Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice.
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.
Irimia
Jose M
JM
Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Meyer
Catalina M
CM
Peper
Caron L
CL
Zhai
Lanmin
L
Bock
Cheryl B
CB
Previs
Stephen F
SF
McGuinness
Owen P
OP
DePaoli-Roach
Anna
A
Roach
Peter J
PJ
D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D005215:Fasting; D005943:Gluconeogenesis / Q000235:genetics; D015309:Glucose Clamp Technique / Q000379:methods; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000235:genetics / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000201:enzymology* / Q000235:genetics; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D013997:Time Factors
D001786:Blood Glucose; D006003:Glycogen; D006006:Glycogen Synthase