Send to

Choose Destination
Gene. 2002 Oct 16;299(1-2):219-25.

Partial rescue of insulin receptor-deficient mice by transgenic complementation with an activated insulin receptor in the liver.

Author information

Department of Genetics, Development and Molecular Pathology, Institut Cochin, INSERM, CNRS, Université René Decartes, CHU Cochin-Port Royal, 24 Rue du Faubourg Saint-Jacques, 75014 Paris, France.


Insulin receptor (IR)-deficient mice develop severe diabetes mellitus, diabetic ketoacidosis (DKA) and liver steatosis and die within 1 week after birth. We examined in this work whether the metabolic phenotype of IR(-/-) mutants could be improved by transgenic complementation with IR selectively in the liver. We first generated transgenic mice expressing a human DNA complementary to RNA encoding a truncated constitutively activated form of IR (IRdelta) under the control of liver-specific phenylalanine hydroxylase (PAH) gene promoter. These mice presented more pronounced fasting hypoglycemia and showed slightly improved glucose tolerance as compared to controls. The transgenic mice were crossed with IR(+/-) mutants to generate IR(-/-) mice carrying the PAH-IRDelta transgene. Although such mutants developed glycosuria, DKA was delayed by more than 1 week and survival was prolonged to 8-20 days in approximately 10% of mice. In these partially rescued pups, serum glucose and triglyceride levels were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with pups which developed strong DKA and died earlier. Thus, lack of insulin action in the liver is responsible in large part for the metabolic disorders seen in IR(+/-) mice. This study should stimulate interest in therapeutic strategies aimed at improving hepatic function in diabetes.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center