Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice

Diabetes and Endocrine Division, Kawasaki Medical School, Kurashiki-shi, Okayama, Japan Submitted 17 March 2004 ; accepted in final form 1 November 2004 To evaluate preventive effects of pioglitazone on pancreatic -cell damage in C57BL/KsJ db / db mice, an obese diabetic animal model, the pancreatic islets were compared morphologically between pioglitazone-treated (100 mg/kg daily po) and untreated db/db mice ( n = 7 for each) after a 12-wk intervention (6–18 wk of age). The fasting blood glucose level was significantly improved by the treatment with pioglitazone (260 ± 12 vs. 554 ± 62 mg/dl, P < 0.05). The islet mass in the pancreas was significantly greater in pioglitazone-treated mice than in untreated mice (10.2 ± 1.1 vs. 4.6 ± 0.2 mg, P < 0.01). Subsequently, biochemical and physiological analyses of the -cell function were employed using pioglitazone-treated and untreated db/db mice ( n = 6 for each) and pioglitazone-treated and untreated db/+ mice ( n = 6 for each). After 2 wk of treatment (10–12 wk of age), the plasma levels of triglyceride and free fatty acid were significantly decreased, whereas the plasma adiponectin level increased significantly compared with the untreated group (65.2 ± 18.0 vs. 18.3 ± 1.3 µg/ml, P < 0.05). Pioglitazone significantly reduced the triglyceride content in the islets (43.3 ± 3.6 vs. 65.6 ± 7.6 ng/islet, P < 0.05) with improved glucose-stimulated insulin secretion. Pioglitazone showed no significant effects on the biochemical and physiological parameters in db/+ mice. The present study first demonstrated that pioglitazone prevents -cell damage in an early stage of the disease progression in db/db mice morphologically and physiologically. Our results suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the pancreatic islets. pancreatic -cells; adiponectin; type 2 diabetes mellitus Address for reprint requests and other correspondence: K. Kaku, Diabetes and Endocrine Division, Dept. of Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama-ken 701-0192, Japan (E-mail: kkaku{at}med.kawasaki-m.ac.jp )