The prostacyclin analog beraprost sodium ameliorates characteristics of metabolic syndrome in obese Zucker (fatty) rats

Nahoko Sato, Masayuki Kaneko, Mitsutaka Tamura, Hajimu Kurumatani, Nahoko Sato, Masayuki Kaneko, Mitsutaka Tamura, Hajimu Kurumatani

Abstract

Objective: The prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications).

Research design and methods: Obese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg x kg(-1) x day(-1) b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed.

Results: BPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post-glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-beta-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS.

Conclusions: BPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.

Figures

FIG. 1.
FIG. 1.
Body weight (BW) (A), food consumption (B), serum glucose (C), insulin (D), A1C (E), TG (F), and total cholesterol (G) in control obese Zucker rats (●), obese Zucker rats treated with BPS (▵, 0.2 mg · kg−1 · day−1; ▴, 0.6), and Zucker lean rats (○) as line graph, and control obese Zucker rats (□), Zucker rats treated with BPS (▨, 0.2 mg · kg−1 · day−1; ■, 0.6), and Zucker lean rats () as bar graph. Data are mean ± SE of 7–8 rats. *P < 0.05, **P < 0.01 versus control rats by parametric Williams test (body weight, food consumption) and nonparametric Williams test (glucose, insulin, TG, and total cholesterol). #P < 0.05, ##P < 0.01 versus control by t test (body weight, food consumption) and Welch test (glucose, insulin, TG, and total cholesterol).
FIG. 2.
FIG. 2.
Time course changes in the level of serum glucose and insulin during OGTT in control obese Zucker rats (●), obese Zucker rats treated with BPS (▵, 0.2 mg · kg−1 · day−1; ▴, 0.6), and Zucker lean rats (○). Data are mean ± SE of 7–8 rats. *P < 0.05, **P < 0.01 versus control rats by nonparametric Williams test. ##P < 0.01 versus control by Welch test.
FIG. 3.
FIG. 3.
Urinary protein (A), NAG (B), systolic blood pressure (SBP) (C), and heart rate (D) in control obese Zucker rats (●), obese Zucker rats treated with BPS (▵, 0.2 mg · kg−1 · day−1; ▴, 0.6), and Zucker lean rats (○) as line graph, and control obese Zucker rats (□), Zucker rats treated with BPS (▨, 0.2 mg · kg−1 · day−1; ■, 0.6), and Zucker lean rats () as bar graph. Data are mean ± SE of 7–8 rats. *P < 0.05 versus control rats by nonparametric (NAG) and parametric (systolic blood pressure) Williams test. #P < 0.05, ##P < 0.01 versus control by Welch test.
FIG. 4.
FIG. 4.
The level of sole temperature after administration. A: Representative thermal images of each groups at 2 h after administration. B: Sole temperature at 2 h after administration in control obese Zucker rats (□) and obese Zucker rats treated with BPS (▨, 0.2 mg · kg−1 · day−1; ■, 0.6). Data are mean ± SE of four rats. *P < 0.05, versus control rats by parametric Williams test. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 5.
FIG. 5.
Photomicrographs of H-E staining of the pancreas in control obese Zucker rats, obese Zucker rats treated with high-dose of BPS, and Zucker lean rat. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 6.
FIG. 6.
Photomicrographs of H-E staining of the liver in control obese Zucker rats, obese Zucker rats treated with BPS, and Zucker lean rat (A) and quantitative analysis of vesicles in control obese Zucker rats (□) and obese Zucker rats treated with BPS (▨, 0.2 mg · kg−1 · day−1; ■, 0.6) (B). Data are mean ± SE of 7–8 rats. **P < 0.01 versus control by parametric Williams test. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 7.
FIG. 7.
Photomicrographs of H-E staining of the adipose tissues in control obese Zucker rats, obese Zucker rats treated with high-dose of BPS, and Zucker lean rat. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 8.
FIG. 8.
Photomicrographs of periodic acid Schiff staining of the kidney in control obese Zucker rats, obese Zucker rats treated with BPS, and Zucker lean rat (A) and semiquantitative analysis of glomerular (B, left) and tubular (B, right) injuries in control obese Zucker rats (□), obese Zucker rats treated with BPS (▨, 0.2 mg · kg−1 · day−1; ■, 0.6), and Zucker lean rats (). Data are mean ± SE of 7–8 rats. *P < 0.05, **P < 0.01 versus control by nonparametric Williams test. ##P < 0.01 versus control by Wilcoxon test. (A high-quality digital representation of this figure is available in the online issue.)

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