(25-08-10) Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.

Davis RC, Castellani LW, Hosseini M, Ben-Zeev O, Mao HZ, Weinstein MM, Jung
DY, Jun JY, Kim JK, Lusis AJ, P?terfy M.

Department of Medicine, University of California, Los Angeles, Los Angeles,
California, USA.
Abstract
OBJECTIVE: To identify metabolic derangements contributing to diabetes
susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db)
mouse strain. RESEARCH DESIGN AND 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.

Source: Diabetes. 2010 Jul;59(7):1616-25. Epub 2010 Apr 14.

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