title: 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.
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.
authors.affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon 442-749, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.forename: Yun Cheong
authors.initials: YC
authors.lastname: Hwang
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Yi
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.forename: Jin-Mo
authors.initials: JM
authors.lastname: Ku
authors.forename: Kwiwan
authors.initials: K
authors.lastname: Jeoung
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D010168:Palmitates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C579716:4-(1H-indazol-6-ylamino)-N-isopropyl-2-(methylthio)pyrimidine-5-carboxamide; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007191:Indazoles; D007328:Insulin; D010168:Palmitates; D011743:Pyrimidines; D005947:Glucose