Fetal programming of perivenous glucose uptake reveals a regulatory mechanism governing hepatic glucose output during refeeding.
Increased hepatic gluconeogenesis maintains glycemia during fasting and has been considered responsible for elevated hepatic glucose output in type 2 diabetes. Glucose derived periportally via gluconeogenesis is partially taken up perivenously in perfused liver but not in adult rats whose mothers were protein-restricted during gestation (MLP rats)-an environmental model of fetal programming of adult glucose intolerance exhibiting diminished perivenous glucokinase (GK) activity. We now show that perivenous glucose uptake rises with increasing glucose concentration (0-8 mmol/l) in control but not MLP liver, indicating that GK is flux-generating. The data demonstrate that acute control of hepatic glucose output is principally achieved by increasing perivenous glucose uptake, with rising glucose concentration during refeeding, rather than by downregulation of gluconeogenesis, which occurs in different hepatocytes. Consistent with these observations, glycogen synthesis in vivo commenced in the perivenous cells during refeeding, MLP livers accumulating less glycogen than controls. GK gene transcription was unchanged in MLP liver, the data supporting a recently proposed posttranscriptional model of GK regulation involving nuclear-cytoplasmic transport. The results are pertinent to impaired regulation of hepatic glucose output in type 2 diabetes, which could arise from diminished GK-mediated glucose uptake rather than increased gluconeogenesis.
Murphy
Helena C
HC
Department of Diabetes and Metabolic Medicine, St. Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, Mile End, London E1 4NS, U.K.
Regan
Gemma
G
Bogdarina
Irina G
IG
Clark
Adrian J L
AJ
Iles
Richard A
RA
Cohen
Robert D
RD
Hitman
Graham A
GA
Berry
Colin L
CL
Coade
Zoe
Z
Petry
Clive J
CJ
Burns
Shamus P
SP
D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D018753:Diet, Protein-Restricted; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005941:Glucokinase / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D007774:Lactation; D008099:Liver / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D001786:Blood Glucose; D008112:Liver Glycogen; D012333:RNA, Messenger; D005941:Glucokinase; D005947:Glucose