We have had a long-standing interest in the etiology of severe insulin resistance. Initially, we 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 lipodystrophy syndromes: a group of heterogeneous syndromes characterized by lack of adipose tissue and severe insulin resistance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern), we have reported mutations in the lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy and also reported a mutation on chromosome 9q34 in a form of congenital generalized lipodystrophy. The gene on chromosome 9q34 codes for an enzyme that is important in triglyceride synthesis. In following patients with lipodystrophy, we have observed that they have a high incidence of proteinuric renal disease. Further, it turns out that the renal abnormality is not diabetic as expected, but most often focal segmental glomerulonephritis or membranoproliferative glomerulonephritis. We are continuing this study in collaboration with Dr. James Balow in an attempt to understand the relationships of these secondary forms of renal disease to lipodystrophy. Another very new observation is that both patients with mutations in their insulin receptors and autoantibodies to the receptor have markedly elevated adiponectin levels in contrast to the low levels that would be expected in this form of extreme insulin resistance. Thus, our longstanding and continued follow-up of patients with syndromic forms of insulin resistance continues to yield new and important information. 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 patients with insulin receptor mutations. 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. In a recent study we have described a new and very effective treatment for the syndrome of autoantibodies to the insulin receptor.

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Payne, Felicity; Lim, Koini; Girousse, Amandine et al. (2014) Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci U S A 111:8901-6
Handelsman, Yehuda; Oral, Elif A; Bloomgarden, Zachary T et al. (2013) The clinical approach to the detection of lipodystrophy - an AACE consensus statement. Endocr Pract 19:107-16
Rother, Kristina I; Brown, Rebecca J (2013) Novel Forms of Lipodystrophy: Why should we care? Diabetes Care 36:2142-5
Savage, David B; Semple, Robert K; Clatworthy, Menna R et al. (2009) Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab 94:10-6
Semple, Robert K; Cochran, Elaine K; Soos, Maria A et al. (2008) Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care 31:977-9
Yauger, Belinda J; Gorden, Phillip; Park, Jean et al. (2008) Effect of depot medroxyprogesterone acetate on glucose tolerance in generalized lipodystrophy. Obstet Gynecol 112:445-7