Dataset Information

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial.

ABSTRACT:

Background

This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss.

Study question

Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight?

Study design

We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18-65 years of age without diabetes and with the body mass index (BMI) of 30-45 kg/m2.

Measures and outcomes

The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points.

Results

Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were -1.99%, -1.69%, and -1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%).

Conclusions

Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30-39.9 kg/m2, especially participants with hyperinsulinemia.

SUBMITTER: Rebello CJ

PROVIDER: S-EPMC9035320 | biostudies-literature | 2021 Jan-Feb 01

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial.

Rebello Candida J CJ Zemel Michael B MB Kolterman Orville O Fleming Gilbert Alexander GA Greenway Frank L FL

American journal of therapeutics 20210101 1

<h4>Background</h4>This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss.<h4>Study question</h4>Will a combination of l-leucine with low-dose metformin and sildenafil produce ...[more]

PMID: 33369909

Similar Datasets

Project description:Skeletal muscle atrophy is dictated by the balance between protein synthesis and protein breakdown, known as proteostasis. With advanced age, muscle atrophy contributes to development of co-morbidities, loss of strength and independence, and all-cause mortality. Aging also coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence associated secretory phenotype. Previously, we found that a metformin + leucine (MET+LEU) combination treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the objective of this study was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during serum-deprivation (SD) atrophy. Single myofibers were isolated from aged (22-23 mo) C57Bl6/J mice, and human primary myoblasts were extracted from a healthy older adult donor. 25 + 125 µM MET+LEU treatment increased differentiation of myotubes and prevented SD induced atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent myotube atrophy and cause transcriptional reprogramming compared to individual therapies. SD increased inflammatory and cellular senescence pathways that was reversed with MET+LEU treatment. SD resulted in dysregulated proteostasis that was rescued with MET+LEU, and proteasome inhibition with MG-132 also rescued myotube atrophy. Cellular senescence transcriptional pathways and markers increased by SD were reversed with MET+LEU treatment, and dasatinib + quercetin (D+Q) senolytic treatment prevented myotube atrophy similar to MET+LEU. In aged myofibers, MET+LEU prevented SD atrophy, and in human primary myotubes MET+LEU prevented reductions in myonuclei fusion. These data provide evidence that MET+LEU has muscle cell intrinsic properties to prevent atrophy by reversing senescence and improving proteostasis

Project description:BackgroundPeople with schizophrenia have a 15-20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap.MethodsWe retrospectively analysed digital health records of patients with TRS aged 18-65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio.ResultsAmong 90 patients initiated on clozapine, metformin use (n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight.ConclusionIn this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

Project description:Obesity was associated with change in gut microbiota composition and their metabolites. We investigated the effects of dietary supplementation with leucine (Leu) in combination with arginine (Arg) or glutamic acid (Glu) on body fat weight, composition of gut microbiota, and short-chain fatty acids (SCFAs) concentration in the colon. Forty-eight Duroc × Large White × Landrace pigs with an initial body weight of 77.08 ± 1.29 kg were randomly assigned to one of the four groups (12 pigs per group). The pigs in the control group were fed a basal diet supplemented with 2.05% alanine (isonitrogenous control, BD group), and those in the three experimental groups were fed a basal diet supplemented with 1.00% Leu + 1.37% alanine (Leu group), 1.00% Leu + 1.00% Arg (Leu_Arg group), or 1.00% Leu + 1.00% Glu (Leu_Glu group). We found that dietary supplementation with Leu alone or in combination with Arg decreased (p < 0.05) body fat weight, and increased (p < 0.05) colonic propionate and butyrate concentrations compared to the BD group. The mRNA expression levels of genes related to lipolysis increased (p < 0.05) in the Leu or Leu_Arg group compared to the BD group. Negative relationships (p < 0.05) were observed between body fat weight, colonic propionate, and butyrate concentrations. Compared to the BD group, the abundance of Actinobacteria was higher (p < 0.05) in the Leu group, and that of Clostridium_sensu_stricto_1, Terrisporobacter, and Escherichia-Shigella were higher in the Leu_Arg group. The abundance of Deinococcus-Thermus was negatively correlated (p < 0.05) with body fat weight, and was positively correlated (p < 0.05) with butyrate, isovalerate, propionate, and isobutyrate concentrations, and that of Cyanobacteria was positively correlated (p < 0.05) with butyrate, propionate, and isobutyrate concentrations. In conclusion, these findings suggest that decreased body fat weight in pigs can be induced by Leu supplementation alone or in combination with Arg and is associated with increased colonic butyrate and propionate concentrations. This provides new insights for potential therapy for obesity.

Dataset Information

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial.

Background

Study question

Study design

Measures and outcomes

Results

Conclusions

Publications

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets