We recently identified fibulin-1-mRNA as the most upregulated transcript in non-atherosclerotic arterial tissue from patients with type 2 diabetes. Fibulin-1 is an elastin- and basement membrane-associated extracellular matrix protein also present in plasma. In addition, we observed higher amounts of fibulin-1-protein in the arterial wall and in the circulation among patients with diabetes. Moreover, we showed an association between increased levels of plasma fibulin-1 and arterial stiffness and demonstrated independent mortality-predictive abilities of plasma fibulin-1 in type 2 diabetes. These published results suggest that fibulin-1 is involved in the development of arterial disease in type 2 diabetes and that the circulating levels may serve as a biomarker for diabetic arteriopathy.

Metformin is an anti-diabetic drug with documented beneficial CVD effects in diabetes. The explanation may include direct, but unknown, effects of metformin on the arterial wall. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes.

The study is an investigator driven, prospective, randomized, and partly placebo controlled trial with 450 type 2 diabetic patients. After a four week run-in period, 371 eligible patients were randomized to one of eight treatment groups in a factorial design with NPH insulin vs. insulin aspart, metformin vs. placebo, or rosiglitazone vs. placebo. Plasma fibulin-1 was analyzed by an ELISA (in house, previously described) and HbA1c by HPLC (TOSOH) at the beginning of the study and after 18 and 24 months.

Plasma fibulin-1 increased in all groups throughout the two-year period; however, the increase was strongly reduced among patients treated with metformin. A highly significant difference was observed, when the mean change in plasma fibulin-1 was compared between metformin and not-metformin treated individuals both at 18 and 24 months of treatment (p<0.001). No such difference was seen when the rosiglitazone treated group was compared to the non-rosiglitazone treated group. Both metformin and rosiglitazone reduced the HbA1c levels to comparable levels. There was no correlation between changes in plasma fibulin-1 and changes in HbA1c.

Metformin treatment reduces plasma fibulin-1 concentrations among patients with type 2 diabetes, an effect which is independent of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy, which can be influenced by metformin.