Effects of Liraglutide on beta-Cell-Specific Glucokinase-Deficient Neonatal Mice

作者：Shirakawa Jun; Tanami Ritsuko; Togashi Yu; Tajima Kazuki; Orime Kazuki; Kubota Naoto; Kadowaki Takashi; Goshima Yoshio; Terauchi Yasuo^*

来源：Endocrinology, 2012, 153(7): 3066-3075.

DOI：10.1210/en.2012-1165

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 beta-cells. In beta-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 beta-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 beta-cells in Gck(+/-) neonates at 4 d after birth. Taken together, beta-cell glucokinase appears to be essential for liraglutide-mediated insulin secretion, but liraglutide may improve glycemic control, steatosis, and beta-cell death in a glucokinase-independent fashion. (Endocrinology 153: 3066-3075, 2012)

• 出版日期2012-7