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Article

Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study

  • Authors:
    • Jeng-Yuan Yao
    • De-Tian-Yu Tzeng
    • Cai-Hong Feng
    • Gong-Man Xiao
    • Tian-Ni You
    • Ru-Yu Zheng
  • View Affiliations / Copyright

    Affiliations: Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University, Xiamen, Fujian 361023, P.R. China, Department of Clinical Medicine, Xiamen Medical College, Xiamen, Fujian 361023, P.R. China
  • Article Number: 17
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    Published online on: November 6, 2025
       https://doi.org/10.3892/etm.2025.13012
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Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of pancreatic β‑cells that causes absolute insulin deficiency and lifelong insulin use. It leads to ketoacidosis and long‑term micro‑/macro‑vascular complications. Globally, ~9 million individuals live with T1DM and ~0.5 million are newly diagnosed each year. Leucine (Leu), a branched‑chain amino acid, improves blood‑glucose control and increases the insulin sensitivity of peripheral tissues. However, its role in modulating lipid metabolism and metabolic pathways in T1DM is yet to be elucidated. In the present study, male C57BL/6J mice were randomly divided into four groups, namely Normal, Normal‑Leu, T1DM and T1DM‑Leu. T1DM was induced by five daily intraperitoneal injections of streptozotocin (50 mg/kg per day), and leucine was provided in the drinking water at 1.5% (w/v) for 6 weeks. After 6 weeks, plasma samples were collected for metabolomics and biochemical analysis. Untargeted LC‑MS/MS profiling showed elevated metabolites mapping to steroid‑hormone biosynthesis, arachidonic/linoleic‑acid and retinol pathways in T1DM vs. Normal; Leu partly lowered these signals and shifted galactose and primary bile‑acid metabolism toward control patterns. Leu supplementation downregulated galactose‑pathway intermediates and reduced signals consistent with primary bile‑acid biosynthesis, shifting both pathways toward control levels in T1DM‑Leu vs. T1DM. Biochemically, T1DM lowered high‑density lipoprotein (HDL) and raised low‑density lipoprotein (LDL) vs. Normal (HDL, 0.597±0.292 mmol/l; LDL, 1.154±0.501 mmol/l); with Leu, these lipids approached control levels: T1DM‑Leu (HDL, 0.958±0.224 mmol/l; LDL, 0.548±0.267 mmol/l) vs. Normal‑Leu (HDL, 0.912±0.121 mmol/l; LDL, 0.392±0.175 mmol/l). In summary, the findings of the present study indicated that dietary Leu may be a useful adjuvant for T1DM due to potentially easing dyslipidemia and reversing key metabolic disturbances.
View Figures

Figure 1

Metabolomic overview of plasma
samples. (A) One-way ANOVA of 1,692 detected ion features after
quality-control filtering (relative SD >30%), followed by
Tukey's post hoc test. Red dots represent ions with P-values of
<0.05; green dots represent non-significant ions. (B) PC
analysis scores plot illustrating the separation of the Normal,
Normal-Leu, T1DM and T1DM-Leu groups. PC1 and PC2 explain 38.2 and
19.9% of the variance, respectively. (C) The top panel shows a
volcano plot of the differential features in the T1DM vs. Normal
group comparison (FC, >2; P<0.05). The bottom panel shows the
KEGG MSEA of the top 10 pathways altered in the mice in the T1DM
group compared with those in the Normal group. (D) The top panel
shows a volcano plot of the differential features in the T1DM-Leu
vs. T1DM group comparison (FC, >2; P<0.05). The bottom panel
shows the KEGG MSEA of the top 10 pathways modulated by Leu
supplementation in mice with T1DM. Leu, leucine; Normal-Leu, Normal
with 1.5% Leu supplementation; T1DM, type 1 diabetes mellitus;
T1DM-Leu, T1DM with 1.5% Leu supplementation; PC, principal
component; FC, fold-change; KEGG, Kyoto Encyclopedia of Genes and
Genomes; MSEA, metabolite-set enrichment analysis.

Figure 2

Relative abundance of selected
metabolites affected by T1DM and Leu supplementation. (A)
Eicosapentaenoic acid; (B) 8,11,14-eicosatrienoic acid; (C)
arachidonic acid; (D) retinyl ester; (E) vitamin A and (F)
norepinephrine. Data are presented as box-and-whisker plots
(median, interquartile range and 10-90th percentiles).
*P<0.05 and **P<0.01 indicate the
significance level of the pairwise comparisons that were obtained
using one-way ANOVA followed by Tukey's post hoc test. Leu,
leucine; Normal-Leu, Normal with 1.5% Leu supplementation; T1DM,
type 1 diabetes mellitus; T1DM-Leu, T1DM with 1.5% Leu
supplementation.

Figure 3

Biochemical parameters in plasma or
whole blood. (A) Relative concentrations of HbA1c. Concentrations
(mM) of (B) fasting blood glucose; (C) triglyceride; (D) total
cholesterol; (E) high-density lipoprotein cholesterol and (F)
low-density lipoprotein cholesterol. Data is presented as mean ± SD
(n=10). *P<0.05 vs. the Normal group (one-way ANOVA
followed by Tukey's post hoc test). Leu, leucine; Normal-Leu,
Normal with 1.5% Leu supplementation; T1DM, type 1 diabetes
mellitus; T1DM-Leu, T1DM with 1.5% Leu supplementation.
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Copy and paste a formatted citation
Spandidos Publications style
Yao J, Tzeng D, Feng C, Xiao G, You T and Zheng R: Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study. Exp Ther Med 31: 17, 2026.
APA
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., & Zheng, R. (2026). Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study. Experimental and Therapeutic Medicine, 31, 17. https://doi.org/10.3892/etm.2025.13012
MLA
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., Zheng, R."Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study". Experimental and Therapeutic Medicine 31.1 (2026): 17.
Chicago
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., Zheng, R."Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study". Experimental and Therapeutic Medicine 31, no. 1 (2026): 17. https://doi.org/10.3892/etm.2025.13012
Copy and paste a formatted citation
x
Spandidos Publications style
Yao J, Tzeng D, Feng C, Xiao G, You T and Zheng R: Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study. Exp Ther Med 31: 17, 2026.
APA
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., & Zheng, R. (2026). Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study. Experimental and Therapeutic Medicine, 31, 17. https://doi.org/10.3892/etm.2025.13012
MLA
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., Zheng, R."Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study". Experimental and Therapeutic Medicine 31.1 (2026): 17.
Chicago
Yao, J., Tzeng, D., Feng, C., Xiao, G., You, T., Zheng, R."Leucine supplementation modulates lipid metabolism and metabolic pathways in mice with type 1 diabetes: A metabolomics study". Experimental and Therapeutic Medicine 31, no. 1 (2026): 17. https://doi.org/10.3892/etm.2025.13012
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