title: Glycine N-methyltransferase deficiency in female mice impairs insulin signaling and promotes gluconeogenesis by modulating the PI3K/Akt pathway in the liver.
abstract: BACKGROUND
  Glycine N-methyltransferase (GNMT) is abundantly expressed in the normal liver but is down-regulated in liver cancer tissues. GNMT knockout (Gnmt-/-) mice can spontaneously develop chronic hepatitis, fatty liver, and liver cancer. We previously demonstrated that hepatic GNMT is decreased in high-fat-diet-induced type 2 diabetes mellitus, but its contribution to metabolic syndrome is unclear. Here we show that GNMT modulates key aspects of metabolic syndrome in mice.
  
  
  METHODS
  Eleven-week-old Gnmt-/- and wild-type (WT) mice with a C57BL/6 genetic background were used in this study. The metabolic defects of GNMT deficiency were measured by glucose and insulin tolerance tests, lipid homeostasis, gluconeogenesis, and insulin signaling.
  
  
  RESULTS
  Gnmt-/- mice, especially females, exhibited glucose intolerance and insulin resistance. However, their body fat and lean mass, food and water intakes, and energy expenditure did not differ from those of WT mice. In addition, glucose-stimulated insulin secretion and insulin-stimulated glucagon secretion were normal in the serum and pancreatic islets of Gnmt-/- mice. Importantly, we found that GNMT deficiency increased lipogenesis and triglycerides in the liver. The elevated triglycerides disrupted the ability of insulin to induce Akt and S6 ribosomal protein phosphorylation, and then triggered insulin resistance and gluconeogenesis in female Gnmt-/- mice.
  
  
  CONCLUSIONS
  Our data indicate that hepatic GNMT regulates lipid and glucose homeostasis, and provide insight into the development of insulin resistance through modulating the PI3K/Akt pathway.
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yuh-Ching
authors.initials: YC
authors.lastname: Twu
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Hsu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Yang
authors.affiliation: Department of International Medicine, Taipei City Hospital Ranai Branch, Taipei, Taiwan.
authors.forename: Chung-Kwe
authors.initials: CK
authors.lastname: Wang
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. arthur@kmu.edu.tw.
authors.forename: Yi-Ming Arthur
authors.initials: YA
authors.lastname: Chen
mesh_terms: D000818:Animals; D005260:Female; D005943:Gluconeogenesis; D050938:Glycine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D050938:Glycine N-Methyltransferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Glycine N-methyltransferase; Insulin signaling; Liver; PI3K/Akt pathway; Triglycerides