title: Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans.
abstract: OBJECTIVE
  To determine fasting and postprandial metabolism of apolipoprotein B48 (apoB48) remnant lipoproteins in subjects with Type 1 diabetes and the relationship to progressive cardiovascular disease, and to investigate the impact of remnant lipoprotein cholesterol accumulation associated with arterial wall biglycan using a rodent model of Type 1 diabetes.
  
  
  METHODS
  Normolipidaemic subjects (n = 9) with long-standing Type 1 diabetes (and advanced cardiovascular disease) and seven healthy control subjects were studied. Fasting and postprandial apoB48 concentration was determined following a sequential meal challenge. A rodent model of streptozotocin-induced diabetes was used to investigate the ex vivo retention of fluorescent-conjugated remnants. Binding of remnant lipoproteins to human recombinant biglycan was assessed in vitro.
  
  
  RESULTS
  A significantly higher concentration of fasting plasma apoB48 remnants was observed in patients with Type 1 diabetes compared with control subjects. Patients with Type 1 diabetes exhibited a greater total plasma apoB48 area under the curve (AUC) and an increased incremental AUC following a second sequential meal compared with control subjects. The arterial retention of remnants ex vivo and associated cholesterol was increased sevenfold in Type 1 diabetes rats relative to controls. Remnants were shown to bind with significant affinity to human biglycan in vitro and a further 2.3-fold increased binding capacity was observed with glycated biglycan. Remnants were shown to colocalize with both arterial biglycan and glycated matrix proteins in the Type 1 diabetes rodent model.
  
  
  CONCLUSIONS
  Impaired metabolism of remnant lipoproteins associated with enhanced binding to proteoglycans appears to contribute to the arterial cholesterol deposition in Type 1 diabetes. Our findings support the hypothesis that impaired remnant metabolism may contribute to accelerated progression of atherosclerosis in the hyperglycaemic and insulin-deficient state.
authors.affiliation: Alberta Institute for Human Nutrition, Alberta Diabetes Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Mangat
authors.forename: J W
authors.initials: JW
authors.lastname: Su
authors.forename: J E
authors.initials: JE
authors.lastname: Lambert
authors.forename: M T
authors.initials: MT
authors.lastname: Clandinin
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: R R
authors.initials: RR
authors.lastname: Uwiera
authors.forename: J M
authors.initials: JM
authors.lastname: Forbes
authors.forename: D F
authors.initials: DF
authors.lastname: Vine
authors.forename: M E
authors.initials: ME
authors.lastname: Cooper
authors.forename: J C
authors.initials: JC
authors.lastname: Mamo
authors.forename: S D
authors.initials: SD
authors.lastname: Proctor
mesh_terms: D000818:Animals; D053283:Apolipoprotein B-48 / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D005109:Extracellular Matrix; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors
chemical_list: D053283:Apolipoprotein B-48; D015415:Biomarkers; D011509:Proteoglycans; D002784:Cholesterol