title: Göttingen minipig model of diet-induced atherosclerosis: influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals.
abstract: BACKGROUND
  From a pharmacological perspective, readily-available, well-characterized animal models of cardiovascular disease, including relevant in vivo markers of atherosclerosis are important for evaluation of novel drug candidates. Furthermore, considering the impact of diabetes mellitus on atherosclerosis in human patients, inclusion of this disease aspect in the characterization of a such model, is highly relevant. The objective of this study was to evaluate the effect of mild streptozotocin-induced diabetes on ex- and in vivo end-points in a diet-induced atherosclerotic minipig model.
  
  
  METHODS
  Castrated male Göttingen minipigs were fed standard chow (CD), atherogenic diet alone (HFD) or with superimposed mild streptozotocin-induced diabetes (HFD-D). Circulating markers of inflammation (C-reactive protein (CRP), oxidized low-density lipoprotein (oxLDL), plasminogen activator inhibitor-1, lipid and glucose metabolism were evaluated together with coronary and aortic atherosclerosis after 22 or 43 diet-weeks. Group differences were evaluated by analysis of variance for parametric data and Kruskal-Wallis test for non-parametric data. For qualitative assessments, Fisher's exact test was applied. For all analyses, p < 0.05 was considered statistically significant.
  
  
  RESULTS
  Overall, HFD and HFD-D displayed increased CRP, oxLDL and lipid parameters compared to CD at both time points. HFD-D displayed impaired glucose metabolism as compared to HFD and CD. Advanced atherosclerotic lesions were observed in both coronary arteries and aorta of HFD and HFD-D, with more advanced plaque findings in the aorta but without differences in lesion severity or distribution between HFD and HFD-D. Statistically, triglyceride was positively (p = 0.0039), and high-density lipoprotein negatively (p = 0.0461) associated with aortic plaque area.
  
  
  CONCLUSIONS
  In this model, advanced coronary and aortic atherosclerosis was observed, with increased levels of inflammatory markers, clinically relevant to atherosclerosis. No effect of mild streptozotocin-induced diabetes was observed on plaque area, lesion severity or inflammatory markers.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. trpl@novonordisk.com.|GLP-1 and Obesity Pharmacology - PK/PD, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. trpl@novonordisk.com.
authors.forename: Trine Pagh
authors.initials: TP
authors.lastname: Ludvigsen
authors.affiliation: Histology & Imaging, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. rkki@novonordisk.com.
authors.forename: Rikke Kaae
authors.initials: RK
authors.lastname: Kirk
authors.affiliation: GLP-1 and Obesity Pharmacology - PK/PD, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. bqc@novonordisk.com.
authors.forename: Berit Østergaard
authors.initials: BØ
authors.lastname: Christoffersen
authors.affiliation: GLP-1 and Obesity Pharmacology - PK/PD, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. hkdp@novonordisk.com.
authors.forename: Henrik Duelund
authors.initials: HD
authors.lastname: Pedersen
authors.affiliation: Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Øster Farimagsgade 5, Postbox 1014 KBH K, Copenhagen, Denmark. tma@sund.ku.dk.
authors.forename: Torben
authors.initials: T
authors.lastname: Martinussen
authors.affiliation: Clamp Competency Center, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. jkip@novonordisk.com.
authors.forename: Jonas
authors.initials: J
authors.lastname: Kildegaard
authors.affiliation: National Veterinary Institute, Technical University of Denmark, Bülowsvej 27, 1870, Frederiksberg, Denmark. pmhh@vet.dtu.dk.
authors.forename: Peter M H
authors.initials: PM
authors.lastname: Heegaard
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. jopl@sund.ku.dk.
authors.forename: Jens
authors.initials: J
authors.lastname: Lykkesfeldt
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. lisbeth.hoier@sund.ku.dk.
authors.forename: Lisbeth Høier
authors.initials: LH
authors.lastname: Olsen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology*; D004032:Diet; D004195:Disease Models, Animal; D007249:Inflammation / Q000097:blood*; D008297:Male; D009765:Obesity / Q000097:blood*; D013311:Streptozocin; D013552:Swine; D013556:Swine, Miniature
chemical_list: D015415:Biomarkers; D013311:Streptozocin