Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10738472 | Free Radical Biology and Medicine | 2011 | 9 Pages |
Abstract
Metallothioneins (MTs) are intracellular low-molecular-weight, cysteine-rich proteins with potent metal-binding and redox functions, but with limited membrane permeativity. The aim of this study was to investigate whether we could enhance delivery of MT-1 to pancreatic islets or β cells in vitro and in vivo. The second goal was to determine whether increased MT-1 could prevent cellular toxicity induced by high glucose and free fatty acids in vitro (glucolipotoxicity) and ameliorate the development of diabetes induced by streptozotocin in mice or delay the development of diabetes by improving insulin secretion and resistance in the OLETF rat model of type 2 diabetes. Expression of HIV-1 Tat-MT-1 enabled efficient delivery of MT into both INS-1 cells and rat islets. Intracellular MT activity increased in parallel with the amount of protein delivered to cells. The formation of reactive oxygen species, glucolipotoxicity, and DNA fragmentation due to streptozotocin decreased after treating pancreatic β cells with Tat-MT in vitro. Importantly, in vivo, intraperitoneal injection resulted in delivery of the Tat-MT protein to the pancreas as well as liver, muscle, and white adipose tissues. Multiple injections increased radical-scavenging activity, decreased apoptosis, and reduced endoplasmic reticulum stress in the pancreas. Treatment with Tat-MT fusion protein delayed the development of diabetes in streptozotocin-induced mice and improved insulin secretion and resistance in OLETF rats. These results suggest that in vivo transduction of Tat-MT may offer a new strategy to protect pancreatic β cells from glucolipotoxicity, may improve insulin resistance in type 2 diabetes, and may have a protective effect in preventing islet destruction in type 1 diabetes.
Keywords
transactivator of transcriptionNF-κBATF6eIF2αXBP1GFPIRE1T2DHOMA-IRSTZ3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideHOMA-βMTTROSER stressstreptozotocinTATInsulin secretionOxidative stressCHOPDiabetes mellitusType 2 diabetes mellitusFree radicalseukaryotic initiation factor 2αactivating transcription factor 6MetallothioneinInsulin resistanceHIV-1Human immunodeficiency virus type 1X-box-binding protein 1green fluorescent proteinCCAAT/enhancer-binding protein homologous proteinReactive oxygen species
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Authors
Leejin Park, Dongsoo Min, Hyunok Kim, Hee-Yong Chung, Chul-Hoon Lee, In-Sun Park, Yonghee Kim, Yongsoo Park,