title: The orphan nuclear receptor small heterodimer partner negatively regulates pancreatic beta cell survival and hyperglycemia in multiple low-dose streptozotocin-induced type 1 diabetic mice.
abstract: The small heterodimer partner (SHP; NR0B2) regulates the transcription of a variety of target genes and controls a variety of physiological functions in various tissues. However, the role of SHP in beta cell has not been fully determined yet. We used SHP knockout (SHP KO) mice to investigate the role of SHP in multiple low-dose streptozotocin (MLDS)-induced diabetes. Blood glucose and insulin levels were measured until 20 days, and intraperitoneal glucose tolerance and glucose-stimulated insulin secretion tests were performed. The expression of apoptotic genes and beta cell markers were detected by quantitative realtime-polymerase chain reaction, immunostaining and western blot analysis. SHP KO mice showed significantly lower blood glucose, higher insulin levels, and enhanced glucose tolerance compared with wild type (WT) mice after MLDS treatment. Moreover, beta cell mass and pancreatic insulin content were remarkably increased in SHP KO mice. In the response to glucose stimulation, islets of SHP KO showed increased insulin secretion via up-regulation of beta cell enriched transcription factors compared to WT mice after streptozotocin (STZ) treatment. In quantification for beta cell apoptosis at day 1 post STZ treatment, the SHP KO mice showed significantly increased anti-apoptotic gene expression and decreased release of apoptotic markers cytochrome c, smac/diablo, and only a few apoptotic beta cells were found in SHP KO pancreas through inactivation of caspase-3, compared to those of WT. These data demonstrate that SHP deficiency ameliorates hyperglycemia and preserves islet function by inhibiting apoptosis of pancreatic beta cells and up-regulating of their enriched transcriptional factors.
authors.affiliation: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon 305-806, Republic of Korea.
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051028:bcl-2-Associated X Protein; C099713:nuclear receptor subfamily 0, group B, member 2; D013311:Streptozocin; D053148:Caspase 3
keywords: Beta cell apoptosis; Diabetes; GSIS; Insulin; PDX-1; SHP; STZ; Small heterodimer partner; Streptozotocin; glucose-stimulated insulin secretion; pancreatic duodenal homeobox factor 1; small heterodimer partner; streptozotocin