Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

Autor: Jacques Jami, Anne Baudry, Rajiv L Joshi, Danielle Bucchini, Malene Jackerott
Přispěvatelé: Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2002
Předmět:
Blood Glucose
medicine.medical_specialty
DNA
Complementary
[SDV]Life Sciences [q-bio]
Endocrinology
Diabetes and Metabolism
Transgene
medicine.medical_treatment
Mice
Transgenic
Diabetic Ketoacidosis
Mice
03 medical and health sciences
0302 clinical medicine
Glycosuria
Internal medicine
Diabetes mellitus
Glucokinase
Internal Medicine
medicine
Animals
Humans
Glucose homeostasis
Cloning
Molecular
Promoter Regions
Genetic
Crosses
Genetic
ComputingMilieux_MISCELLANEOUS
Pancreatic hormone
030304 developmental biology
Mice
Knockout
0303 health sciences
Base Sequence
biology
Reverse Transcriptase Polymerase Chain Reaction
Insulin
Homozygote
Phenylalanine Hydroxylase
Glucose Tolerance Test
medicine.disease
Receptor
Insulin
Rats
3. Good health
Ketoacidosis
Insulin receptor
Endocrinology
Liver
Organ Specificity
030220 oncology & carcinogenesis
biology.protein
Zdroj: Diabetologia
Diabetologia, Springer Verlag, 2002, 45 (9), pp.1292-1297. ⟨10.1007/s00125-002-0881-y⟩
ISSN: 1432-0428
0012-186X
Popis: 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.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.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.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.
Databáze: OpenAIRE
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