title: Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress.
abstract: In order to assess the beneficial effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone on reduction of mass and alteration of function of pancreatic beta 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 beta cells. The capacity for glucose-induced insulin secretion from isolated islets and their insulin content were improved by pioglitazone treatment (P <.01). When beta 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 beta-cell mass. Treatment with pioglitazone thus protects against beta-cell damage and would be useful for restoration of insulin secretory capacity in obese diabetes individuals.
authors.affiliation: Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishida
authors.forename: Makoto
authors.initials: M
authors.lastname: Takizawa
authors.forename: Sachihiko
authors.initials: S
authors.lastname: Ozawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Katsuta
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maruyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katahira
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Itagaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006490:Hemostatics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000097:blood / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D000447:Aldehydes; D001786:Blood Glucose; D006490:Hemostatics; D007004:Hypoglycemic Agents; D007328:Insulin; D008565:Membrane Proteins; D045162:Thiazolidinediones; D014280:Triglycerides; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D005947:Glucose; C027576:4-hydroxy-2-nonenal; D000077205:Pioglitazone