Multiple different biochemical defects have been identified in patients with genetic forms of extreme insulin resistance. These defects have included: (1) a decreased number of insulin receptors, (2) qualitatively abnormal insulin receptors which are impaired in their ability to couple insulin binding to insulin action, and (3) post-receptor defects in insulin action. We have applied the methods of cell biology to further define the nature of the receptor defects. Using cultured cells derived from insulin resistant patients with a decrease in receptor number, we have identified several different types of defects in the pathway of receptor biosynthesis. In a patient with qualitative abnormalities in insulin binding, we have obtained evidence suggesting that the patient is a genetic compound, having inherited two distinct mutant alleles which impair receptor function. In addition, with monocytes from a patient whose receptor-associated tyrosine kinase activity is defective, evidence has been obtained which suggests an abnormality in the molecular weight of the alpha-subunit of the insulin receptor. Most recently, in collaboration with Dr. Axel Ullrich, we have begun to apply recombinant DNA technology to determine whether there are mutations in the insulin receptor genes of these patients. In a related project, we have embarked upon studies to identify the cause of insulin resistance in an animal model of obesity and diabetes (the ob/ob mouse). Preliminary studies suggest that adenylate cyclase fat cells from ob/ob mice have abnormally increased sensitivity to adenosine.
| Javor, Edward D; Moran, Stephanie Ann; Young, Janice Ryan et al. (2004) Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy. J Clin Endocrinol Metab 89:3199-207 |
| Musso, Carla; Cochran, Elaine; Moran, Stephanie Ann et al. (2004) Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 83:209-22 |
| Moran, Stephanie Ann; Patten, Nicole; Young, Janice Ryan et al. (2004) Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 53:513-9 |
| Cochran, Elaine; Young, Janice Ryan; Sebring, Nancy et al. (2004) Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. J Clin Endocrinol Metab 89:1548-54 |
| Agarwal, Anil K; Simha, Vinaya; Oral, Elif Arioglu et al. (2003) Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840-7 |
| Gorden, Phillip; Gavrilova, Oksana (2003) The clinical uses of leptin. Curr Opin Pharmacol 3:655-9 |
| Oral, Elif Arioglu; Ruiz, Elaine; Andewelt, Alexa et al. (2002) Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110-7 |
| Petersen, Kitt Falk; Oral, Elif Arioglu; Dufour, Sylvie et al. (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345-50 |
| Bolan, Charles; Oral, Elif Arioglu; Gorden, Phillip et al. (2002) Intensive, long-term plasma exchange therapy for severe hypertriglyceridemia in acquired generalized lipoatrophy. J Clin Endocrinol Metab 87:380-4 |
| Oral, Elif Arioglu; Simha, Vinaya; Ruiz, Elaine et al. (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-8 |
Showing the most recent 10 out of 15 publications
