Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats

Abstract

This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.

Figure 1

Effects of JTT-501 and troglitazone on body weight and food consumption of ZDF rats. JTT-501 and troglitazone were given to ZDF rats as a food admixture for 15 weeks. Body weight (A) and food consumptions (B) were measured weekly. Each point represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).

Figure 2

Effects of JTT-501 and troglitazone on blood biochemical parameters in ZDF rats. Blood samples were taken from tail vein weekly. Serum insulin (A), serum glucose (B), blood HbA1c (C), serum triglyceride (D), and serum cholesterol (E) were measured as described in Methods. Each point represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).

Figure 3

Histopathological analysis of pancreatic islets. Haematoxylin and eosin staining (A–C) and immunohistochemical staining by insulin antibody (D–F) were performed as described in Methods. Original magnification ×320: A, D, lean; B, E, ZDF control; C, F, ZDF treated with JTT-501 (147 mg kg⁻¹ day⁻¹).

Figure 4

Histopathological analysis of lens by haematoxylin and eosin staining. Original magnification ×160: A, lean; B, ZDF control; C, ZDF treated with JTT-501 (147 mg kg⁻¹ day⁻¹).

Figure 5

Effects of JTT-501 and troglitazone on water consumption and urinary biochemical parameters in ZDF rats. After administration for 13 weeks, urine samples were taken. Water consumption (A), urine volume (B), urinary protein (C), urinary albumin (D), and urinary NAG (E) were measured as described in Methods. Each column represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).

Figure 6

Histopathological analysis of glomerulae by periodic acid-Schiff staining. Original magnification ×320: A, lean; B, ZDF control; C, ZDF treated with JTT-501 (147 mg kg⁻¹ day⁻¹).

Figure 7

Effect of JTT-501 and troglitazone on MNCV in ZDF rats. After administration for 14 weeks, the measurement MNCV was performed as described in Methods. Each column represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).

Figure 8

Effects of JTT-501 and troglitazone on BMD in ZDF rats. After administration for 15 weeks, BMC (A) and scanned area (B) were measured as described in Methods. BMD (C) was calculated by BMC dividing by scanned area. Each column represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).

Figure 9

Effects of JTT-501 and troglitazone on serum or urinary calcium, serum osteocalcin, and urinary DPD in ZDF rats. Using serum and urine samples at 13–15 weeks administration, serum calcium (A), urinary calcium (B), serum osteocalcin (C), and urinary DPD (D) were measured as described in Methods. Each column represents the mean±s.e.mean (n=8). ¶P<0.05, ¶¶P<0.01 vs lean (Student's t-test). ^*P<0.05, ^**P<0.01 vs ZDF control (ANOVA followed by Dunnett's test). †P<0.05, ††P<0.01 vs ZDF control (Student's t-test).