title: Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs.
abstract: OBJECTIVE
  Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9(+) transgenic minipig.
  
  
  METHODS
  Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type.
  
  
  RESULTS
  Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs.
  
  
  CONCLUSIONS
  Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of human-like atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important.
authors.affiliation: Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark, rham@clin.au.dk.
authors.forename: Rozh H
authors.initials: RH
authors.lastname: Al-Mashhadi
authors.forename: Martin M
authors.initials: MM
authors.lastname: Bjørklund
authors.forename: Martin B
authors.initials: MB
authors.lastname: Mortensen
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.forename: Torben
authors.initials: T
authors.lastname: Larsen
authors.forename: Erling
authors.initials: E
authors.lastname: Falk
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Bentzon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050197:Atherosclerosis / Q000097:blood / Q000150:complications / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000473:pathology*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002784:Cholesterol; D003404:Creatinine