The major objectives of this proposal are: to assess the nature of the severe insulin resistance seen in association with acanthosis nigricans and/or hyperandrogenemia; to determine the relationship of the three components of this syndrome to one another; and to develop a rational therapeutic approach to the syndrome based on a better understanding of the pathophysiology involved. Glucose and insulin responses tgo an oral glucose challenge, acute glucose reponse to an intravenous insulin bolus, and generation of a biologic insulin dose response curve via the euglycemic clamp technique will provide a detailed in vivo assessment of insulin action. In vivo results will be compared with a detailed in vitro analysis of insulin binding to freshly isolated cells (monocytes, adipocytes), insulin receptor autophosphorylation, and basal and insulin stimulated glucose transport in human adipocytes. Potential intrinsic defects in insulin action will be assessed through family studies and by analysis of receptor and post receptor function (glucose oxidation and transport) in cultured fibroblasts obtained from these subjects. The relationship of insulin resistance, acanthosis nigricans, and hyperandrogenemia will be assessed in the basal state and following sequential therapeutic intervention with diet, a sulfonylurea agent, and an oral contraceptive. The systematic approach as outlined in these affected individuals, combined with similar studies in appropriate weight matched subjects, as well as subjects with evidence of hyperandrogenemia without acanthosis nigricans should allow the accomplishment of the objectives. A clearer understanding of the exact nature of the defects in insulin action in this syndrome and its relation to the other associated components should provide a more rational therapeutic approach not only to this syndrome but other more common disease states as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033749-02
Application #
3232156
Study Section
Metabolism Study Section (MET)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Stuart, C A; Wen, G; Williamson, M E et al. (2001) Altered GLUT1 and GLUT3 gene expression and subcellular redistribution of GLUT4: protein in muscle from patients with acanthosis nigricans and severe insulin resistance. Metabolism 50:771-7
Stuart, C A; Wen, G; Gustafson, W C et al. (2000) Comparison of GLUT1, GLUT3, and GLUT4 mRNA and the subcellular distribution of their proteins in normal human muscle. Metabolism 49:1604-9
Stuart, C A; Wen, G; Peng, B H et al. (2000) GLUT-3 expression in human skeletal muscle. Am J Physiol Endocrinol Metab 279:E855-61
Stuart, C A; Wen, G; Jiang, J (1999) GLUT3 protein and mRNA in autopsy muscle specimens. Metabolism 48:876-80
Stuart, C A; Gilkison, C R; Smith, M M et al. (1998) Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr (Phila) 37:73-9
Nagamani, M; Stuart, C A (1998) Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture. Am J Obstet Gynecol 179:6-12
Dowlati, B; Dunhardt, P A; Smith, M M et al. (1998) Quantification of insulin in dried blood spots. J Lab Clin Med 131:370-4
Stuart, C A; Driscoll, M S; Lundquist, K F et al. (1998) Acanthosis nigricans. J Basic Clin Physiol Pharmacol 9:407-18
Stuart, C A; Gilkison, C R; Keenan, B S et al. (1997) Hyperinsulinemia and acanthosis nigricans in African Americans. J Natl Med Assoc 89:523-7
Nagamani, M; Stuart, C A (1996) Specific receptors and growth effects of insulin and insulin-like growth factors in a human cell line derived from mixed mesodermal tumor of the uterus. J Soc Gynecol Investig 3:281-8

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