Hyperglycemia and Hyperinsulinemia Increase Circulating Tissue Factor Activity in Human Subjects.

Abstract Patients with diabetes mellitus (DM) have increased atherosclerotic and acute vascular events, and both hyperglycemia and hyperinsulinemia are independent risk factors for increased mortality. To evaluate the effects of hyperglycemia and hyperinsulinemia on the tissue factor (TF) pathway, we studied 3 groups of healthy individuals. Group A(Euglycemia and Hyperinsulinemia): 7 subjects were infused for 24h with insulin to maintain serum insulin levels at ~ 1000 pmol/l and with glucose at variable rates to maintain at 5.6 mmol/l (~ 100 mg/dl). Group B (Hyperglycemia and Hyperinsulinemia): 7 subjects were infused with glucose to maintain levels at ~ 11 mmol/l (~ 200 mg/dl) for 24 h. Group C(Euglycemia and Euinsulinemia): 4 subjects received saline for 24 h. Glucose was maintained at ~ 5.6 mmol/l with variable, small glucose infusions. Blood samples collected every 6 h. We assessed TF procoagulant activity (TF-PCA) in whole blood by clotting assay (Key et al, Blood1998; 91: 4216), and plasma levels of activated factor VII (FVIIa), FVII activity (FVIIC), FVIII coagulant activity (FVIIIC), and thrombin-antithrombin (TAT) complexes. TF-PCA levels increased significantly from basal levels of 14 ± 1 and 20 ± 3 U/ml (mean±SE) to 79 ± 4 and 172 ± 6 U/ml at 24 h in Groups A and B, respectively. There was no increase in Group C. Groups TFPCA (U/ml) FVIIa (mU/ml) FVIIC (U/ml) FVIIIC (U/ml) Shown mean±SE;†p<0.05;*p<0.001:Analysis of variance; comparison 0 to 24 hrs. 0 hr/24 hr 0 hr/24 hr 0 hr/24 hr 0 hr/ 24 hr A)Euglycemia - Hyperinsulinemia(n=7) 14 ± 1 / 79 ± 4* 83 ± 9 / 45 ± 8* 0.88 ± 0.09 / 0.72 ± 0.08* 0.93 ± 0.05 / 0.98 ± 0.06† B)Hyperglycemia -HyperInsulinemia(n=7) 20 ± 1 / 172 ± 6* 85 ± 10 / 52 ± 6* 1.02 ± 0.1 / 0.84 ± 0.1* 1.03± 0.04 / 1.28 ± 0.07* C)Euglycemia and Euinsulinemia (n=4) 19 ± 2 / 19 ± 1 56 ± 13 / 55 ± 14 0.83 ± 0.05 / 0.81 ± 0.08 0.86± 0.08 / 0.85 ± 0.08 By flow cytometry, percentage of monocytes expressing TF (Groups A and B combined) increased from 19.5 ± 4.2% at 0 h to 25.2 ± 4.4 % at 24 h (p = 0.03). Plasma FVIIa and FVIIC were significantly decreased, and plasma FVIIIC increased at 24 h in Groups A and B. There was an inverse relationship between plasma FVIIa and TF-PCA (Group A r = −0.51; Group B r = −0.51, p =0.002). Plasma FVIII levels correlated with TF-PCA in Group B (r = 0.48, p = 0.003). At 18 h, TAT levels increased from 13.4 ± 8 and 6.8 ± 2.5 to 46.9 ± 6.2 (p = 0.04) and 39.4 ± 6.7 μg/l (p=0.015) in Group A and B, respectively. No changes were noted in any measurements in Group C. Conclusions: Both hyperinsulinemia (Group A) alone and hyperglycemia with hyperinsulinemia (Group B) induce an increase in circulating TF-PCA, which is greater with the combination. This is associated with a decline in FVIIa and FVIIC, and increase in FVIIIC. We postulate that the decrease in FVIIa and FVIIC reflects enhanced binding of FVII to cellular TF. These studies provide evidence for enhanced expression of circulating TF by hyperglycemia and hyperinsulinemia even in healthy individuals. This increase may contribute to acute vascular events in DM patients.