Jenni Virta1, Sanna Hellberg2, Heidi Liljenbäck3, Mia Ståhle1, Johanna M U Silvola1, Jenni Huusko4, Mirva Söderström5, Juhani Knuuti6, Pirjo Nuutila7, Seppo Ylä-Herttuala8, Maria F Gomez9, Anne Roivainen10, Antti Saraste11. 1. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland. 2. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Department of Medicine, Karolinska Institutet, Akademiska stråket 1, SE-17164, Solna, Sweden. 3. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, FI-20520, Turku, Finland. 4. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Neulanniementie 2, FI-70210, Kuopio, Finland. 5. Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, FI-20520, Turku, Finland. 6. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland. 7. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Department of Endocrinology, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland. 8. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Neulanniementie 2, FI-70210, Kuopio, Finland; Heart Center, Kuopio University Hospital, Puijonlaaksontie 2, FI-70210, Kuopio, Finland. 9. Department of Clinical Sciences, Lund University, Jan Waldenströms gata 35, SE-21428, Malmö, Sweden. 10. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, FI-20520, Turku, Finland; Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland. 11. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Heart Center, Turku University Hospital, Hämeentie 11, FI-20520, Turku, Finland. Electronic address: antti.saraste@utu.fi.
Abstract
BACKGROUND AND AIMS: Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes. METHODS: Igf2/Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18F-FDG, and histology were studied. RESULTS: Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18F-FDG uptake. Compared with chow diet, uptake of 18F-FDG was similar in the aorta, but higher in the liver after HFD. CONCLUSIONS: Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18F-FDG uptake, in atherosclerotic mice with type 2 diabetes.
BACKGROUND AND AIMS: Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes. METHODS:Igf2/Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18F-FDG, and histology were studied. RESULTS:Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18F-FDG uptake. Compared with chow diet, uptake of 18F-FDG was similar in the aorta, but higher in the liver after HFD. CONCLUSIONS:Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18F-FDG uptake, in atheroscleroticmice with type 2 diabetes.
Authors: Andrea Coppola; Giada Zorzetto; Filippo Piacentino; Valeria Bettoni; Ida Pastore; Paolo Marra; Laura Perani; Antonio Esposito; Francesco De Cobelli; Giulio Carcano; Federico Fontana; Paolo Fiorina; Massimo Venturini Journal: Acta Diabetol Date: 2021-11-15 Impact factor: 4.280