title: Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver.
abstract: OBJECTIVE
  Insulin receptor null mutant mice develop severe diabetes, ketoacidosis and liver steatosis and die within 1 week after birth. Since the liver plays an essential role in the control of glucose homeostasis, we examined in this work whether the metabolic disorders of insulin receptor-deficient mice could be improved upon restoration of hepatic glucose metabolism by transgenic constitutive overexpression of glucokinase selectively in the liver.
  
  
  METHODS
  We first generated transgenic mice overexpressing rat glucokinase cDNA under control of the liver-specific phenylalanine hydroxylase gene promoter. These transgenic mice were crossed with heterozygous insulin-receptor-null mutants to produce homozygous insulin-receptor-null mice overexpressing glucokinase in the liver.
  
  
  RESULTS
  The transgenic mice overexpressing glucokinase in the liver showed improved glucose tolerance and were mildly hypoglycaemic and hyperlipidaemic under starved conditions. The introduction of the glucokinase transgene in insulin receptor null mice did not prevent the development of glycosuria. However, ketoacidosis was delayed by more than 1 week and survival was prolonged to 10 to 16 days in 16% of the pups. In these longer surviving pups, serum glucose and triglyceride concentrations were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with the pups which had developed strong ketoacidosis and died earlier.
  
  
  CONCLUSIONS
  These results show that overexpression of hepatic glucokinase can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice. This shows the importance of improving hepatic function in diabetes and must revive interest in enhancement of glucokinase activity as a therapeutic strategy for the treatment of diabetes.
authors.affiliation: Department of Genetics, Development and Molecular Pathology, Cochin Institute, INSERM, CNRS, University of René Decartes, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Jackerott
authors.forename: A
authors.initials: A
authors.lastname: Baudry
authors.forename: D
authors.initials: D
authors.lastname: Bucchini
authors.forename: J
authors.initials: J
authors.lastname: Jami
authors.forename: R L
authors.initials: RL
authors.lastname: Joshi
mesh_terms: D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism*; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D018076:DNA, Complementary; D016883:Diabetic Ketoacidosis / Q000235:genetics; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006029:Glycosuria / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D010651:Phenylalanine Hydroxylase / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D018076:DNA, Complementary; D010651:Phenylalanine Hydroxylase; D005941:Glucokinase; D011972:Receptor, Insulin