Stimulation in vivo of expression of intra-abdominal adipose tissue plasminogen activator inhibitor Type I by proinsulin.
OBJECTIVE
Impaired fibrinolytic system capacity secondary to increased plasminogen activator inhibitor type-1 expression has been suggested as a pathogenetic link between insulin resistance and increased cardiovascular risk in patients with Type II (non-insulin-dependent) diabetes mellitus, obesity, or both. In patients with syndromes of insulin resistance including those with Type II diabetes, precursors of insulin such as proinsulin can constitute more than 50% of insulin-like molecules in blood. The aim of this study was to determine whether proinsulin can increase plasminogen activator inhibitor type-1 expression in intra-abdominal adipose tissue in vivo, potentially contributing to the increased PAI-1 seen with insulin resistance.


METHODS
Lightly sedated normal rabbits were given intravenous proinsulin, insulin, or vehicle alone under euglycaemic clamp conditions with serial sampling of blood and assessment of PAI-1 expression in visceral fat.


RESULTS
Both proinsulin and insulin increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue, 5.3-fold (p = 0.006 vs control) and 2.5-fold (p = 0.031 vs control) respectively. PAI-1 inhibitor activity in blood peaked 3 h after administration of each, 5.1-fold, p = 0.020, and 3.4-fold, p = 0.004, respectively but did not change under control conditions.


CONCLUSIONS
Hyperproinsulinaemia can contribute to increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue implicated in increasing PAI-1 activity in blood, impaired fibrinolysis, and accelerated atherogenesis typical of Type II diabetes.
Nordt
T K
TK
Department of Cardiology, University of Freiburg, Germany.
Bode
C
C
Sobel
B E
BE
D000005:Abdomen; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011384:Proinsulin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits
D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011384:Proinsulin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases