Abstract
BackgroundTreatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease.MethodsIn a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS).ResultsIn total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism.ConclusionsCompared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted.Trial registration: NCT01425580
Highlights
In type 2 diabetes (T2D), insulin resistance and increasing adiposity result in increased levels of free fatty acids (FFAs) which lead to fat storage in the liver and in the heart [1]
It was recently shown that ameliorative effects occur in non-alcoholic steatohepatitis (NASH) in patients treated with liraglutide [7]
Treatment groups were well-balanced except for triacylglycerols (TGs) and haemoglobin A1c (HbA1c) which was higher in subjects randomized to liraglutide treatment (Table 1)
Summary
Trial design A post-hoc analysis from an assessor-blinded and activecontrolled, parallel-group trial in combination with metformin in subjects with T2D and subclinical heart failure identified as NCT01425580 (www.clinicaltrials.gov). 40 μL of sample was extracted with 400 μL of cold MeOH/H2O containing the following internal standard mixture: valine-d8, glutamic acid-d5, succinic acid-d4, heptadecanoic acid, lactic acid-d3, citric acid-d4. Quantitation of the following metabolites (aspartic acid, glutamic acid, isoleucine, methionine, fumaric acid, malic acid, leucine, valine, glycerol-3-phosphate, alanine, threonine, 3-hydroxybutyric acid, isocitric acid, arachidonic acid, glutamine, lactic acid, linoleic acid, oleic acid, palmitic acid, stearic acid and lysine, beta-muricholic acid (b-MCA), cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycohyocholic acid (GHCA), glycohyodeoxycholic acid (GHDCA), glycolitocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), hyocholic acid (HCA), hyodeoxycholic acid (HDCA), lithocholic acid (LCA), tauro-alpha/beta-muricholic acid (Ta,bMCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), Taurodeoxycholic acid (TDCA) taurodehydrocholic acid (TDHCA), trihydroxycholestanoic acid (THCA), taurohyodeoxycholic acid (THDCA), taurolitocholic acid (TLCA), tauroursodeoxycholic acid (TUDCA), tauro-omega-muricholic acid (TwMCA), ursodeoxycholic acid (UDCA), omega/alpha-muricholic acid (w/a-MCA) was done using authentic standards at six different concentrations, other metabolites were determined semi-quantitatively. The analytical method covers polar and semipolar metabolites, such as bile acids, amino acids, free fatty acids and their derivatives and polar lipids
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