The Diabetes Branch of NIDDK has a long-standing interest in the etiology of severe insulin resistance. Initially, we have identified mutations in the insulin receptor gene and studied a group of patients with autoantibodies against the insulin receptor. More recently, we have concentrated on lipoatrophy syndromes: a group of heterogeneous syndromes characterized by lack of adipose tissue and severe insulin reisitance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern) and Anne Bowcock (University of Washington, St. Louis), we have reported mutations on the Lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy and we have reported a linkage of congenital generalized lipodystrophy to chromosome 9q34. Dr. Garg has recently found with our collaboration the mutated gene in this form of lipodystrophy. The gene codes for an enzyme that is important in triglyceride synthesis. Our major effort has been in a clinical trial of leptin therapy and lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1C, fasting blood glucose, triglyceride values, a reduction in liver size, and an improvement in liver function. Thus leptin therapy appears to have a major beneficial effect for metabolic abnormalities seen in these patients. Furthermore, in those patients who have normal reproductive organs, leptin therapy results in a robust increase in gonadotropin secretion following GNRH, and this is associated with the beginning of menses in these otherwise amenorrhic patients. We are continuing our studies on the genetics of lipodystrophy, the natural history of other insulin resistance syndromes and espcecially the follow-up of the clinical effects of leptin on lipodystrophy. More recently, we have initiated a novel research study that tests the efficacy of the adipocyte-derived leptin hormone replacement in ameliorating the metabolic abnormalities in lipoatrophy syndromes. This study provides a unique opportunity to study the peripheral effects of leptin on the muscle and liver, and preliminary results show a favorable response. While the major focus has been on lipaotrophy syndromes, we are continuing our efforts to understand the natural history of other severe insulin resistant states.
| 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 |
| 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 |
| 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 |
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