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

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.