title: Thiazolidinediones protect mouse pancreatic β-cells directly from cytokine-induced cytotoxicity through PPARγ-dependent mechanisms.
abstract: Since most of the current studies of thiazolidinediones (TZDs) are only focused on improving glycemic control, increasing insulin sensitivity, and regulating inflammatory states in Type 2 Diabetes, it is still controversial whether TZDs have direct, protective effects on pancreatic β-cells in autoimmune diabetes. Here, we show the protective effects of TZDs on mouse pancreatic β-cell line cells (NIT-1) impaired by exposure to inflammatory cytokines (IL-1β and IFN-γ) and explore the potential mechanisms for this. The apoptosis rate and caspase-3 activity were remarkably increased, and insulin secretion response to glucose was impaired severely by exposure to IL-1β/IFN-γ for 48 h compared to control cells, whereas apoptosis rate and caspase-3 activity were significantly decreased in cells with treatment of rosiglitazone (RGZ) or pioglitazone (PIG), and the capacity for insulin secretion response to glucose was recovered. TZDs protect pancreatic β-cells from cytokine-induced cytotoxicity through PPARγ activation. The protective effects of the TZDs on NIT-1 cells disappeared when PPARγ was blocked with PPARγ-siRNA interference or treatment with GW9662, the PPARγ antagonist. Additionally, the enhancement of PPARγ expression by treatment with TZDs inhibited the expression of caspase 3 in IL-1β/IFN-γ-induced NIT-cells. Also, the inhibition of caspase 3 expression by TZDs was blocked by co-treatment with GW9662 or infection with PPARγ-siRNA. Taken together, our data suggest that TZDs might serve to protect pancreatic β-cells directly from cytokine-induced cytotoxicity through a PPARγ-dependent pathway, and caspase-3 may play an important role in the mechanisms involved.
authors.affiliation: Diabetes Center, Metabolic Syndrome Research Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: An-ping
authors.initials: AP
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Bi-lian
authors.initials: BL
authors.lastname: Liu
authors.forename: Gan
authors.initials: G
authors.lastname: Huang
authors.forename: Xiang
authors.initials: X
authors.lastname: Yan
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000502:physiology; D061945:Caspase Inhibitors / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
chemical_list: D061945:Caspase Inhibitors; D016207:Cytokines; D007328:Insulin; D053583:Interleukin-1beta; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D007371:Interferon-gamma; D053148:Caspase 3; D005947:Glucose