title: Effects of liraglutide on β-cell-specific glucokinase-deficient neonatal mice.
abstract: The glucagon-like peptide-1 receptor agonist liraglutide is used to treat diabetes. A hallmark of liraglutide is the glucose-dependent facilitation of insulin secretion from pancreatic β-cells. In β-cells, the glycolytic enzyme glucokinase plays a pivotal role as a glucose sensor. However, the role of glucokinase in the glucose-dependent action of liraglutide remains unknown. We first examined the effects of liraglutide on glucokinase haploinsufficient (Gck(+/-)) mice. Single administration of liraglutide significantly improved glucose tolerance in Gck(+/-) mice without increase of insulin secretion. We also assessed the effects of liraglutide on the survival rates, metabolic parameters, and histology of liver or pancreas of β-cell-specific glucokinase-deficient (Gck(-/-)) newborn mice. Liraglutide reduced the blood glucose levels in Gck(-/-) neonates but failed to prolong survival, and all the mice died within 1 wk. Furthermore, liraglutide did not improve glucose-induced insulin secretion in isolated islets from Gck(-/-) neonates. Liraglutide initially prevented increases in alanine aminotransferase, free fatty acids, and triglycerides in Gck(-/-) neonates but not at 4 d after birth. Liraglutide transiently prevented liver steatosis, with reduced triglyceride contents and elevated glycogen contents in Gck(-/-) neonate livers at 2 d after birth. Liraglutide also protected against reductions in β-cells in Gck(-/-) neonates at 4 d after birth. Taken together, β-cell glucokinase appears to be essential for liraglutide-mediated insulin secretion, but liraglutide may improve glycemic control, steatosis, and β-cell death in a glucokinase-independent fashion.
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Tanami
authors.forename: Yu
authors.initials: Y
authors.lastname: Togashi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tajima
authors.forename: Kazuki
authors.initials: K
authors.lastname: Orime
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D000069450:Liraglutide; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase