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

Kyoung Min Kim, Kuy Sook Lee, Gha Young Lee, Hyunjin Jin, Eunice Sung Durrance, Ho Seon Park, Sung Hee Choi, Kyong Soo Park, Young Bum Kim, Hak Chul Jang, Soo Lim

Research output: Contribution to journalArticle

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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)-3. H-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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume409
DOIs
StatePublished - 5 Jul 2015

Keywords

  • Diabetes
  • Diet-induced obese mice
  • GLUT
  • Glycogen synthase kinase-3
  • OLETF rat
  • Obesity

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