? Reduction in the expression of the glucose transporter-4 in adipose tissue is one of the earliest changes that occur in human conditions characterized by insulin resistance, including type 2 diabetes. Mice harboring an adipose tissue-specific genetic knockout of Glut4 display reduced insulin-stimulated glucose transport in adipose tissue and develop systemic insulin resistance affecting hepatic glucose production and skeletal muscle glucose transport. Since only adipose tissue is genetically altered in this model, we hypothesized that one or more circulating factors causing systemic insulin resistance may be secreted into the circulation by adipose tissue with reduced Glut4 expression. We used Affymetrix global gene analysis to identify retinol binding protein-4 (RBP4) as a candidate molecule for mediating systemic insulin resistance in this model. The mRNA of RBP4 is up-regulated in adipose tissue, but not in liver, of adipose-Glut4 knockout mice. Serum levels of RBP4 are increased in adipose-Glut4 knockout mice and five other mouse models of insulin resistance, suggesting that RBP4 may be a marker for insulin resistance or hyperinsulinemia. However, we find that RBP4 knockout mice exhibit a phenotype of increased sensitivity to insulin. Thus, elevations of circulating RBP4 may serve not only as a marker but as an actual cause of systemic insulin resistance. In humans we find a strong correlation between serum RBP4 levels and insulin resistance measured by euglycemic hyperinsulinemic clamp, indicating that RBP4 could be a novel endocrine mediator of systemic insulin resistance in humans. To test the hypothesis that RBP4 is a cause of insulin resistance, we will analyze the metabolic features of mice with genetic alterations in RBP4 expression. We will test the effects of pharmacologically altering circulating RBP4 levels, either by treating with fenretinide, a drug that causes urinary wasting of RBP4, or by injecting purified RBP4. We will investigate potential mechanisms, both retinoid-dependent and retinoid-independent, by which RBP4 may influence insulin-glucose homeostasis ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Beth Israel Deaconess Medical Center
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Goodman, Elizabeth; Graham, Timothy E; Dolan, Lawrence M et al. (2009) The relationship of retinol binding protein 4 to changes in insulin resistance and cardiometabolic risk in overweight black adolescents. J Pediatr 154:67-73.e1
Preitner, Frederic; Mody, Nimesh; Graham, Timothy E et al. (2009) Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am J Physiol Endocrinol Metab 297:E1420-9
Mody, Nimesh; Graham, Timothy E; Tsuji, Yuki et al. (2008) Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice. Am J Physiol Endocrinol Metab 294:E785-93
Hammarstedt, A; Pihlajamaki, J; Graham, T E et al. (2008) High circulating levels of RBP4 and mRNA levels of aP2, PGC-1alpha and UCP-2 predict improvement in insulin sensitivity following pioglitazone treatment of drug-naive type 2 diabetic subjects. J Intern Med 263:440-9
Kovacs, Peter; Geyer, Michaela; Berndt, Janin et al. (2007) Effects of genetic variation in the human retinol binding protein-4 gene (RBP4) on insulin resistance and fat depot-specific mRNA expression. Diabetes 56:3095-100
Balagopal, Prabhakaran; Graham, Timothy E; Kahn, Barbara B et al. (2007) Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: association with subclinical inflammation. J Clin Endocrinol Metab 92:1971-4
Kloting, Nora; Graham, Timothy E; Berndt, Janin et al. (2007) Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab 6:79-87
Graham, T E; Wason, C J; Bluher, M et al. (2007) Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects. Diabetologia 50:814-23
Graham, T E; Kahn, B B (2007) Tissue-specific alterations of glucose transport and molecular mechanisms of intertissue communication in obesity and type 2 diabetes. Horm Metab Res 39:717-21
Graham, Timothy E; Yang, Qin; Bluher, Matthias et al. (2006) Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354:2552-63