In:
Endocrinology, The Endocrine Society, Vol. 153, No. 7 ( 2012-07-01), p. 3066-3075
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.
Type of Medium:
Online Resource
ISSN:
0013-7227
,
1945-7170
DOI:
10.1210/en.2012-1165
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2012
detail.hit.zdb_id:
2011695-0
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