Differential expression of genes and changes in glucose metabolism in the liver of liver-specific glucokinase gene knockout mice

• Published in: Gene Vol. 516; no. 2; pp. 248 - 254
• Main Authors: Wang, Rong, Gao, Hui, Xu, Wei, Li, Hui, Mao, Yiqing, Wang, Yi, Guo, Tingting, Wang, Xi, Song, Rongjing, Li, Zhixin, Irwin, David M., Niu, Gang, Tan, Huanran
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.03.2013
• Subjects: Age Factors; Animals; blood glucose; Carbohydrate Metabolism - genetics; diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Differentially expressed genes; Disease Models, Animal; Disease Progression; fasting; gene expression; Gene Expression Regulation; gene targeting; genes; glucokinase; Glucokinase (GCK); Glucokinase - genetics; Glucokinase - metabolism; gluconeogenesis; Gluconeogenesis - genetics; Gluconeogenesis - physiology; glucose; Glucose - metabolism; glycogen; hyperglycemia; Liver; Liver - metabolism; messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; MODY2; Organ Specificity - genetics; pathogenesis; phosphorylase; reverse transcriptase polymerase chain reaction; suppression subtractive hybridization; Transcriptome; MODY-2; PEPCK; Liver; GP; SSH; IPGTT; GS; GCK; TC; Differentially expressed genes; TG; APC; SOAT2; Glucokinase (GCK); MODY2; GAPDH
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2012.12.036

To investigate the role of liver-specific expression of glucokinase (GCK) in the pathogenesis of hyperglycemia and to identify candidate genes involved in mechanisms of the onset and progression of maturity onset diabetes of the young, type 2 (MODY-2), we examined changes in biochemical parameters and gene expression in GCK knockout (gckw/–) and wild-type (gckw/w) mice as they aged. Fasting blood glucose levels were found to be significantly higher in the gckw/– mice, compared to age-matched gckw/w mice, at all ages (P<0.05), except at 2weeks. GCK activity of gckw/– mice was about 50% of that of wild type (gckw/w) mice (P<0.05). Glycogen content at 4 and 40weeks of age was lower in gckw/– mice compared to gckw/w mice. Differentially expressed genes in the livers of 2 and 26week-old liver-specific GCK knockout (gckw/–) mice were identified by suppression subtractive hybridization (SSH), which resulted in the identification of phosphoenolpyruvatecarboxykinase (PEPCK, also called PCK1) and Sterol O-acyltransferase 2 (SOAT2) as candidate genes involved in pathogenesis. The expressions of PEPCK and SOAT2 along with glycogen phosphorylase (GP) and glycogen synthase (GS) were then examined in GCK knockout (gckw/–) and wild-type (gckw/w) mice at different ages. Changes in PEPCK mRNA levels were confirmed by real-time RT-PCR, while no differences in the levels of expression of SOAT2 or GS were observed in age-matched GCK knockout (gckw/–) and wild-type (gckw/w) mice. GP mRNA levels were decreased in 40-week old gckw/– mice compared to age-matched gckw/w mice. Changes in gluconeogenesis, delayed development of GCK and impaired hepatic glycogen synthesis in the liver potentially lead to the onset and progression of MODY2. ► Changes in gluconeogenesis lead to onset and progression of MODY2. ► Delayed development of GCK potentially leads to onset and progression of MODY2. ► Impaired hepatic glycogen synthesis potentially leads to progression of MODY2.