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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    • "Gene deletion and overexpression technology have been well established in mice for over two decades, allowing researchers to create single gene mutant mice that display phenotypes which are useful in the development of type 2 diabetes therapy [2]. There are also mouse models of type 2 diabetes that have arisen due to spontaneous mutations such as the leptin deficient ob/ob and leptin receptor deficient db/db mice [3]. The C57/BL6 mouse strain fed a high-fat diet is a commonly used animal model in the development of potential therapies for type 2 diabetes [4]. "
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    • "Mutations in the leptin receptor gene cause severe obesity and insulin resistance in rodents and humans. The cause of obesity in db/db mice is associated with a deficiency of leptin receptors depending on the genetic background, and these animals exhibit most of the human characteristics of type 2 diabetes including hyperglycemia in fasting and fed states, hyperinsulinemia, and insulin resistance [23, 24]. For this reason, db/db mice are valuable as an experimental model associated with type 2 diabetes. "
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