A Novel Serotonin Blocker, Sarpogrelate, Increases Circulating Adiponectin Levels in Diabetic Patients With Arteriosclerosis Obliterans

The recent article by Tsunekawa et al. (1) demonstrates that adiponectin plays an important role in improving insulin resistance. Inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), are associated with the risk of development of arteriosclerosis among both diabetic and nondiabetic patients (2).

Low plasma adiponectin concentrations were clinically observed in patients with type 2 diabetes (3). These findings suggest that adiponectin might have anti-inflammatory properties and might act as an endogenous modulator for the development of obesity-related diseases.

Serotonin is a naturally occurring vasoactive substance and has also been involved with vascular inflammation leading to the atherosclerosis (4). Sarpogrelate hydrochloride is a serotonin 2A receptor antagonist and is clinically used for the cutaneous ulcer and ischemic change resulting from the arteriosclerosis.

Cryesthesia was defined as a feeling of cold in the feet and toes. We examined the grade (0–10) of cryesthesia by using a visual analog scale (5) and measured circulating adiponectin, high-sensitive CRP (hsCRP), IL-6, and lipid protein concentrations in eight diabetic patients with arteriosclerosis obliterans (ASO), who received a 3-month treatment course of a selective serotonin 2A receptor antagonist and sarpogrelate hydrochloride (100 mg three times a day). The changes in cryesthesia were considered the clinical outcome for the diabetic patients with ASO. Insulin resistance was evaluated by homeostasis model assessment = fasting insulin (μU/ml) × glucose (mmol/l)/22.5, as described elsewhere (6). Their mean ± SD age was 64 ± 13 years, and the male-to-female ratio was three to one. Informed consent for participation was obtained from each individual. Written informed consent was obtained from all subjects. Sarpogrelate hydrochloride was supplied by Mitsubishi Pharma (Osaka, Japan). Blood samples were taken for all the enrolled individuals at baseline, 2 weeks, 1 month, 2 months, and 3 months after sarpogrelate hydrochloride treatment. Plasma adiponectin concentrations were determined with a radioimmunoassay kit according to the manufacturer’s instructions (Linco Research, St. Charles, MO). Circulating IL-6 levels were measured by an enzyme-linked immunosorbent assay kit according to the manufacturer’s guidelines (Amersham International, Tokyo, Japan). The concentrations of hsCRP and lipid proteins, including triglyceride, total cholesterol, and HDL cholesterol, were also examined with a standard method.

Data are expressed as means ± SD. The association between the baseline and the changes after sarpogrelate hydrochloride treatment were analyzed by the one-tailed ANOVA. A P value <0.05 was considered statistically significant.

Significantly decreased scales of cryesthesia in the lower extremities were observed in this study (0.7 ± 1.1 at 1 month vs. 10 ± 0 at baseline). Circulating adiponectin concentrations were significantly increased at the 2- and 3-month treatment courses after the sarpogrelate hydrochloride start (36.2 ± 10.8 and 34.5 ± 11.1 vs. 13.4 ± 9.8 μg/ml). The significant lower hsCRP values were found at 2 weeks, 1 month, and 3 months after the treatment (0.02 ± 0.01, 0.03 ± 0.03, and 0.03 ± 0.02 vs. 0.20 ± 0.13 mg/dl), whereas the IL-6 levels in blood were not significantly changed during the treatment course. The concentrations of lipid proteins, including triglyceride, total cholesterol, and HDL cholesterol, were not also significantly altered during the treatment. We found the decreased insulin resistance associated with the increase of adiponectin levels (4.5 ± 1.9 at 3 months vs. 15.8 ± 2.9 at baseline).

Sarpogrelate hydrochloride has recently been reported to be effective against diabetic nephropathy through the reduction of serotonin binding (7).

Plasma adiponectin concentrations were significantly increased in diabetic patients with ASO at 2 and 3 months after the sarpogrelate hydrochloride start, and the significant lower hsCRP values were found at 2 weeks, 1 month, and 3 months during the treatment. Our results suggest that sarpogrelate hydrochloride treatment might contribute to the inhibition of progression of ASO in diabetic patients.