Thiazolidinediones, insulin sensitizers, are widely used for the treatment of insulin resistance in type 2 diabetic patients. One of the adverse effects is fluid retention. We evaluated the effect of pioglitazone, a thiazolidinedione, on plasma vascular endothelial growth factor (VEGF) in comparison with that of metformin in type 2 diabetic patients. A 4-week administration of pioglitazone significantly increased plasma VEGF levels, whereas levels were unchanged by metformin. The results suggest that thiazolidinediones may increase plasma VEGF levels, possibly one of the causes of the drug-induced fluid retention and edema. Type 2 diabetes is characterized by fasting hyperglycemia caused by increased insulin resistance with or without decreased insulin secretion (1). Appropriate weight reduction and physical exercise in obese type 2 diabetic patients are useful in reducing the insulin resistance in these patients. Thiazolidinediones are a widely used class of drugs for the treatment of insulin resistance in type 2 diabetic patients (2). Two of the known adverse effects of this class are fluid retention and edema (2), especially in female patients. The pathogenic mechanism(s) behind the fluid retention is not yet clear.
VEGF is a cytokine that acts as an endothelial cell mitogen and also induces microvascular permeability (3), thus named a vascular permeability factor (VPF). Recent findings in in vivo studies suggest that thiazolidinediones may increase VEGF production (4,5). Therefore, we studied the effect of pioglitazone, a potent thiazolidinedione, on plasma VEGF levels in type 2 diabetic patients to elucidate whether a clinical dose of thiazolidinediones would increase VEGF secretion in diabetic patients. The effect was compared with that of metformin, another class of drug that is known to improve insulin resistance in type 2 diabetic patients (6). The study was approved by the Ethical Committee of Fukushima Medical University.
A total of 16 type 2 diabetic patients with normal kidney function (serum creatinine level <100 μmol/l) and an elevated HbA1c level (>7.5%), despite on-going diabetic treatment, participated in the study after informed consent was given (3 men and 13 women, mean age 52 years [range 30–75], and known diabetes duration 13 years [5–21]). The patients were randomly allocated to receive either pioglitazone (15 mg once daily) or metformin (500 mg twice daily) for 4 weeks. Blood samples for the measurement of plasma VEGF were obtained from each patient before and after the 4-week administration of pioglitazone or metformin. The plasma VEGF level was determined by using a commercial enzyme-linked immunosorbent assay kit (Quantikine Human VEGF Immunoassay; R&D System). Comparison of the values between the two treatment groups and the values before and after each treatment was made by Wilcoxon’s rank-sum and signed-rank tests, respectively.
The plasma VEGF level increased significantly with the administration of pioglitazone (from 33 pg/ml [3–81] to 180 pg/ml [22–430], P = 0.0117; n = 7), whereas the level remained unchanged with metformin (from 47 pg/ml [12–80] to 25 pg/ml [4–82]; n = 9). The posttreatment VEGF level was significantly higher in the pioglitazone group than in the metformin group (P = 0.0070). The result is summarized in Fig. 1.
This preliminary observation suggests that pioglitazone may increase plasma VEGF levels. The assumption can be further supported by recent experimental findings that troglitazone, a thiazolidinedione, increased VEGF secretion and VEGF mRNA levels in vascular smooth muscle cells (4) and adipocytes (5) in a time- and dose-dependent manner. The results seem to be consistent with a clinical observation that troglitazone-treated patients had higher VEGF levels compared with those treated with diet alone, sulfonylurea, or insulin (5).
Our study implies the possibility that VEGF may have some role in developing thiazolidinedione-induced edema and fluid retention in type 2 diabetic patients. Meanwhile, VEGF is likely to contribute to the development and progression of diabetic retinopathy (7). Nevertheless, we do not yet know whether pioglitazone-induced increases in plasma VEGF adversely influence existing diabetic retinopathy (7) and nephropathy (8) or whether these increases can be useful for therapeutic angiogenesis for ischemic artery disease (4), which is often seen in type 2 diabetic patients. However, the possibility that VEGF is a potential tumor angiogenesis factor in human tumors (9) must be taken into account. For clarification, these speculations may deserve further study.
VEGF levels before and after 4-week treatment with metformin (500 mg/day) (□) and pioglitazone (15 mg/day) (▪). Plasma VEGF after pioglitazone administration was significantly higher than its basal level (P = 0.0117) and the value after metformin treatment (P = 0.0070), respectively. Data are medians, 75th and 90th percentiles.
VEGF levels before and after 4-week treatment with metformin (500 mg/day) (□) and pioglitazone (15 mg/day) (▪). Plasma VEGF after pioglitazone administration was significantly higher than its basal level (P = 0.0117) and the value after metformin treatment (P = 0.0070), respectively. Data are medians, 75th and 90th percentiles.
References
Address correspondence to Dr. T. Baba, Internal Medicine 3, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. E-mail: [email protected].
