title: Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
abstract: OBJECTIVE
  To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db) mouse strain.
  
  
  METHODS
  Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains.
  
  
  RESULTS
  Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities.
  
  
  CONCLUSIONS
  Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of beta-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Davis
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.forename: Maryam
authors.initials: M
authors.lastname: Hosseini
authors.forename: Osnat
authors.initials: O
authors.lastname: Ben-Zeev
authors.forename: Hui Z
authors.initials: HZ
authors.lastname: Mao
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weinstein
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: John Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008049:Lipase / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005227:Fatty Acids; D007328:Insulin; D008049:Lipase
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