Early Hepatic Insulin Resistance Precedes the Onset of Diabetes in Obese C57BLKS-db/db Mice

Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Diabetes (Impact Factor: 8.1). 07/2010; 59(7):1616-25. DOI: 10.2337/db09-0878
Source: PubMed


To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db) mouse strain.
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.
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.
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.

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