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

Author:

Davis Richard C.1,Castellani Lawrence W.1,Hosseini Maryam123,Ben-Zeev Osnat12,Mao Hui Z.23,Weinstein Michael M.1,Jung Dae Young45,Jun John Y.5,Kim Jason K.456,Lusis Aldons J.1,Péterfy Miklós123

Affiliation:

1. Department of Medicine, University of California, Los Angeles, Los Angeles, California;

2. Lipid Research Laboratory, VA Greater Los Angeles Healthcare System, Los Angeles, California;

3. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California;

4. Program in Molecular Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts;

5. Department of Cellular and Molecular Physiology, Pennsylvania State University School of Medicine, Hershey, Pennsylvania;

6. Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts.

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 β-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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference47 articles.

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