Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

Abstract

OBJECTIVEThe extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes (T2D) and circulates in increased concentrations in diabetes. Metformin is an antidiabetic drug with beneficial cardiovascular disease effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. RESEARCH DESIGN AND METHODSAfter a 4-week run-in period, 371 eligible patients with T2D were randomized to treatment groups in a factorial design including insulin alone (control), +metfor-min, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. RESULTSPlasma fibulin-1 increased in all groups throughout the 2-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed when the mean change in plasma fibulin-1 was compared between metformin-and non-metformin-treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA 1c levels to comparable levels and in combination even further. CONCLUSIONSMetformin attenuates the increase in plasma fibulin-1 concentrations in T2D, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy that can be influenced by metformin. Increased mortality and morbidity owing to a higher incidence of cardiovascular diseases (CVDs) is a major clinical challenge in type 2 diabetes (T2D) (1,2). Several studies have demonstrated that management of hypertension, LDL cholesterol, and other major CVD risk factors have reduced micro-and macrovascular complications in patients with T2D; however, optimal risk reduction is still not achieved when these important risk factors are controlled, indicating that further attempts are needed to control the CVD risk burden (3-5). One assumption is that improvement

Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries From Patients With Type 2 Diabetes Mellitus and Lower Levels Among Metformin Users

“…A more detailed insight into the interaction between DM, metformin, and collagens will, however, have to await further studies. Nevertheless, the present results fit well to recent observations in a randomized study, where metformin reduced plasma concentrations of the basement membrane protein fibulin-1 independent of glycemia, 23 strongly suggesting that the use of metformin exerts effects in pathways directly involved in vascular matrix production. This notion is moreover compatible with recent experimental results showing that AMPkinase (activated by metformin) is reduced in kidney tissue in experimental DM and that activation of the enzyme (with AICAAR) normalizes matrix accumulation and albuminuria.…”

“…22 In addition, we have, in a randomized study, shown that plasma levels of the basement membrane protein fibulin-1 are reduced by metformin, unrelated to the glycemic control. 23 In relation to the development of diabetic complications, it is also of interest that a study recently showed that mitochondrial dysfunction and reduced activated protein kinase (AMPK) activity in DM are involved in the development of matrix accumulation and proteinuria as part of the diabetic kidney complications and that the kidney damage was corrected by another AMPK stimulator, that is, 5-Aminoimidazole-4-carboxamide ribonucleotide. 24 Thus, it can be hypothesized that metformin through AMPK activation may exert beneficial effects on matrix accumulation as part of diabetic vascular complications.…”

Galectin-3 and fibulin-1 in systolic heart failure - relation to glucose metabolism and left ventricular contractile reserve

“…The mean fibulin-1 level in our HF population was 57 ± 16 μg/mL, which is slightly higher than the mean level observed in a DM population (46 ± 1.3 μg/mL [19]). Fibulin-1 is a novel biomarker and high concentrations have primarily been reported in patients with aortic stenosis and DM compared to a level of 5.6 (4.1–8.4) μg/mL reported in healthy men [11, 20, 21].…”

Serum and Vitreous Fibulin-1 Concentrations in Patients with Diabetic Retinopathy

“…Scholze et al 's investigation indicated that diabetes was an independent predictor of plasma fibulin-1 after a multivariable regression model. Skov et al 13 reported that plasma fibulin-1 was elevated in diabetic patients during the 2-year follow-up. And metformin treatment markedly reduced plasma fibulin-1 concentrations in those diabetic patients 13.…”