The effects of liraglutide in mice with diet-induced obesity studied by metabolomics

Bugáňová, Martina; Pelantová, Helena; Holubová, Martina; Šedivá, Blanka; Maletı́nská, Lenka; Železná, Blanka; Kuneš, Jaroslav; Kačer, Petr; Kuzma, Marek; Haluzı́k, Martin

doi:10.1530/joe-16-0478

Cited by 25 publications

(13 citation statements)

References 34 publications

(49 reference statements)

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“…Metabolomic studies in mice using nuclear magnetic resonance (NMR) spectroscopy, which is more restricted in terms of metabolomics coverage due to lower sensitivity than mass spectrometry, found that treatment with liraglutide alters β-oxidation in fatty acids also affects the microbiome, independently of other metabolic changes [ 23 ]. In agreement with this, recent human intervention studies using NMR spectroscopy (although with limited lipid coverage compared to mass spectrometry) were in line with our results, independent of other metabolic changes such as alterations in lipid and lipoprotein profile after liraglutide treatment compared to placebo [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Jendle

Hyötyläinen

Orešič

et al. 2021

Cardiovasc Diabetol

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Background Treatment 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. Methods In 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). Results In 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. Conclusions Compared 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

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Section: Discussionmentioning

confidence: 99%

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Jendle

Hyötyläinen

Orešič

et al. 2021

Cardiovasc Diabetol

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“…Namely, glucose tolerance in the db/db mice and liver weights and combined NAFLD activity scores in the MS-NASH mice were the main endpoints for which 0602K+Lira outperformed 0602K-only treatment. This could be due to a rather low dose of Liraglutide used in these studies (0.2mg/kg every-other-day), compared to other rodent studies that use similar doses with daily or even twice daily injections [32,43,44]. However, we are confident that we provided an effective dose…”

Section: Discussionmentioning

confidence: 89%

MSDC-0602K, A Novel Insulin-Sensitizer Improves Insulinemia and Fatty Liver Disease Alone and in Addition to Liraglutide in Mice

Kamm

Pyles

Sharpe

et al. 2020

Preprint

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Aims/hypothesisInsulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Additionally, while thiazolidinedione (TZD) insulin sensitizers are associated with the side-effect of weight gain, glucagon-like peptide-1 receptor agonists (GLP-1RAs) can induce weight loss. We hypothesized that combination therapy with a novel TZD insulin sensitizer and the GLP-1RA Liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH) compared to individual therapy.Methodsdb/db mice were treated with the novel TZD MSDC-0602K by oral gavage, Liraglutide (Lira) by s.c. injection, combination 0602K+Lira, or both vehicle solutions. Vehicle-treated db/+ mice were included as non-obese controls. To assess treatment effects on nonalcoholic fatty liver disease, MS-NASH mice were similarly treated with vehicle, either drug individually, or in combination. Lastly, islets were isolated from C57BL/6J mice to assess glucose-stimulated insulin secretion (GSIS).Results0602K-treated db/db mice displayed slight weight gain but completely corrected glycemia and markedly improved glucose tolerance. Lira slightly reduced body weights and modestly improved glycemia. 0602K+Lira combination still induced slight weight gain but completely corrected glycemia and improved glucose tolerance beyond lean db/+ levels. As expected, 0602K resulted in reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not directly reduce GSIS in isolated islets, thus the reduced insulinemia with 0602K is likely compensatory due to improved insulin action. In the MS-NASH mouse model, both 0602K or Lira alone improved plasma ALT and AST, and liver histology, but more significant improvements were observed with 0602K+Lira combination therapy. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice.ConclusionsMSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance in db/db mice, and more significantly improved liver histology in MS-NASH mice.

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“…Namely, glucose tolerance in the db/db mice and liver weights and combined NAFLD activity scores in the MS-NASH mice were the main endpoints for which 0602K+Lira outperformed 0602K-only treatment. This could be due to a rather low dose of liraglutide used in these studies (0.2 mg/kg every other day), compared with other rodent studies that use similar doses with daily or even twice daily injections ( 28 , 39 , 40 ). However, we are confident that we provided an effective dose of liraglutide as Lira-treated animals displayed weight loss, increased plasma insulin concentrations, and improved glycemia.…”

Section: Discussionmentioning

confidence: 92%

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide

Kamm

Pyles

Sharpe

et al. 2021

Journal of Biological Chemistry

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The effects of liraglutide in mice with diet-induced obesity studied by metabolomics

Cited by 25 publications

References 34 publications

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

MSDC-0602K, A Novel Insulin-Sensitizer Improves Insulinemia and Fatty Liver Disease Alone and in Addition to Liraglutide in Mice

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide

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