Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene

Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan, United States
Diabetes (Impact Factor: 8.47). 08/2002; 51(8):2450-8. DOI: 10.2337/diabetes.51.8.2450
Source: PubMed

ABSTRACT 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-Ahsg(tm1Mbl)). 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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    ABSTRACT: The purpose of this review is to summarize the role of fetuin-A in disease processes prevalent in postmenopausal women and synthesize effective interventions in obtaining healthy fetuin-A levels. A review of databases for articles related to fetuin-A and diseases associated with postmenopausal women was conducted. Articles were limited to full-text access, published in English since 1944. High fetuin-A levels are closely associated with decreased bone mineral density, increased cardiovascular disease risks, impairment of insulin signaling and disruption of adipocyte functioning. Postmenopausal women have increased risk of osteoporosis, cardiovascular disease, insulin-resistance, intra-abdominal fat accumulation and vascular calcification. Low-levels of fetuin-A have been shown to be protective against the latter. The role of fetuin-A is multi-factorial and the mechanisms in which it is involved in each of these processes are vast. The present body of literature is inconsistent in defining high versus low levels of fetuin-A and their association with healthy-matched controls. The diseases associated with high levels of fetuin-A mimic diseases most prevalent in postmenopausal women. In addition, there is no research, to date, exploring fetuin-A levels in postmenopausal women and the associations it may or may not have in related diseases.