title: Anti-diabetic efficacy of KICG1338, a novel glycogen synthase kinase-3β inhibitor, and its molecular characterization in animal models of type 2 diabetes and insulin resistance.
abstract: Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor.
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Kyoung Min
authors: KM
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Kuy-Sook
authors: KS
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Gha Young
authors: GY
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Hyunjin
authors: H
authors: Jin
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Eunice Sung
authors: ES
authors: Durrance
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Ho Seon
authors: HS
authors: Park
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Sung Hee
authors: SH
authors: Choi
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine Seoul National University, Seoul, Republic of Korea.
authors: Kyong Soo
authors: KS
authors: Park
authors: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine Seoul National University, Seoul, Republic of Korea; Division of Endocrinology, Metabolism and Diabetes, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors: Young-Bum
authors: YB
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Hak Chul
authors: HC
authors: Jang
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address: limsoo@snu.ac.kr.
authors: Soo
authors: S
authors: Lim
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002264:Carboxylic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D020334:Rats, Inbred OLETF; D054411:Receptors, Leptin / Q000172:deficiency
chemical_list: D000631:Aminopyridines; D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D007093:Imidazoles; C000604719:KICG1338; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D038362:Glycogen Synthase Kinase 3; D005947:Glucose
keywords: Diabetes; Diet-induced obese mice; GLUT; Glycogen synthase kinase-3; OLETF rat; Obesity