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Diabetes 51:2450-2458, 2002
© 2002 by the American Diabetes Association, Inc.

Improved Insulin Sensitivity and Resistance to Weight Gain in Mice Null for the Ahsg Gene

Suresh T. Mathews1,2, Gurmant P. Singh1, Mollie Ranalletta3, Vivian J. Cintron2, Xiaoling Qiang2, Anton Scott Goustin2, Kai-Lin Catherine Jen4, Maureen J. Charron3, Willi Jahnen-Dechent5, and George Grunberger1,2

1 Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan
2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan
3 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York
4 Nutrition and Food Science Department, Wayne State University, Detroit, Michigan
5 IZKF BIOMAT, Klinikum der RWTH Aachen, Aachen, Germany

Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsgtm1Mbl). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.


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