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A compound (DW1182v) protecting high glucose/palmitate-induced glucolipotoxicity to INS-1 beta cells preserves islet integrity and improves hyperglycemia in obese db/db mouse

Authors
Lee, SJ; Choi, SE; Hwang, YC; Jung, IR; Yi, SA; Jung, JG; Ku, JM; Jeoung, K; Han, SJ; Kim, HJ; Kim, DJ; Lee, KW; Kang, Y
Citation
European journal of pharmacology, 696(1-3):187-193, 2012
Journal Title
European journal of pharmacology
ISSN
0014-29991879-0712
Abstract
Loss of beta cells is a pathogenic cause for the development of type 2 diabetes. High glucose/free fatty acid (HG/FFA)-induced glucolipotoxicity was thought to play a role in the beta cell loss. Thus, application of small molecules capable of preventing HG/FFA-induced glucolipotoxicty to beta cells could be an avenue for a therapeutic intervention for the development of type 2 diabetes. We screened a representative library supplied from Korean Chemical Bank for prevention of high glucose/palmitate (HG/PA)-induced viability reduction of INS-1 beta cells and were able to identify a new small molecule (DW1182v) with a function to protect HG/PA-induced glucolipotoxicity. The protective effect was specific to HG/PA-induced beta cell death since DW1182v did not protect streptozotocin- or cytokine-induced INS-1 cell death. The protective effect by DW1182v was likely due to the reduction of death-promoting endoplasmic reticulum (ER) stress responses such as phospho-C-Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP). Treatment of obese diabetic db/db mice with DW1182v preserved islet integrity and thus increased insulin secretion and lowered blood glucose after glucose infusion. These results suggest that a small molecule protecting HG/PA-induced glucolipotoxicity to beta cells can be a new therapeutic candidate to prevent the development of type 2 diabetes.
MeSH terms
AnimalsBlood Glucose/analysisCell LineCell Survival/drug effectsEndoplasmic Reticulum Stress/drug effectsGlucose/pharmacologyGlucose Tolerance TestHyperglycemia/blood/drug therapy/pathologyHypoglycemic Agents/*pharmacology/therapeutic useIndazoles/*pharmacology/therapeutic useInsulin/bloodInsulin-Secreting Cells/*drug effectsMaleMiceMice, ObeseObesity/blood/drug therapy/pathologyPalmitates/pharmacologyPyrimidines/*pharmacology/therapeutic use
DOI
10.1016/j.ejphar.2012.09.023
PMID
23026370
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
한, 승진김, 혜진김, 대중이, 관우강, 엽
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