured SCFAs and reported glucose homeostasis parameters were included in the analysis. Standardized mean differences (SMDs) with 95%CIs were calculated using a random-effects model in the data extraction tool Review Manager version 5.4 (RevMan 5.4). The risk-of-bias assessment was performed following the Cochrane checklist for randomized and crossover studies.Data analysisIn total, 6040 nonduplicate studies were identified, 23 of which met the defined criteria, reported fasting insulin, fasting glucose, or HOMA-IR values, and reported change in SCFA concentrations post intervention. Meta-analyses of these studies indicated that fasting insulin concentrations were significantly reduced (overall effect: SMD = -0.15; 95%CI = -0.29 to -0.01, P = 0.04) in treatment groups, relative to placebo groups, at the end of the intervention. Studies with a confirmed increase in SCFAs at the end of intervention also had a significant effect on lowering fasting insulin (P = 0.008). Elevated levels of SCFAs, compared with baseline levels, were associated with beneficial effects on HOMA-IR (P < 0.00001). There was no significant change in fasting glucose concentrations.ConclusionIncreased postintervention levels of SCFAs are associated with lower fasting insulin concentrations, offering a beneficial effect on insulin sensitivity.Systematic review registrationPROSPERO registration number CRD42021257248.

Dataset Information

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy.

Publications

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy.

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