Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist.
Pioglitazone preserves pancreatic beta-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects beta-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved beta-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves beta-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).
Kanda
Yukiko
Y
Diabetes and Endocrine Division, Kawasaki Medical School, Kurashiki, Japan.
Shimoda
Masashi
M
Hamamoto
Sumiko
S
Tawaramoto
Kazuhito
K
Kawasaki
Fumiko
F
Hashiramoto
Mitsuru
M
Nakashima
Koji
K
Matsuki
Michihiro
M
Kaku
Kohei
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone