Pioglitazone improves insulin secretory capacity and prevents the loss of β-cell mass in obese diabetic db/db mice: possible protection of β cells from oxidative stress

• Published in: Metabolism, clinical and experimental clinical and experimental, 2004-04, Vol.53 (4), p.488-494
• Main Authors: Ishida, Hitoshi, Takizawa, Makoto, Ozawa, Sachihiko, Nakamichi, Yoko, Yamaguchi, Shinya, Katsuta, Hidenori, Tanaka, Toshiaki, Maruyama, Masahiro, Katahira, Hiroshi, Yoshimoto, Katsuhiko, Itagaki, Eiji, Nagamatsu, Shinya
• Format: Article
• Language: English
• Subjects: Aldehydes - metabolism; Animals; Biological and medical sciences; Blood Glucose - analysis; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - metabolism; Glucose - pharmacology; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Hemostatics; Hypoglycemic Agents - pharmacology; Immunohistochemistry; Insulin - blood; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - pathology; Islets of Langerhans - physiology; Islets of Langerhans - ultrastructure; Male; Medical sciences; Membrane Proteins; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Obesity - blood; Obesity - metabolism; Obesity - pathology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pioglitazone; Thiazolidinediones - pharmacology; Triglycerides - blood
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2003.11.021

In order to assess the beneficial effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on reduction of mass and alteration of function of pancreatic β cells under diabetic conditions, diabetic C57BL/KsJ db/db mice were treated with pioglitazone for 6 weeks, and insulin secretory capacity and insulin content of isolated pancreatic islets were evaluated. In addition, the expression of oxidative stress markers, 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1, in endocrine pancreas was examined to measure reduction of oxidative stress in pancreatic β cells. The capacity for glucose-induced insulin secretion from isolated islets and their insulin content were improved by pioglitazone treatment ( P < .01). When β cells were stained with anti-insulin antibodies, those of db/db mice treated with pioglitazone exhibited strong staining, as also observed in their lean littermates. The density of immunostaining for oxidative stress markers was significantly reduced in pancreatic islets of pioglitazone-treated db/db mice ( P < .05). This study clearly demonstrates the benefit of long-term treatment with pioglitazone in decreasing hyperglycemia and improving glucose-induced insulin secretory capacity in diabetic db/db mice. The results of immunocytochemical examination suggest that this treatment reduces oxidative stress and thereby preserves β-cell mass. Treatment with pioglitazone thus protects against β-cell damage and would be useful for restoration of insulin secretory capacity in obese diabetes individuals.