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Skeletal muscle metabolomics post liraglutide and metformin treatments

Introduction: Type 2 diabetes (T2D) is a metabolic disease affecting many tissues and altering their cellular metabolism. Skeletal muscle plays a major role in glucose homeostasis and often displays insulin resistance in T2D patients. We investigated effectsof high fat-high sugar diet (HFHSD) and diabetes drugs, metformin and liraglutide on skeletal muscle metabolism of male and female rats. Methods: 24 Sprague-Dawley male and 24 female rats were fed standard diet for 44 weeks. When they reached 45 weeks, rats were randomly separated into 3 groups per sex of 8 rats each and were fed HFHSD till the end of experiment. After 5 weeks of HFHSD only feeding, two groups per sex underwent 13 week-long treatments with metformin (HFHSD-M) or liraglutide (HFHSD-L). Skeletal muscle biopsies of 64 weeks- old rats were performed, and tissues were analyzed using imaging mass spectrometry instrument iMScope TRIO(Shimadzu, Japan). Data analysis was performed using R software for Statistical Computing (R Foundation for Statistical Computing, Vienna, Austria) using packages FELLA, resampleand KEGGREST, and custom script. Results: For HFHSD-L compared to HFHSD, in females we discovered 5 altered metabolites of which only 1 was identified, whereas for males there were 16 altered compounds of which 5 were identified. When comparing HFHSD- M to HFHSD, there were none detected differences in females. However, in males there were 83 altered compounds of which we identified 14. Based on identified metabolites, metabolic pathway analysis elucidated 11 altered pathways in HFHSD-L males and 18 in HFHSD-M males, both compared to HFHSD males. Discussion: Our study suggests that metformin and liraglutide disproportionately affect male rats compared to females. This isn’t surprising, given the fact that drugs are usually developed and tested in males. However, this common practice might produce drugs that aren’t as efficacious in females and therefore not provide same benefits as seen in males.

Type 2 diabetes ; Skeletal muscle ; high fat-high sugar diet ; metformin ; liraglutide ; imaging mass spectrometry

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