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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.

CILJ ISTRAŽIVANJA: Osnovni cilj ovog istraživanja bio je identificirati značajno promijenjene metabolite u skeletnom mišiću s obzirom na spol i tretman GLP-1 analogom liraglutidom. Na temelju takve liste spojeva istražili smo koji su metabolički putevi zahvaćeni te postoje li spolne razlike u metabolizmu izazvane administracijom liraglutida. NACRT STUDIJE: Istraživanje je provedeno kao studija parova. MATERIJAL I METODE: U istraživanju su uključena oba spola 44 tjedna starih Sprague-Dawley štakora, podijeljena u 2 skupine po spolu. Obje skupine hranjene su dijetom bogatom mastima i šećerima (HFHSD). Nakon 5 tjedana HFHSD prehrane, jedna od skupina podvrgnuta je tretiranju liraglutidom u trajanju od 13 tjedana (HFHSD+L). Kada su životinje dosegle 64 tjedana starosti učinjena je biopsija skeletnih mišića, a analiza tkiva provedena je slikovnom spektrometrijom masa uređajem iMScope TRIO (Shimadzu, Japan) pomoću računalnog programa IMAGEREVEAL inačice 1.1. proizvođača Shimadzu Inc. (Japan). Razina značajnosti postavljena je na 0.05, a statistička analiza provedena je Studentovim t-testom s Benjamini-Hochbergovom korekcijom. Za identifikaciju spojeva korištena je baza podataka Human Metabolome Database, a za analizu metabolizma hipergeometrijska metoda putem paketa FELLA, programskog jezika R. REZULTATI: Identificirana su 3 metabolita promijenjena u oba spola, 8 specifičnih za mužjake i 6 za ženke. Analiza metaboličkih puteva identificirala je promjenu u metabolizmu purina i pirimidina oba spola. Dodatno, kod ženki su uočene promjene u metaboličkim putevima održavanja energetske homeostaze, a kod mužjaka nekoliko abnormalnih dNTP-a, uz moguće promjene povezane s tumorskim procesima i/ili oksidativnim stresom. ZAKLJUČAK: Prehrana i tretman liraglutidom imaju značajan utjecaj na metabolizam skeletnih mišića oba spola, a promjene metabolizma su u znatnoj mjeri spolno-specifične.

Gangliosides are sialic acid-containing glycosphingolipids found on the mammalian cell surface. They are involved in cell-cell interactions and in regulation of signaling pathways. Changes of their expression, because of environmental or genetic factors, might lead to neurological disorders. The aim of this study is to compare the expression of four major brain gangliosides in the hippocampi of healthy and obese diabetic rats. Both male and female Sprague-Dawley rats aged 10 months were included in the study. For 5 months the control group was fed with standard diet and experimental group with food rich in fats and carbohydrates. This type of diet led to obesity and development of type 2 diabetes (T2D). When the animals were 15 months old, the brains were collected and 35 µm-thick cryosections were prepared. The expression of GM1, GD1a, GD1b and GT1b was revealed in the hippocampus CA1 field and dentate gyrus (DG) using immunohistochemistry and was quantified using FIJI. In comparison to control group, the male experimental group had significantly less expressed GM1 within CA1 and DG (p=0.026 ; p=0.031), while in females its expression level was unaltered. Obese diabetic males had significantly more GD1b and GT1b in CA1 (p=0.001 ; p=0.0008) and GD1b in DG (p

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