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Publication
Impaired glucose tolerance and predisposition to the fasted state in liver
glycogen synthase knock-out mice.
Authors Irimia JM, Meyer CM, Peper CL, Zhai L, Bock CB, Previs SF, McGuinness OP,
DePaoli-Roach A, Roach PJ
Submitted By David Wasserman on 7/16/2010
Status Published
Journal The Journal of biological chemistry
Year 2010
Date Published
Volume : Pages 285 : 12851 - 12861
PubMed Reference 20178984
Abstract Conversion to glycogen is a major fate of ingested glucose in the body. A
rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded
by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily
expressed in liver (liver glycogen synthase). Defects in GYS2 cause the
inherited monogenic disease glycogen storage disease 0. We have generated mice
with a liver-specific disruption of the Gys2 gene (liver glycogen synthase
knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying
floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin
promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase
deficiency, and have a 95% reduction in fed liver glycogen content. They have
mild hypoglycemia but dispose glucose less well in a glucose tolerance test.
Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared
with mice carrying floxed alleles, but the difference disappears after an
overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood
glucose levels attained by control floxed mice only after 24 h of food
deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h.
Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of
endogenous glucose production is impaired as assessed by
euglycemic-hyperinsulinemic clamp. This observation correlates with an increase
in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression
and activity. This mouse model mimics the pathophysiology of glycogen storage
disease 0 patients and highlights the importance of liver glycogen stores in
whole body glucose homeostasis.






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