Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene.
Plasminogen activator inhibitor 1 (PAI-1) activity is increased in patients with non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to their excess risk of cardiovascular disease. We examined the determinants of PAI-1 activity in 146 NIDDM subjects by using specific assays of insulin and intact and des-31,32-proinsulin and measures of insulin resistance, relating these measurements to serum lipids, hypoglycemic therapy, and a common 4G/5G polymorphism in the promoter region of the PAI-1 gene. Subjects were treated with insulin, sulfonylurea, sulfonylurea plus metformin, metformin, and diet alone. In the whole group, PAI-1 activity correlated significantly with serum triglycerides (r = 0.39, P < 0.001), specific insulin (r = 0.29, P < 0.001), intact proinsulin (r = 0.24, P = 0.004), and des-31,32-proinsulin (r = 0.30, P < 0.001) and in subjects not on insulin (n = 110), with insulin sensitivity (r = -0.42, P < 0.001). There was a significant difference in PAI-1 activity among the three genotypic groups (P = 0.016); subjects with the genotype 4G/4G had PAI-1 levels one-third higher than those with the 5G/5G genotype. In the 4G/4G group, PAI-1 activity correlated significantly with triglyceride levels (r = 0.65, P < 0.0001). There was no significant difference in PAI-1 activity in the different treatment groups despite a significant difference in concentrations of intact and des-31,32-proinsulin. In a multiple regression model, insulin sensitivity and the interaction between PAI-1 4G/5G genotype and triglyceride were the strongest determinants of PAI-1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Panahloo
A
A
Department of Medicine, University College London Medical School, Whittington Hospital, U.K.
Mohamed-Ali
V
V
Lane
A
A
Green
F
F
Humphries
S E
SE
Yudkin
J S
JS
D000328:Adult; D000368:Aged; D001483:Base Sequence; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012044:Regression Analysis; D014280:Triglycerides / Q000097:blood
D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides