Pioglitazone attenuates fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells.
OBJECTIVE
Thiazolidinediones (TZDs), ligands for peroxisome proliferator-activated receptor gamma, are antidiabetic agents that improve hyperglycemia by decreasing insulin resistance in obese diabetic animal models and patients with type 2 diabetes. We have studied whether pioglitazone, a TZD, can exert a direct effect against pancreatic beta-cell lipoapoptosis.


METHODS
MIN6 cells were cultured in medium containing either 5.6 (low glucose) or 25 mM glucose (high glucose) in the presence or absence of 0.5 mM palmitate for 48 h. We examined the effect of 10 microM pioglitazone on MIN6 cells on glucose-stimulated insulin secretion, cellular ATP, uncoupling protein-2 (UCP-2) mRNA expression, intracellular triglyceride content, reactive oxygen species production, the number of apoptotic cells and nuclear factor-kappaB (NF-kappaB) activity.


RESULTS
Pioglitazone recovered partly impaired glucose-stimulated insulin secretion and cellular ATP in MIN6 cell exposed to high glucose with 0.5 mM palmitate. Pioglitazone suppressed intracellular triglyceride accumulation in cells exposed to high glucose with 0.5 mM palmitate. Palmitate-induced upregulation of UCP-2 mRNA levels was suppressed by pioglitazone in a dose-dependent manner. Pioglitazone decreased palmitate-induced reactive oxygen species production in MIN6 cells by 24% and in mouse islet cells by 53%. Pioglitazone also decreased palmitate-induced NF-kappaB activity by 40% and protected beta-cells from palmitate-induced apoptosis by 22% in MIN6 cell.


CONCLUSIONS
Pioglitazone attenuated fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. TZDs might be used as a mean for maintaining beta-cell survival and preserving capacity of insulin secretion in patients with diabetes mellitus.
Saitoh
Y
Y
Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki, Japan.
Chun-ping
C
C
Noma
K
K
Ueno
H
H
Mizuta
M
M
Nakazato
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D010168:Palmitates / Q000009:adverse effects; D000077205:Pioglitazone; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D045162:Thiazolidinediones / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000187:drug effects; D014280:Triglycerides / Q000037:antagonists & inhibitors
D007004:Hypoglycemic Agents; D007328:Insulin; D010168:Palmitates; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D014280:Triglycerides; D000255:Adenosine Triphosphate; D000077205:Pioglitazone