ER stress에 의한 당뇨병 발병연구

초록

Purpose : The cluster of pathologies known as metabolic syndrome, including obesity, insulin resistance and type 2 diabetes has become one of the most serious threats to human health. However, understanding the molecular mechanisms underlying these individual disorders and their links with each other has been challenging. Various conditions can interfere with ER function and these conditions are called ER stress, recently, known to be associated with several diseases including Alzheimer and T2DM. Therefore, the aim of this study is to characterize molecular processes of T2DM by ER stress. Methods : In an effort to identify gene network related to T2DM, we analysed microarray data using PAGE(parametrical analysis of gene enrichment) in liver and adipose cells, and selected candidate genes related to diabetes. Also, we investigated the molecular mechanism of the disease development. Cells containing functionally inactivated mitochondria were obtained by a treatment of electron transporter inhibitors in sk-HepI or MIN6N cells and, the relationship between mitochondrial dysfunction and the diabetes was verified by using western, confocal microscopy and FACS. Finally, the antidiabetic effects of macelignan were explored in obese diabetic mice or in thapsigargin-incubated sk-HepI and 3T3-L1 cells. Results : We verified from the BSEA(binding site enrichment analysis) results that proteins involved in ubiquitination(liver and adipose), glucose metabolism(liver), and β-oxidation(adipose) were changed by ER stress. In addition, we demonstrated that mitochondrial dysfunction and ER stress coordinately increased gluconeogenesis in liver and apoptosis in beta cells, thereby caused a metabolic disorder like type 2 diabetes. Also, a natural PPAR α/ϒ dual agonist macelignan reduced ER stress in the liver and white adipose tissue of db/db mice as well as in thapsigargin-incubated sk-HepI and 3T3-L1 cells and ameliorated insulin resistance and hyperglycemia. Conclusions : Agents, such as macelignan, which reduced endoplasmic reticulum(ER) stress could improve insulin signaling. Based on these results, it appears that drugs reducing ER stress might be a potentially new treatment for type 2 diabetes.

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