The effect of blood glucose control on fibrin network characteristics of African subjects with uncontrolled type 2 diabetes

Abstract

Type 2 diabetes is a growing health problem worldwide. People affected face increased cardiovascular (CVD) disease risk. Cardiovascular disease is a recognised leading cause of mortality among people with type 2 diabetes. It is suspected that alterations in fibrin network structure may, in part, contribute to the increased CVD risk. A possible mechanism contributing to the altered fibrin network structure is the non-enzymatic glycation of fibrinogen due to continuous exposure to high glucose levels in the diabetic condition. Twenty Black South Africans with uncontrolled type 2 diabetes were recruited for the study and 20 age and BMI matched non-diabetic volunteers were included as a reference group. The diabetic volunteers were treated with insulin under outpatient conditions to control both fasting and post-prandial glucose in order to determine if glycaemic control would reduce fibrinogen glycation and improve fibrin network structure. Blood samples of the diabetic volunteers were drawn at the beginning and the end of the study once glycaemic control was achieved and maintained for a further 8-day period. Blood samples were collected from the non-diabetic volunteers who underwent no intervention at times comparable to those of the matched diabetic volunteers. Fibrin network structure variables were measured both in plasma and in fibrinogen purified from the volunteers' plasma. The purified fibrinogen results would indicate the individual effects of fibrinogen glycation, while the plasma results would indicate the contribution of the effect of fibrinogen glycation on fibrin network structure in the presence of other plasma constituents. There was no difference in fibrinogen concentration between the two groups (4.25 vs 4.02 g/l, respectively) and the fibrinogen concentrations were higher than expected for the population group. The uncontrolled diabetic volunteers at baseline had higher fibrinogen glycation than the non-diabetic volunteers (7.84 vs 3.89 mol glucose/mol fibrinogen, respectively; p=0.0002). Fibrinogen glycation in the diabetic volunteers was significantly reduced with achievement of glycaemic control (7.84 to 5.24 mol glucose/mol fibrinogen; p=0.0007). In the purified fibrinogen model, permeability improved in the diabetic group after achievement of glycaemic control (p=0.02). The rate of lateral aggregation (slope) for the diabetic volunteers was higher than for non-diabetic volunteers at baseline. The slope correlated positively with fibrinogen glycation (r=0.47; p=0.01) and glycaemic control measured by HbA1c (r=0.59; p=0.001) and venous glucose (r=0.51; p=0.005). In the plasma model, clot rigidity (p=0.013) and time taken for the proto-fibrils to reach a sufficient length for lateral aggregation to take place (lag-time) (p=0.03) increased, in the diabetic group, with glycaemic control. None of the fibrin network structure variables correlated with glycaemic control or fibrinogen glycation. Permeability, slope and fibre size did however, correlate with fibrinogen concentration. Fibrinogen glycation was reduced by glycaemic control resulting in alterations to fibrin network structure. From the purified fibrinogen model, reduction in fibrinogen glycation resulted in an improvement in clot permeability, but when other plasma constituents were introduced, in the plasma model, these effects were obscured. The high fibrinogen concentrations that prevailed in the study population may have masked the effect of fibrinogen glycation in the plasma model. Having done this intervention under out-patient conditions makes these results applicable to the general diabetic population.