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.
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.
Ishida
Hitoshi
H
Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
Takizawa
Makoto
M
Ozawa
Sachihiko
S
Nakamichi
Yoko
Y
Yamaguchi
Shinya
S
Katsuta
Hidenori
H
Tanaka
Toshiaki
T
Maruyama
Masahiro
M
Katahira
Hiroshi
H
Yoshimoto
Katsuhiko
K
Itagaki
Eiji
E
Nagamatsu
Shinya
S
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
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